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What was the outcome of reaction 'Exposure to toxic agent'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638947 | 18,475,028 | 2021 |
What was the outcome of reaction 'Hypothermia'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acidosis'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Altered state of consciousness'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood ketone body increased'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure congestive'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, INSULIN NOS, METFORMIN HYDROCHLORIDE, SODIUM CHLORIDE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Confusional state'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depressed level of consciousness'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, INSULIN NOS, METFORMIN HYDROCHLORIDE, SODIUM CHLORIDE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetic ketoacidosis'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disorientation'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram ST segment elevation'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, INSULIN NOS, METFORMIN HYDROCHLORIDE, SODIUM CHLORIDE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperglycaemia'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Insulin C-peptide decreased'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional dose omission'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lethargy'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial injury'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, INSULIN NOS, METFORMIN HYDROCHLORIDE, SODIUM CHLORIDE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | DULAGLUTIDE, INSULIN DEGLUDEC, INSULIN LISPRO, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What is the weight of the patient? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | 71.4 kg. | Weight | CC BY-NC-ND | 32654423 | 19,902,948 | 2021-03 |
What was the administration route of drug 'INSULIN NOS'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Abdominal pain'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Acidosis'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Altered state of consciousness'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Blood ketone body increased'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Cardiac failure congestive'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Confusional state'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Depressed level of consciousness'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Diabetic ketoacidosis'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Disorientation'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Electrocardiogram ST segment elevation'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Hyperglycaemia'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Hypophosphataemia'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Insulin C-peptide decreased'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Lethargy'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
What was the outcome of reaction 'Myocardial injury'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 19,908,831 | 2021-03 |
What was the outcome of reaction 'Nausea'? | Impaired cardiac and neurological function with mild hypophosphatemia during insulin therapy for diabetic ketoacidosis and marked improvement with phosphate supplementation: A case report.
Insulin treatment for diabetic ketoacidosis occasionally results in hypophosphatemia, which is often mild and does not require treatment. However, we experienced a case in which intravenous insulin administration resulted in myocardial injury and altered consciousness despite mild hypophosphatemia. Phosphate replacement therapy resulted in a marked improvement in symptoms. As overlapping conditions that result in hypophosphatemia can cause severe complications after insulin therapy for diabetic ketoacidosis, even in patients with mild hypophosphatemia, physicians should pay more attention to changes in phosphate levels in patients undergoing treatment for diabetic ketoacidosis.
Introduction
Intravenous (i.v.) administration of insulin for diabetic ketoacidosis (DKA) occasionally results in hypophosphatemia. As insulin promotes glucose uptake into cells, this glucose movement induces hypophosphatemia as a result of massive phosphate shifts from the extracellular fluid into cells to produce adenosine triphosphate by oxidative phosphorylation 1 . However, this does not usually require any particular treatment, because severe hypophosphatemia rarely occurs 2 . We report a patient with impaired consciousness and myocardial injury in the recovery phase of DKA, despite only a slight decrease in serum phosphate levels. After phosphate replacement therapy, the patient showed remarkable improvements.
Case Report
A 52‐year‐old man presented to International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan, because of disturbed consciousness and abdominal pain. He had previously undergone 8 years of treatment for diabetes at a nearby clinic. He was currently taking metformin, dulaglutide (glucagon‐like peptide‐1 analog) once‐weekly, 8 units of insulin lispro before meals, and 6 and 16 units of insulin degludec before breakfast and bedtime, respectively. The day before the visit, he did not take his insulin injection, because he skipped a meal as a result of nausea. He went to see a physician the next day, but the doctor referred him to our hospital because of disorientation. Blood chemistry and urine tests showed DKA with hyperglycemia, acidosis, increased β‐hydroxybutyrate levels and undetectable C‐peptide values (Table 1). A positive antiglutamic acid decarboxylase auto‐antibody result led to the diagnosis of type 1A diabetes (Table 1).
Table 1 Laboratory findings on admission
Laboratory test Reference range Initial value
Glucose (mg/dL) 75–100 784
Hemoglobin A1c (%) 4.6–6.2 9.9
Blood pH 7.35–7.45 6.923
Bicarbonate (mmol/L) 22.0–26.0 3.7
Sodium (mmol/L) 135–147 118
Potassium (mmol/L) 3.3–4.8 6.4
Chloride (mmol/L) 98–108 76
Phosphate (mg/dL) 2.5–4.5 2.0 †
Blood urea nitrogen (mg/dL) 8–20 50
Creatinine (mg/dL) 0.7–1.2 2.37
Albumin (g/dL) 4.0–5.1 4.6
Aspartate transaminase (IU/L) 8–38 43
Creatinine kinase (IU/L) 30–200 1,035 †
N‐terminal‐pro‐B‐type natriuretic peptide (pg/mL) ≤125 6,029 †
Beta‐hydroxybutyrate (µmol/L) ≤85 14,354
C‐peptide (ng/mL) 0.6–1.8 ≤0.03
Urinary C‐peptide (µg/day) 20.1–155 ≤0.8 ‡
Anti‐GAD65 antibody (U/mL) ≤1.5 9.1
Anti‐GAD65 antibody, anti‐glutamic acid decarboxylase 65 antibody.
† Measured on day 2.
‡ Measured on day 8.
John Wiley & Sons, Ltd
On physical examination, the patient was lethargic and confused, and his Glasgow Coma Scale was 12 (E3V4M5). His blood pressure was 136/68 mmHg, pulse rate 92 b.p.m., body temperature 36.6ºC, height 174.9 cm and weight 71.4 kg, with a body mass index of 23.3 kg/m2. We started an isotonic saline infusion with thiamine (100 mg/day) and continuous i.v. administration of insulin. During the first 2 h, the blood glucose declined at an average rate of 74.5 mg/dL/h, which subsequently >28 h after admission was 25.6 mg/dL/h (Figure 1). A total of 24 h later, his plasma glucose level decreased to 107 mg/dL; we then started potassium replacement therapy, as serum potassium levels dropped from 6.4 to 4.3 mEq/L. Although his blood pH and estimated serum osmolality improved to 7.379 and 296.9 mOsm/kg H2O, respectively, his level of consciousness was slightly worse than at the time of admission (Glasgow Coma Scale 11; E2V4M5; Figure 1). Brain magnetic resonance imaging did not show any evidence of cerebral edema (data not shown). Furthermore, ST‐segment elevation was observed on an electrocardiogram monitor, and was evident in II and aVF on a 12‐lead electrocardiogram, which was not initially apparent (Figure 2; days 1 and 2). High levels of creatinine kinase and N‐terminal pro‐B‐type natriuretic peptide (Table 1), and an increased cardiothoracic ratio with a costophrenic angle blunting on a chest X‐ray (Figure 1) indicated myocardial injury. However, the cardiologist recommended against coronary intervention due to a left ventricular ejection fraction of 60.3% and ambiguity of wall motion asynergy on a transthoracic echocardiogram. The estimated water deficit was 7,100 mL3, and we maintained the fluid balance at +2,500 mL on the first day (Figure 1). However, as we noticed signs of congestive heart failure on the chest X‐ray, we maintained it in a negative balance from the second day onwards (Figure 1).
Figure 1 Changes in laboratory test results and chest X‐ray findings during treatment. The main treatments are shown in the top part of the figure. AST, aspartate aminotransferase; CK, creatinine kinase; GCS, Glasgow Coma Scale; i.v., intravenous; MDI, multiple daily injections.
Figure 2 Electrocardiographic changes during treatment. All electrocardiograms were recorded at the standard electrocardiogram paper speed of 25 mm/s and 10 mm/mV.
Further testing showed a moderately decreased serum phosphate level (2.0 mg/dL; Table 1) that continued to decrease 1 h after the initial test (1.8 mg/dL; Figure 1). As the pathophysiology can only be explained by hypophosphatemia, we initiated phosphate replacement therapy (i.v. administration of neutral sodium phosphate buffer solution dissolved in isotonic saline 30 mmol/6 h). By the early morning of the second day, despite some disorientation, the patient opened his eyes in response to speech. However, he complained of nausea around 10.00 hours, and at around 13.00 hours, he could not open his eyes without a painful stimulus. The patient was unable to obey commands and was repeatedly getting entangled in the i.v. tube. We started phosphate replacement around 18.00 hours, and 1 h later, his condition recovered to a level where there was an eye‐opening response to speech. His disorientation disappeared on the third day of hospitalization (Figure 1). Furthermore, there were definite improvements in the ST‐segment elevation on electrocardiogram (Figure 2) 5 days after the initiation of the treatment. Improvements in the cardiothoracic ratio and costophrenic angle blunting on a chest X‐ray, as well as biochemical markers of myocardial infarction (Figure 1, lower panel), were observed. The qualitative cardiac troponin T‐test was negative on day 2, turned positive on days 3–5 and became negative again on day 12 (Figure 1). On the transthoracic echocardiogram carried out on day 12, the left ventricular ejection fraction was 64.9%, and left ventricular wall motion asynergy was not observed. He recovered without any sequela and was discharged from hospital 17 days after admission.
On publication, the local ethics committee approved this study, and the patient consented in writing to the case report.
Discussion
Phosphate is a source of adenosine triphosphate, which supplies energy to cells and regulates 2,3‐diphosphoglycerate levels, thereby affecting hemoglobin–oxygen affinity. Therefore, hypophosphatemia results in a deterioration of cellular function as a result of reduced energy and oxygen supply to tissues, as well as various neuromuscular symptoms 1 . Furthermore, cardiac dysfunction might result from profound hypophosphatemia 3 . In the present patient, myocardial dysfunction and impaired consciousness appeared after insulin treatment for DKA with mild hypophosphatemia, and disappeared after phosphate administration. Therefore, it seems that the decrease in phosphate concentration affected the patient’s condition, which improved with phosphate supplementation. In contrast, it is necessary to consider the possibility that the glucose‐lowering rate might have affected the patient’s state. However, it is unlikely that this rate caused the symptoms in the patient, as it did not exceed the general glucose‐lowering pace described in the American Diabetes Association guidelines 4 , 5 .
However, in a previous randomized controlled trial, Fisher and Kitabchi 6 examined the efficacy of phosphate therapy, and showed that phosphate replacement did not confer any advantages during DKA therapy. Post‐treatment, 2,3‐diphosphoglycerate levels were higher in the treatment group than in the control group; however, the difference was not statistically significant. Conversely, in the phosphate‐treated group, serum calcium levels were significantly decreased. From these results, the authors concluded that phosphate therapy for DKA treatment‐associated hypophosphatemia was unnecessary. The present study was limited to 30 patients; however, significantly favorable effects of phosphate therapy might be observed in a larger sample population. Furthermore, the treatment group received a total of 204 mmol of phosphate – a dose considered too high. Even 10–50 mmol of phosphate can resolve hypophosphatemia‐induced symptoms without side‐effects 1 .
Additionally, reports show that even mild hypophosphatemia can negatively affect respiratory muscle contractility 7 , 8 . Furthermore, in patients with mild hypophosphatemia (<2.2 mg/dL), approximately 30% reportedly had rhabdomyolysis 1 . Therefore, the diagnosis of rhabdomyolysis induced by hypophosphatemia might be overlooked. In addition, serum phosphate concentration does not necessarily reflect intracellular phosphate levels. Libanati and Tandler 9 reported that mean extranuclear phosphate concentration was sixfold less than the phosphate concentration in the nucleus. Additionally, metformin can result in severe hypophosphatemia in patients with renal failure 10 , as well as increase intracellular phosphate demand through activation of adenosine monophosphate‐activated protein kinase, especially in hepatocytes 11 . The present patient was taking metformin even though he had a prerenal failure as a result of dehydration, which can lead to a rapid drop in phosphate concentration. Insulin therapy for DKA might further increase intracellular phosphate demand, resulting in severe symptoms that generally occur in cases of severe hypophosphatemia.
In conclusion, we report a patient with impaired consciousness and myocardial injury during the recovery phase of DKA despite mild hypophosphatemia. Even mild hypophosphatemia associated with insulin therapy for DKA might cause severe complications in the presence of multiple overlapping causes 1 . As such, physicians should consider patients’ serum phosphate levels during DKA treatment.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
We thank Editage (www.editage.com) for English language editing. This research was supported by 2019 IUHW Research Grant. | Recovered | ReactionOutcome | CC BY-NC-ND | 32654423 | 18,205,731 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | New lung mass in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (GPA) is a potentially lethal ANCA-associated small-vessel vasculitis characterized by a typical triad of upper respiratory tract, lung, and kidney involvement. Lung involvement in GPA occurs in 25-80% of cases. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. As there are various clinical presentations, the diagnosis of GPA can be challenging, and the illness is difficult to distinguish from other diseases such as infection or malignancy. Following the improved survival rates in patients with GPA, there is accumulating evidence to suggest an increased occurrence of different types of cancer. Exposure to cyclophosphamide seems to be one of its main causes. We present the case of a patient with chronic GPA who was hospitalized owing to a new infiltrate in the lung, suggesting relapse of the disease, and finally diagnosed with small cell lung cancer. Data regarding lung cancer in GPA patients are limited. While there are some case reports and short case series in the literature, there are no detailed data regarding an association between CYC exposure and lung cancer development in vasculitis. It is necessary to consider the causes of pulmonary masses other than a GPA relapse. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor for the development of complications during treatment.
Introduction
Granulomatosis with polyangiitis (GPA) is a rare, potentially lethal, multisystem disease that belongs to the group of primary systemic ANCA-associated small-vessel vasculitides (AAV). Granulomatous inflammation and necrotizing vasculitis of small blood vessels lead to diverse clinical presentations with a classic triad of symptoms involving the upper and, lower respiratory tract as well as the kidneys. The disease can occur in several forms, from mild to very severe, and can be life threatening. With a standard therapy regimen, remission can be induced in about 70–90% of patients, but the typical course of the disease is with remissions and exacerbations, which lead to the necessity for repeated courses of immunosuppressive treatment [1–4]. Pulmonary involvement in GPA occurs in 25–80% of cases [5]. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. Infiltrates, air-space, and ground-glass opacities are also frequent findings. This variety in clinical presentation can make the diagnosis of GPA challenging and it can be difficult to distinguish it from other diseases such as an infection, sarcoidosis, or malignancy [6, 7].
We present a case of a patient with chronic GPA, who was hospitalized as a result of new infiltrate in the lung suggestive of a relapse of the disease, and who was finally diagnosed with small cell lung cancer. Following this case report, we discuss the risk of the development of lung cancer in GPA.
The patient has provided informed consent for publication of the case.
Methods
Search strategy
A literature search for patients with GPA and lung cancer was carried out using MEDLINE/PubMed, Google Scholar, and EBSCO, with no time limit. The search was conducted using the following keywords: “granulomatosis with polyangiitis”, “lung neoplasm,” and “carcinogenesis” (Fig. 1). Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting lung cancer development in GPA. We identified six case reports and summarize the findings in Table 1. Lung cancer prevalence in patients with ANCA-associated vasculitis is presented in Table 2.Fig. 1 Search strategy
Table 1 Review of granulomatosis with polyangiitis cases associated with lung cancer
Year, author No. of cases with lung cancer Age (years)/gender Organ involvement in GPA Time interval between GPA diagnosis and detection of cancer (years) Cumulative cyclophosphamide dose (g) Smoking Outcome
Campainha (2013) [3] 1 45, M Lung GPA 15 months after cancer treatment NR Yes Died
López (2008) [18] 1 50, M Kidney 23 NR NR NR
Toriyama (2018) [19] 1 65, M Lung 18 NR NR NR
Doberstein (2017) [20] 1 69, M Eye, lung 2 NR Yes Died
Xie (2019) [21] 1 78, M Lung, kidney 1 NR Yes NR
Yamada (2019) [22] 1 79, M Lung, kidney, upper respiratory tract 3 NR NR Alive
NR not reported
Table 2 Prevalence of lung cancer among patients with ANCA-associated vasculitis
Year, author Type of the disease No. of study group No. of cases with lung cancer SIR of lung cancer 95% CI
Knight (2002) [6] GPA 1065 8 2.0 0.9–3.9
Faurschou (2015) [8] GPA 293 5 1.1 0.3, 2.5
Rahmattulla (2015) [3] GPA and MPA 138 2 0.75 0.23–3.30
Życińska (2013) [12] GPA 117 2 1.7 0.5–3.4
Heijl (2011) [17] GPA 535 5 1.3 0.4–3.0
Sriskandarajah (2017) [23] ANCA-associated glomerulonephritis 419 7 1.73 0.83–3.63
SIR standardized incidence ratios
Case report
A 63-year-old man had been diagnosed with granulomatosis with polyangiitis (GPA) at the age of 51 on the basis of the presence of a pulmonary nodular mass (Fig. 2a), pansinusitis and cytoplasmic anti-neutrophil cytoplasmic antibody (PR3-ANCA). During the course of the disease, relapses were observed with progression and cavitation of the infiltrates in the lungs (Fig. 2b), exacerbations in the sinus lesions, and the occurrence of an inflammatory orbital pseudotumor. The patient had been treated with prednisone in varying doses, cyclophosphamide (CYC, total dose 70 g orally and 5 g intravenously) and then azathioprine and methotrexate following the diagnosis. Despite the treatment, a persistent orbital tumor, joint pain and exacerbations in the paranasal sinusitis were observed each time steroids were reduced below 10 mg/day. However, there were no new infiltrations in his lungs and PR3-ANCA titers were low (PR3-ANCA 18 RU/ml, n < 20 RU/ml). In November 2019, the patient was hospitalized because of headaches, general weakness, decrease in exercise capacity, and a tear of the left eye over 2 months. He did not present fever, hemoptysis or weight loss. Physical examination revealed exophthalmos (stable compared to previous months) and there were no obvious abnormalities during lung auscultation. Laboratory findings on admission showed mild anemia (Hb 12.7 g/dl), slightly elevated inflammatory markers (CRP 7.8 mg/l, n < 5 mg/l), and a greatly increased level of PR3-ANCA (PR3 > 200 RU/ml, n < 20 RU/ml). A relapse of GPA was suspected and a chest CT scan was performed, which revealed enlarged lymph nodes in the hilus of the left lung that impressed the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, raised concerns regarding proliferation (Fig. 2c, d). Because the patient had a history of smoking 27 packets of cigarettes a year it was decided to perform bronchoscopy. This showed left lower lobe bronchial stenosis with granulomatous hypertrophy of the mucosa. Inflammatory cells, including macrophages, partial hemosiderophages and epithelial cells without atypical features, were found in the sediment from bronchoalveolar lavage. Unexpectedly, histopathology of the tissue that has been narrowing the bronchus revealed the presence of small cell lung cancer. Chemotherapy and radiotherapy were started.Fig. 2 a High-resolution CT image revealing a large nodule in the lower lobes. b High-resolution CT image revealing a cavitated nodule. c CT pulmonary window revealing enlarged lymph nodes in the hilus of the left lung that impress the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, aroused suspicion of a proliferative process (2C1 axial scan, 2C2 coronal scan). d CT soft tissue window revealing a pathological mass in the hilus of the left lung (2D1 axial scan, 2D2 coronal scan)
Discussion
Since the late 1970s, the introduction of glucocorticoids and cyclophosphamide (CYC) as standard therapy in GPA has substantially improved the prognosis, thus increasing cumulative survival at 1, 2, and 5 years to 88%, 85%, and 78%, respectively [8]. However, the disease runs with remissions and exacerbations, resulting in the necessity of repeated courses of immunosuppressive treatment [3]. Alongside the improved survival rates in AAV patients, many reports suggest an increased occurrence of various malignancies [9, 10]. The increased risk of acute myeloid leukemia and bladder cancer is mainly attributed to CYC exposure and its carcinogenic effects and the toxic metabolite acrolein that becomes highly concentrated in the urine [9, 10]. The development of malignancies following CYC use is related to the duration of exposure and the cumulative doses of CYC. A high prevalence of cancer has been demonstrated in AAV patients who received cumulative CYC doses exceeding 36 g or who were treated for more than a year [11–16]. In most of the population-based studies, a pronounced increase was reported in bladder cancer, squamous cell skin cancer, and malignant lymphomas in particular [10, 12, 15–17]. Rahmattulla et al. found in their cohort of 138 patients with AAV a total of 85 malignancies in 36 individuals during a mean follow-up of 9.7 years, resulting in a 2.21-fold higher malignancy risk in comparison with the general population. They found the highest risk for non-melanoma skin cancers (NMSC), with a standardized incidence ratio of 4.23, but the incidence rates of other malignancies were not significantly increased [16]. Meta-analysis performed by Shang et al. shows that patients treated with CYC were at increased risk of late-occurring malignancies, particularly of NMSC, leukemia and bladder cancer, but not of kidney, prostate, colon and breast cancers [18]. Data from several studies suggest a standardized incidence ratio of cancer in AAV from 1.6 to 3.8 compared to that of the general population [13, 19]. An important measure in reducing cancer risk in patients with AAV has been the replacement of CYC with azathioprine for maintenance treatment. This change in practice occurred after the CYCAZAREM study in 2003 [20]. Recent studies suggest that with a reduction in CYC dosage, only NMSC risk remains increased [21].
Data regarding lung cancer in GPA patients are limited. There are some case reports and short case series in the literature [7, 22–26]. López et al. presented a patient with ANCA-positive GPA, who developed lung cancer that imitated GPA relapse. The ANCA were negative at the time of cancer diagnosis, suggesting immunological remission of vasculitis [22]. Toriyama et al. reported an interesting case of GPA with lung cancer that developed while taking long-term cyclophosphamide. The authors did not refer to ANCA status during the cancer diagnosis [23]. Our patient had a definite increase in ANCA titer which, with the presence of new infiltrations in the lungs, strongly suggested GPA relapse. Differential diagnosis of lung mass or cavitary lung disease is extensive and includes, for instance, various infections, autoimmune conditions, and primary and metastatic malignancies [27]. GPA, although rare, can also be a paraneoplastic syndrome [28]. In many published cases, it was only the prolonged detailed diagnostics, based on imaging and histopathological examinations, that made it possible to determine the proper diagnosis and appropriate treatment [29–31]. It remains currently unknown whether there is an association between solid tumors and elevated serum levels of ANCAs [32, 33].
The link between lung cancer and GPA has not yet been investigated. The scale of the problem is illustrated by data from population-based studies. Sriskandarajah et al. found, on the basis of data from 419 patients with ANCA-associated glomerulonephritis, 46 cancer cases in 41 (9.5%) patients with 7 lung cancers [34]. A study in Denmark linking the identification of cancer in 293 granulomatosis with polyangiitis patients from 1973 to 1999 who were followed through to 2010, showed 73 cancers with 5 lung cancers among them (SIR 1,1) [12]. Jardel et al. in a retrospective analysis of the French Vasculitis Study Group registry found that lung cancer was the most common cause of death due to malignancy in systemic necrotizing vasculitides [35]. Many chronic primary autoimmune diseases have been associated with an increased risk of de novo cancer development [36–39]. There was found to be a fourfold risk of lung cancer in patients from Sweden with systemic sclerosis, discoid lupus erythematosus, and polymyositis/dermatomyositis [40]. Yu et al. found an increased prevalence of lung cancer in patients with systemic sclerosis, Sjögren syndrome, lupus, and dermatomyositis, particularly in those with pulmonary involvement during the disease [41].
Detailed studies of lung cancer formation in vasculitis have not, to our knowledge, been carried out. Several potential mechanisms of increased malignancy risk in vasculitis have been suggested [42]. Evidence for CYC exposure as a lung carcinogen remains inconclusive. Cyclophosphamide is one of the immunosuppressive agents used as part of a chemotherapy regimen in lung cancer [43]. Pulmonary side effects of CYC are rare (< 1%) and are manifest either as an early-onset pneumonitis or as a late fibrosis [44]. There are no data regarding lung mass or lymphadenopathy induction by CYC.
The immune system dysfunction associated with autoimmunity may increase the risk of certain cancers [45, 46]. Dysregulation of both the innate and the adaptive immune system might have led to the observed associations between autoimmunity and cancer. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses, and the actual mechanism of the autoimmune or inflammatory disease, such as the type of cells mediating the inflammation, seems not to affect cancer risk significantly [47]. An exaggerated anti-self-tissue immune response appears to cause the damage with subsequent inflammation leading to focal and systemic malignancy [46]. Pathogenic mechanisms with continuous accumulation and the proliferation of differentiated fibroblasts in the regions of repeated epithelial injury, connected with decreased apoptosis as well as pulmonary fibrosis, seem very similar to those followed by cancer cells, featuring unrestricted cell multiplication, immortality, or rapid immigration [41]. Uncontrolled inflammation can become chronic, prompting cellular events that induce malignant cell transformation and carcinogenesis in surrounding tissues. The observation that tumors generally arise in the inflammatory tissue underlines the importance of the role of the local inflammatory mediators in carcinogenesis [41]. In AAV, inflammation at disease sites is perpetuated by necrosis of the blood vessel walls and infiltration of immune cells into damaged organs. Immune aberrations in T cell response, in terms of both the cytokine profile (Th1/Th2/Th17) and of Tregs, play a major role in the pathogenesis of GPA [48]. Interleukin (IL)-17 and IL-23 play roles in inflammation and autoimmunity and are increased in patients with ANCA-associated vasculitis [49]. Recent studies have shown that the serum IL-23 level, but not that of IL-17, is also elevated in small cell lung cancer [50, 51]. As lung cancer is not a common event in GPA patients, it seems that there might be another possible triggering factor.
Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products, occupational lung carcinogens, radiation and air pollution. Smoking is one of the environmental factors that play an important role in the genesis of aberrant immune response and the development of different inflammatory diseases and has immuno-modulatory effects in several chronic inflammatory disorders [52]. Smoking is associated with a more intensive development of inflammatory diseases and is a significant and dose-dependent risk factor for relapse. Above all, cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death [52–57].
In the patient whose case has been presented, the cumulative dose of CYC was about 75 g, which, in combination with a smoking habit, a family history of lung cancer (the patient’s sister), repeated exposure to X-rays (several lung and head-CTs were carried out during the course of GPA), could be associated with cancer development. It cannot, of course, be ruled out that the cancer as an accompanying disease was accidental in character.
Despite symptoms suggesting an exacerbation of vasculitis, such as a new mass and a high level of ANCA, it is still necessary to consider causes of pulmonary masses other than GPA relapse. It is also necessary to further evaluate the drugs used to treat GPA and their impact on the mechanisms leading to carcinogenesis. There is a continued need for alternatives to CYC that are less toxic and for cancer screening in patients with a high risk of neoplasm development [58]. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor the possible development of complications during the treatment.
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Author contributions
Conceptualization: AM; literature search and data analysis: AM, ŻS, SN, and JF; writing—original draft preparation: AM, SN, and ŻS; writing—review and editing: AM, SN, and ZZ; supervision: ZZ.
Funding
None.
Compliance with ethical standards
Conflict of interest
Anna Masiak, Jadwiga Fijałkowska, Szymon Nowakowski, Żaneta Smoleńska, and Zbigniew Zdrojewski declare that they have no conflict of interest.
Informed consent
The patient presented in this report gave his written informed consent prior to his inclusion and publication. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, PREDNISONE | DrugsGivenReaction | CC BY | 32671469 | 19,077,216 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus disorder'. | New lung mass in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (GPA) is a potentially lethal ANCA-associated small-vessel vasculitis characterized by a typical triad of upper respiratory tract, lung, and kidney involvement. Lung involvement in GPA occurs in 25-80% of cases. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. As there are various clinical presentations, the diagnosis of GPA can be challenging, and the illness is difficult to distinguish from other diseases such as infection or malignancy. Following the improved survival rates in patients with GPA, there is accumulating evidence to suggest an increased occurrence of different types of cancer. Exposure to cyclophosphamide seems to be one of its main causes. We present the case of a patient with chronic GPA who was hospitalized owing to a new infiltrate in the lung, suggesting relapse of the disease, and finally diagnosed with small cell lung cancer. Data regarding lung cancer in GPA patients are limited. While there are some case reports and short case series in the literature, there are no detailed data regarding an association between CYC exposure and lung cancer development in vasculitis. It is necessary to consider the causes of pulmonary masses other than a GPA relapse. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor for the development of complications during treatment.
Introduction
Granulomatosis with polyangiitis (GPA) is a rare, potentially lethal, multisystem disease that belongs to the group of primary systemic ANCA-associated small-vessel vasculitides (AAV). Granulomatous inflammation and necrotizing vasculitis of small blood vessels lead to diverse clinical presentations with a classic triad of symptoms involving the upper and, lower respiratory tract as well as the kidneys. The disease can occur in several forms, from mild to very severe, and can be life threatening. With a standard therapy regimen, remission can be induced in about 70–90% of patients, but the typical course of the disease is with remissions and exacerbations, which lead to the necessity for repeated courses of immunosuppressive treatment [1–4]. Pulmonary involvement in GPA occurs in 25–80% of cases [5]. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. Infiltrates, air-space, and ground-glass opacities are also frequent findings. This variety in clinical presentation can make the diagnosis of GPA challenging and it can be difficult to distinguish it from other diseases such as an infection, sarcoidosis, or malignancy [6, 7].
We present a case of a patient with chronic GPA, who was hospitalized as a result of new infiltrate in the lung suggestive of a relapse of the disease, and who was finally diagnosed with small cell lung cancer. Following this case report, we discuss the risk of the development of lung cancer in GPA.
The patient has provided informed consent for publication of the case.
Methods
Search strategy
A literature search for patients with GPA and lung cancer was carried out using MEDLINE/PubMed, Google Scholar, and EBSCO, with no time limit. The search was conducted using the following keywords: “granulomatosis with polyangiitis”, “lung neoplasm,” and “carcinogenesis” (Fig. 1). Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting lung cancer development in GPA. We identified six case reports and summarize the findings in Table 1. Lung cancer prevalence in patients with ANCA-associated vasculitis is presented in Table 2.Fig. 1 Search strategy
Table 1 Review of granulomatosis with polyangiitis cases associated with lung cancer
Year, author No. of cases with lung cancer Age (years)/gender Organ involvement in GPA Time interval between GPA diagnosis and detection of cancer (years) Cumulative cyclophosphamide dose (g) Smoking Outcome
Campainha (2013) [3] 1 45, M Lung GPA 15 months after cancer treatment NR Yes Died
López (2008) [18] 1 50, M Kidney 23 NR NR NR
Toriyama (2018) [19] 1 65, M Lung 18 NR NR NR
Doberstein (2017) [20] 1 69, M Eye, lung 2 NR Yes Died
Xie (2019) [21] 1 78, M Lung, kidney 1 NR Yes NR
Yamada (2019) [22] 1 79, M Lung, kidney, upper respiratory tract 3 NR NR Alive
NR not reported
Table 2 Prevalence of lung cancer among patients with ANCA-associated vasculitis
Year, author Type of the disease No. of study group No. of cases with lung cancer SIR of lung cancer 95% CI
Knight (2002) [6] GPA 1065 8 2.0 0.9–3.9
Faurschou (2015) [8] GPA 293 5 1.1 0.3, 2.5
Rahmattulla (2015) [3] GPA and MPA 138 2 0.75 0.23–3.30
Życińska (2013) [12] GPA 117 2 1.7 0.5–3.4
Heijl (2011) [17] GPA 535 5 1.3 0.4–3.0
Sriskandarajah (2017) [23] ANCA-associated glomerulonephritis 419 7 1.73 0.83–3.63
SIR standardized incidence ratios
Case report
A 63-year-old man had been diagnosed with granulomatosis with polyangiitis (GPA) at the age of 51 on the basis of the presence of a pulmonary nodular mass (Fig. 2a), pansinusitis and cytoplasmic anti-neutrophil cytoplasmic antibody (PR3-ANCA). During the course of the disease, relapses were observed with progression and cavitation of the infiltrates in the lungs (Fig. 2b), exacerbations in the sinus lesions, and the occurrence of an inflammatory orbital pseudotumor. The patient had been treated with prednisone in varying doses, cyclophosphamide (CYC, total dose 70 g orally and 5 g intravenously) and then azathioprine and methotrexate following the diagnosis. Despite the treatment, a persistent orbital tumor, joint pain and exacerbations in the paranasal sinusitis were observed each time steroids were reduced below 10 mg/day. However, there were no new infiltrations in his lungs and PR3-ANCA titers were low (PR3-ANCA 18 RU/ml, n < 20 RU/ml). In November 2019, the patient was hospitalized because of headaches, general weakness, decrease in exercise capacity, and a tear of the left eye over 2 months. He did not present fever, hemoptysis or weight loss. Physical examination revealed exophthalmos (stable compared to previous months) and there were no obvious abnormalities during lung auscultation. Laboratory findings on admission showed mild anemia (Hb 12.7 g/dl), slightly elevated inflammatory markers (CRP 7.8 mg/l, n < 5 mg/l), and a greatly increased level of PR3-ANCA (PR3 > 200 RU/ml, n < 20 RU/ml). A relapse of GPA was suspected and a chest CT scan was performed, which revealed enlarged lymph nodes in the hilus of the left lung that impressed the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, raised concerns regarding proliferation (Fig. 2c, d). Because the patient had a history of smoking 27 packets of cigarettes a year it was decided to perform bronchoscopy. This showed left lower lobe bronchial stenosis with granulomatous hypertrophy of the mucosa. Inflammatory cells, including macrophages, partial hemosiderophages and epithelial cells without atypical features, were found in the sediment from bronchoalveolar lavage. Unexpectedly, histopathology of the tissue that has been narrowing the bronchus revealed the presence of small cell lung cancer. Chemotherapy and radiotherapy were started.Fig. 2 a High-resolution CT image revealing a large nodule in the lower lobes. b High-resolution CT image revealing a cavitated nodule. c CT pulmonary window revealing enlarged lymph nodes in the hilus of the left lung that impress the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, aroused suspicion of a proliferative process (2C1 axial scan, 2C2 coronal scan). d CT soft tissue window revealing a pathological mass in the hilus of the left lung (2D1 axial scan, 2D2 coronal scan)
Discussion
Since the late 1970s, the introduction of glucocorticoids and cyclophosphamide (CYC) as standard therapy in GPA has substantially improved the prognosis, thus increasing cumulative survival at 1, 2, and 5 years to 88%, 85%, and 78%, respectively [8]. However, the disease runs with remissions and exacerbations, resulting in the necessity of repeated courses of immunosuppressive treatment [3]. Alongside the improved survival rates in AAV patients, many reports suggest an increased occurrence of various malignancies [9, 10]. The increased risk of acute myeloid leukemia and bladder cancer is mainly attributed to CYC exposure and its carcinogenic effects and the toxic metabolite acrolein that becomes highly concentrated in the urine [9, 10]. The development of malignancies following CYC use is related to the duration of exposure and the cumulative doses of CYC. A high prevalence of cancer has been demonstrated in AAV patients who received cumulative CYC doses exceeding 36 g or who were treated for more than a year [11–16]. In most of the population-based studies, a pronounced increase was reported in bladder cancer, squamous cell skin cancer, and malignant lymphomas in particular [10, 12, 15–17]. Rahmattulla et al. found in their cohort of 138 patients with AAV a total of 85 malignancies in 36 individuals during a mean follow-up of 9.7 years, resulting in a 2.21-fold higher malignancy risk in comparison with the general population. They found the highest risk for non-melanoma skin cancers (NMSC), with a standardized incidence ratio of 4.23, but the incidence rates of other malignancies were not significantly increased [16]. Meta-analysis performed by Shang et al. shows that patients treated with CYC were at increased risk of late-occurring malignancies, particularly of NMSC, leukemia and bladder cancer, but not of kidney, prostate, colon and breast cancers [18]. Data from several studies suggest a standardized incidence ratio of cancer in AAV from 1.6 to 3.8 compared to that of the general population [13, 19]. An important measure in reducing cancer risk in patients with AAV has been the replacement of CYC with azathioprine for maintenance treatment. This change in practice occurred after the CYCAZAREM study in 2003 [20]. Recent studies suggest that with a reduction in CYC dosage, only NMSC risk remains increased [21].
Data regarding lung cancer in GPA patients are limited. There are some case reports and short case series in the literature [7, 22–26]. López et al. presented a patient with ANCA-positive GPA, who developed lung cancer that imitated GPA relapse. The ANCA were negative at the time of cancer diagnosis, suggesting immunological remission of vasculitis [22]. Toriyama et al. reported an interesting case of GPA with lung cancer that developed while taking long-term cyclophosphamide. The authors did not refer to ANCA status during the cancer diagnosis [23]. Our patient had a definite increase in ANCA titer which, with the presence of new infiltrations in the lungs, strongly suggested GPA relapse. Differential diagnosis of lung mass or cavitary lung disease is extensive and includes, for instance, various infections, autoimmune conditions, and primary and metastatic malignancies [27]. GPA, although rare, can also be a paraneoplastic syndrome [28]. In many published cases, it was only the prolonged detailed diagnostics, based on imaging and histopathological examinations, that made it possible to determine the proper diagnosis and appropriate treatment [29–31]. It remains currently unknown whether there is an association between solid tumors and elevated serum levels of ANCAs [32, 33].
The link between lung cancer and GPA has not yet been investigated. The scale of the problem is illustrated by data from population-based studies. Sriskandarajah et al. found, on the basis of data from 419 patients with ANCA-associated glomerulonephritis, 46 cancer cases in 41 (9.5%) patients with 7 lung cancers [34]. A study in Denmark linking the identification of cancer in 293 granulomatosis with polyangiitis patients from 1973 to 1999 who were followed through to 2010, showed 73 cancers with 5 lung cancers among them (SIR 1,1) [12]. Jardel et al. in a retrospective analysis of the French Vasculitis Study Group registry found that lung cancer was the most common cause of death due to malignancy in systemic necrotizing vasculitides [35]. Many chronic primary autoimmune diseases have been associated with an increased risk of de novo cancer development [36–39]. There was found to be a fourfold risk of lung cancer in patients from Sweden with systemic sclerosis, discoid lupus erythematosus, and polymyositis/dermatomyositis [40]. Yu et al. found an increased prevalence of lung cancer in patients with systemic sclerosis, Sjögren syndrome, lupus, and dermatomyositis, particularly in those with pulmonary involvement during the disease [41].
Detailed studies of lung cancer formation in vasculitis have not, to our knowledge, been carried out. Several potential mechanisms of increased malignancy risk in vasculitis have been suggested [42]. Evidence for CYC exposure as a lung carcinogen remains inconclusive. Cyclophosphamide is one of the immunosuppressive agents used as part of a chemotherapy regimen in lung cancer [43]. Pulmonary side effects of CYC are rare (< 1%) and are manifest either as an early-onset pneumonitis or as a late fibrosis [44]. There are no data regarding lung mass or lymphadenopathy induction by CYC.
The immune system dysfunction associated with autoimmunity may increase the risk of certain cancers [45, 46]. Dysregulation of both the innate and the adaptive immune system might have led to the observed associations between autoimmunity and cancer. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses, and the actual mechanism of the autoimmune or inflammatory disease, such as the type of cells mediating the inflammation, seems not to affect cancer risk significantly [47]. An exaggerated anti-self-tissue immune response appears to cause the damage with subsequent inflammation leading to focal and systemic malignancy [46]. Pathogenic mechanisms with continuous accumulation and the proliferation of differentiated fibroblasts in the regions of repeated epithelial injury, connected with decreased apoptosis as well as pulmonary fibrosis, seem very similar to those followed by cancer cells, featuring unrestricted cell multiplication, immortality, or rapid immigration [41]. Uncontrolled inflammation can become chronic, prompting cellular events that induce malignant cell transformation and carcinogenesis in surrounding tissues. The observation that tumors generally arise in the inflammatory tissue underlines the importance of the role of the local inflammatory mediators in carcinogenesis [41]. In AAV, inflammation at disease sites is perpetuated by necrosis of the blood vessel walls and infiltration of immune cells into damaged organs. Immune aberrations in T cell response, in terms of both the cytokine profile (Th1/Th2/Th17) and of Tregs, play a major role in the pathogenesis of GPA [48]. Interleukin (IL)-17 and IL-23 play roles in inflammation and autoimmunity and are increased in patients with ANCA-associated vasculitis [49]. Recent studies have shown that the serum IL-23 level, but not that of IL-17, is also elevated in small cell lung cancer [50, 51]. As lung cancer is not a common event in GPA patients, it seems that there might be another possible triggering factor.
Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products, occupational lung carcinogens, radiation and air pollution. Smoking is one of the environmental factors that play an important role in the genesis of aberrant immune response and the development of different inflammatory diseases and has immuno-modulatory effects in several chronic inflammatory disorders [52]. Smoking is associated with a more intensive development of inflammatory diseases and is a significant and dose-dependent risk factor for relapse. Above all, cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death [52–57].
In the patient whose case has been presented, the cumulative dose of CYC was about 75 g, which, in combination with a smoking habit, a family history of lung cancer (the patient’s sister), repeated exposure to X-rays (several lung and head-CTs were carried out during the course of GPA), could be associated with cancer development. It cannot, of course, be ruled out that the cancer as an accompanying disease was accidental in character.
Despite symptoms suggesting an exacerbation of vasculitis, such as a new mass and a high level of ANCA, it is still necessary to consider causes of pulmonary masses other than GPA relapse. It is also necessary to further evaluate the drugs used to treat GPA and their impact on the mechanisms leading to carcinogenesis. There is a continued need for alternatives to CYC that are less toxic and for cancer screening in patients with a high risk of neoplasm development [58]. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor the possible development of complications during the treatment.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
Conceptualization: AM; literature search and data analysis: AM, ŻS, SN, and JF; writing—original draft preparation: AM, SN, and ŻS; writing—review and editing: AM, SN, and ZZ; supervision: ZZ.
Funding
None.
Compliance with ethical standards
Conflict of interest
Anna Masiak, Jadwiga Fijałkowska, Szymon Nowakowski, Żaneta Smoleńska, and Zbigniew Zdrojewski declare that they have no conflict of interest.
Informed consent
The patient presented in this report gave his written informed consent prior to his inclusion and publication. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, PREDNISONE | DrugsGivenReaction | CC BY | 32671469 | 19,077,216 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small cell lung cancer'. | New lung mass in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (GPA) is a potentially lethal ANCA-associated small-vessel vasculitis characterized by a typical triad of upper respiratory tract, lung, and kidney involvement. Lung involvement in GPA occurs in 25-80% of cases. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. As there are various clinical presentations, the diagnosis of GPA can be challenging, and the illness is difficult to distinguish from other diseases such as infection or malignancy. Following the improved survival rates in patients with GPA, there is accumulating evidence to suggest an increased occurrence of different types of cancer. Exposure to cyclophosphamide seems to be one of its main causes. We present the case of a patient with chronic GPA who was hospitalized owing to a new infiltrate in the lung, suggesting relapse of the disease, and finally diagnosed with small cell lung cancer. Data regarding lung cancer in GPA patients are limited. While there are some case reports and short case series in the literature, there are no detailed data regarding an association between CYC exposure and lung cancer development in vasculitis. It is necessary to consider the causes of pulmonary masses other than a GPA relapse. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor for the development of complications during treatment.
Introduction
Granulomatosis with polyangiitis (GPA) is a rare, potentially lethal, multisystem disease that belongs to the group of primary systemic ANCA-associated small-vessel vasculitides (AAV). Granulomatous inflammation and necrotizing vasculitis of small blood vessels lead to diverse clinical presentations with a classic triad of symptoms involving the upper and, lower respiratory tract as well as the kidneys. The disease can occur in several forms, from mild to very severe, and can be life threatening. With a standard therapy regimen, remission can be induced in about 70–90% of patients, but the typical course of the disease is with remissions and exacerbations, which lead to the necessity for repeated courses of immunosuppressive treatment [1–4]. Pulmonary involvement in GPA occurs in 25–80% of cases [5]. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. Infiltrates, air-space, and ground-glass opacities are also frequent findings. This variety in clinical presentation can make the diagnosis of GPA challenging and it can be difficult to distinguish it from other diseases such as an infection, sarcoidosis, or malignancy [6, 7].
We present a case of a patient with chronic GPA, who was hospitalized as a result of new infiltrate in the lung suggestive of a relapse of the disease, and who was finally diagnosed with small cell lung cancer. Following this case report, we discuss the risk of the development of lung cancer in GPA.
The patient has provided informed consent for publication of the case.
Methods
Search strategy
A literature search for patients with GPA and lung cancer was carried out using MEDLINE/PubMed, Google Scholar, and EBSCO, with no time limit. The search was conducted using the following keywords: “granulomatosis with polyangiitis”, “lung neoplasm,” and “carcinogenesis” (Fig. 1). Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting lung cancer development in GPA. We identified six case reports and summarize the findings in Table 1. Lung cancer prevalence in patients with ANCA-associated vasculitis is presented in Table 2.Fig. 1 Search strategy
Table 1 Review of granulomatosis with polyangiitis cases associated with lung cancer
Year, author No. of cases with lung cancer Age (years)/gender Organ involvement in GPA Time interval between GPA diagnosis and detection of cancer (years) Cumulative cyclophosphamide dose (g) Smoking Outcome
Campainha (2013) [3] 1 45, M Lung GPA 15 months after cancer treatment NR Yes Died
López (2008) [18] 1 50, M Kidney 23 NR NR NR
Toriyama (2018) [19] 1 65, M Lung 18 NR NR NR
Doberstein (2017) [20] 1 69, M Eye, lung 2 NR Yes Died
Xie (2019) [21] 1 78, M Lung, kidney 1 NR Yes NR
Yamada (2019) [22] 1 79, M Lung, kidney, upper respiratory tract 3 NR NR Alive
NR not reported
Table 2 Prevalence of lung cancer among patients with ANCA-associated vasculitis
Year, author Type of the disease No. of study group No. of cases with lung cancer SIR of lung cancer 95% CI
Knight (2002) [6] GPA 1065 8 2.0 0.9–3.9
Faurschou (2015) [8] GPA 293 5 1.1 0.3, 2.5
Rahmattulla (2015) [3] GPA and MPA 138 2 0.75 0.23–3.30
Życińska (2013) [12] GPA 117 2 1.7 0.5–3.4
Heijl (2011) [17] GPA 535 5 1.3 0.4–3.0
Sriskandarajah (2017) [23] ANCA-associated glomerulonephritis 419 7 1.73 0.83–3.63
SIR standardized incidence ratios
Case report
A 63-year-old man had been diagnosed with granulomatosis with polyangiitis (GPA) at the age of 51 on the basis of the presence of a pulmonary nodular mass (Fig. 2a), pansinusitis and cytoplasmic anti-neutrophil cytoplasmic antibody (PR3-ANCA). During the course of the disease, relapses were observed with progression and cavitation of the infiltrates in the lungs (Fig. 2b), exacerbations in the sinus lesions, and the occurrence of an inflammatory orbital pseudotumor. The patient had been treated with prednisone in varying doses, cyclophosphamide (CYC, total dose 70 g orally and 5 g intravenously) and then azathioprine and methotrexate following the diagnosis. Despite the treatment, a persistent orbital tumor, joint pain and exacerbations in the paranasal sinusitis were observed each time steroids were reduced below 10 mg/day. However, there were no new infiltrations in his lungs and PR3-ANCA titers were low (PR3-ANCA 18 RU/ml, n < 20 RU/ml). In November 2019, the patient was hospitalized because of headaches, general weakness, decrease in exercise capacity, and a tear of the left eye over 2 months. He did not present fever, hemoptysis or weight loss. Physical examination revealed exophthalmos (stable compared to previous months) and there were no obvious abnormalities during lung auscultation. Laboratory findings on admission showed mild anemia (Hb 12.7 g/dl), slightly elevated inflammatory markers (CRP 7.8 mg/l, n < 5 mg/l), and a greatly increased level of PR3-ANCA (PR3 > 200 RU/ml, n < 20 RU/ml). A relapse of GPA was suspected and a chest CT scan was performed, which revealed enlarged lymph nodes in the hilus of the left lung that impressed the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, raised concerns regarding proliferation (Fig. 2c, d). Because the patient had a history of smoking 27 packets of cigarettes a year it was decided to perform bronchoscopy. This showed left lower lobe bronchial stenosis with granulomatous hypertrophy of the mucosa. Inflammatory cells, including macrophages, partial hemosiderophages and epithelial cells without atypical features, were found in the sediment from bronchoalveolar lavage. Unexpectedly, histopathology of the tissue that has been narrowing the bronchus revealed the presence of small cell lung cancer. Chemotherapy and radiotherapy were started.Fig. 2 a High-resolution CT image revealing a large nodule in the lower lobes. b High-resolution CT image revealing a cavitated nodule. c CT pulmonary window revealing enlarged lymph nodes in the hilus of the left lung that impress the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, aroused suspicion of a proliferative process (2C1 axial scan, 2C2 coronal scan). d CT soft tissue window revealing a pathological mass in the hilus of the left lung (2D1 axial scan, 2D2 coronal scan)
Discussion
Since the late 1970s, the introduction of glucocorticoids and cyclophosphamide (CYC) as standard therapy in GPA has substantially improved the prognosis, thus increasing cumulative survival at 1, 2, and 5 years to 88%, 85%, and 78%, respectively [8]. However, the disease runs with remissions and exacerbations, resulting in the necessity of repeated courses of immunosuppressive treatment [3]. Alongside the improved survival rates in AAV patients, many reports suggest an increased occurrence of various malignancies [9, 10]. The increased risk of acute myeloid leukemia and bladder cancer is mainly attributed to CYC exposure and its carcinogenic effects and the toxic metabolite acrolein that becomes highly concentrated in the urine [9, 10]. The development of malignancies following CYC use is related to the duration of exposure and the cumulative doses of CYC. A high prevalence of cancer has been demonstrated in AAV patients who received cumulative CYC doses exceeding 36 g or who were treated for more than a year [11–16]. In most of the population-based studies, a pronounced increase was reported in bladder cancer, squamous cell skin cancer, and malignant lymphomas in particular [10, 12, 15–17]. Rahmattulla et al. found in their cohort of 138 patients with AAV a total of 85 malignancies in 36 individuals during a mean follow-up of 9.7 years, resulting in a 2.21-fold higher malignancy risk in comparison with the general population. They found the highest risk for non-melanoma skin cancers (NMSC), with a standardized incidence ratio of 4.23, but the incidence rates of other malignancies were not significantly increased [16]. Meta-analysis performed by Shang et al. shows that patients treated with CYC were at increased risk of late-occurring malignancies, particularly of NMSC, leukemia and bladder cancer, but not of kidney, prostate, colon and breast cancers [18]. Data from several studies suggest a standardized incidence ratio of cancer in AAV from 1.6 to 3.8 compared to that of the general population [13, 19]. An important measure in reducing cancer risk in patients with AAV has been the replacement of CYC with azathioprine for maintenance treatment. This change in practice occurred after the CYCAZAREM study in 2003 [20]. Recent studies suggest that with a reduction in CYC dosage, only NMSC risk remains increased [21].
Data regarding lung cancer in GPA patients are limited. There are some case reports and short case series in the literature [7, 22–26]. López et al. presented a patient with ANCA-positive GPA, who developed lung cancer that imitated GPA relapse. The ANCA were negative at the time of cancer diagnosis, suggesting immunological remission of vasculitis [22]. Toriyama et al. reported an interesting case of GPA with lung cancer that developed while taking long-term cyclophosphamide. The authors did not refer to ANCA status during the cancer diagnosis [23]. Our patient had a definite increase in ANCA titer which, with the presence of new infiltrations in the lungs, strongly suggested GPA relapse. Differential diagnosis of lung mass or cavitary lung disease is extensive and includes, for instance, various infections, autoimmune conditions, and primary and metastatic malignancies [27]. GPA, although rare, can also be a paraneoplastic syndrome [28]. In many published cases, it was only the prolonged detailed diagnostics, based on imaging and histopathological examinations, that made it possible to determine the proper diagnosis and appropriate treatment [29–31]. It remains currently unknown whether there is an association between solid tumors and elevated serum levels of ANCAs [32, 33].
The link between lung cancer and GPA has not yet been investigated. The scale of the problem is illustrated by data from population-based studies. Sriskandarajah et al. found, on the basis of data from 419 patients with ANCA-associated glomerulonephritis, 46 cancer cases in 41 (9.5%) patients with 7 lung cancers [34]. A study in Denmark linking the identification of cancer in 293 granulomatosis with polyangiitis patients from 1973 to 1999 who were followed through to 2010, showed 73 cancers with 5 lung cancers among them (SIR 1,1) [12]. Jardel et al. in a retrospective analysis of the French Vasculitis Study Group registry found that lung cancer was the most common cause of death due to malignancy in systemic necrotizing vasculitides [35]. Many chronic primary autoimmune diseases have been associated with an increased risk of de novo cancer development [36–39]. There was found to be a fourfold risk of lung cancer in patients from Sweden with systemic sclerosis, discoid lupus erythematosus, and polymyositis/dermatomyositis [40]. Yu et al. found an increased prevalence of lung cancer in patients with systemic sclerosis, Sjögren syndrome, lupus, and dermatomyositis, particularly in those with pulmonary involvement during the disease [41].
Detailed studies of lung cancer formation in vasculitis have not, to our knowledge, been carried out. Several potential mechanisms of increased malignancy risk in vasculitis have been suggested [42]. Evidence for CYC exposure as a lung carcinogen remains inconclusive. Cyclophosphamide is one of the immunosuppressive agents used as part of a chemotherapy regimen in lung cancer [43]. Pulmonary side effects of CYC are rare (< 1%) and are manifest either as an early-onset pneumonitis or as a late fibrosis [44]. There are no data regarding lung mass or lymphadenopathy induction by CYC.
The immune system dysfunction associated with autoimmunity may increase the risk of certain cancers [45, 46]. Dysregulation of both the innate and the adaptive immune system might have led to the observed associations between autoimmunity and cancer. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses, and the actual mechanism of the autoimmune or inflammatory disease, such as the type of cells mediating the inflammation, seems not to affect cancer risk significantly [47]. An exaggerated anti-self-tissue immune response appears to cause the damage with subsequent inflammation leading to focal and systemic malignancy [46]. Pathogenic mechanisms with continuous accumulation and the proliferation of differentiated fibroblasts in the regions of repeated epithelial injury, connected with decreased apoptosis as well as pulmonary fibrosis, seem very similar to those followed by cancer cells, featuring unrestricted cell multiplication, immortality, or rapid immigration [41]. Uncontrolled inflammation can become chronic, prompting cellular events that induce malignant cell transformation and carcinogenesis in surrounding tissues. The observation that tumors generally arise in the inflammatory tissue underlines the importance of the role of the local inflammatory mediators in carcinogenesis [41]. In AAV, inflammation at disease sites is perpetuated by necrosis of the blood vessel walls and infiltration of immune cells into damaged organs. Immune aberrations in T cell response, in terms of both the cytokine profile (Th1/Th2/Th17) and of Tregs, play a major role in the pathogenesis of GPA [48]. Interleukin (IL)-17 and IL-23 play roles in inflammation and autoimmunity and are increased in patients with ANCA-associated vasculitis [49]. Recent studies have shown that the serum IL-23 level, but not that of IL-17, is also elevated in small cell lung cancer [50, 51]. As lung cancer is not a common event in GPA patients, it seems that there might be another possible triggering factor.
Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products, occupational lung carcinogens, radiation and air pollution. Smoking is one of the environmental factors that play an important role in the genesis of aberrant immune response and the development of different inflammatory diseases and has immuno-modulatory effects in several chronic inflammatory disorders [52]. Smoking is associated with a more intensive development of inflammatory diseases and is a significant and dose-dependent risk factor for relapse. Above all, cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death [52–57].
In the patient whose case has been presented, the cumulative dose of CYC was about 75 g, which, in combination with a smoking habit, a family history of lung cancer (the patient’s sister), repeated exposure to X-rays (several lung and head-CTs were carried out during the course of GPA), could be associated with cancer development. It cannot, of course, be ruled out that the cancer as an accompanying disease was accidental in character.
Despite symptoms suggesting an exacerbation of vasculitis, such as a new mass and a high level of ANCA, it is still necessary to consider causes of pulmonary masses other than GPA relapse. It is also necessary to further evaluate the drugs used to treat GPA and their impact on the mechanisms leading to carcinogenesis. There is a continued need for alternatives to CYC that are less toxic and for cancer screening in patients with a high risk of neoplasm development [58]. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor the possible development of complications during the treatment.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
Conceptualization: AM; literature search and data analysis: AM, ŻS, SN, and JF; writing—original draft preparation: AM, SN, and ŻS; writing—review and editing: AM, SN, and ZZ; supervision: ZZ.
Funding
None.
Compliance with ethical standards
Conflict of interest
Anna Masiak, Jadwiga Fijałkowska, Szymon Nowakowski, Żaneta Smoleńska, and Zbigniew Zdrojewski declare that they have no conflict of interest.
Informed consent
The patient presented in this report gave his written informed consent prior to his inclusion and publication. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, PREDNISONE | DrugsGivenReaction | CC BY | 32671469 | 18,111,229 | 2021-02 |
What was the dosage of drug 'PREDNISONE'? | New lung mass in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (GPA) is a potentially lethal ANCA-associated small-vessel vasculitis characterized by a typical triad of upper respiratory tract, lung, and kidney involvement. Lung involvement in GPA occurs in 25-80% of cases. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. As there are various clinical presentations, the diagnosis of GPA can be challenging, and the illness is difficult to distinguish from other diseases such as infection or malignancy. Following the improved survival rates in patients with GPA, there is accumulating evidence to suggest an increased occurrence of different types of cancer. Exposure to cyclophosphamide seems to be one of its main causes. We present the case of a patient with chronic GPA who was hospitalized owing to a new infiltrate in the lung, suggesting relapse of the disease, and finally diagnosed with small cell lung cancer. Data regarding lung cancer in GPA patients are limited. While there are some case reports and short case series in the literature, there are no detailed data regarding an association between CYC exposure and lung cancer development in vasculitis. It is necessary to consider the causes of pulmonary masses other than a GPA relapse. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor for the development of complications during treatment.
Introduction
Granulomatosis with polyangiitis (GPA) is a rare, potentially lethal, multisystem disease that belongs to the group of primary systemic ANCA-associated small-vessel vasculitides (AAV). Granulomatous inflammation and necrotizing vasculitis of small blood vessels lead to diverse clinical presentations with a classic triad of symptoms involving the upper and, lower respiratory tract as well as the kidneys. The disease can occur in several forms, from mild to very severe, and can be life threatening. With a standard therapy regimen, remission can be induced in about 70–90% of patients, but the typical course of the disease is with remissions and exacerbations, which lead to the necessity for repeated courses of immunosuppressive treatment [1–4]. Pulmonary involvement in GPA occurs in 25–80% of cases [5]. The most common radiographic and computed tomography (CT) abnormalities of pulmonary GPA are lung nodules and masses, very often multiple and with cavitation. Infiltrates, air-space, and ground-glass opacities are also frequent findings. This variety in clinical presentation can make the diagnosis of GPA challenging and it can be difficult to distinguish it from other diseases such as an infection, sarcoidosis, or malignancy [6, 7].
We present a case of a patient with chronic GPA, who was hospitalized as a result of new infiltrate in the lung suggestive of a relapse of the disease, and who was finally diagnosed with small cell lung cancer. Following this case report, we discuss the risk of the development of lung cancer in GPA.
The patient has provided informed consent for publication of the case.
Methods
Search strategy
A literature search for patients with GPA and lung cancer was carried out using MEDLINE/PubMed, Google Scholar, and EBSCO, with no time limit. The search was conducted using the following keywords: “granulomatosis with polyangiitis”, “lung neoplasm,” and “carcinogenesis” (Fig. 1). Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting lung cancer development in GPA. We identified six case reports and summarize the findings in Table 1. Lung cancer prevalence in patients with ANCA-associated vasculitis is presented in Table 2.Fig. 1 Search strategy
Table 1 Review of granulomatosis with polyangiitis cases associated with lung cancer
Year, author No. of cases with lung cancer Age (years)/gender Organ involvement in GPA Time interval between GPA diagnosis and detection of cancer (years) Cumulative cyclophosphamide dose (g) Smoking Outcome
Campainha (2013) [3] 1 45, M Lung GPA 15 months after cancer treatment NR Yes Died
López (2008) [18] 1 50, M Kidney 23 NR NR NR
Toriyama (2018) [19] 1 65, M Lung 18 NR NR NR
Doberstein (2017) [20] 1 69, M Eye, lung 2 NR Yes Died
Xie (2019) [21] 1 78, M Lung, kidney 1 NR Yes NR
Yamada (2019) [22] 1 79, M Lung, kidney, upper respiratory tract 3 NR NR Alive
NR not reported
Table 2 Prevalence of lung cancer among patients with ANCA-associated vasculitis
Year, author Type of the disease No. of study group No. of cases with lung cancer SIR of lung cancer 95% CI
Knight (2002) [6] GPA 1065 8 2.0 0.9–3.9
Faurschou (2015) [8] GPA 293 5 1.1 0.3, 2.5
Rahmattulla (2015) [3] GPA and MPA 138 2 0.75 0.23–3.30
Życińska (2013) [12] GPA 117 2 1.7 0.5–3.4
Heijl (2011) [17] GPA 535 5 1.3 0.4–3.0
Sriskandarajah (2017) [23] ANCA-associated glomerulonephritis 419 7 1.73 0.83–3.63
SIR standardized incidence ratios
Case report
A 63-year-old man had been diagnosed with granulomatosis with polyangiitis (GPA) at the age of 51 on the basis of the presence of a pulmonary nodular mass (Fig. 2a), pansinusitis and cytoplasmic anti-neutrophil cytoplasmic antibody (PR3-ANCA). During the course of the disease, relapses were observed with progression and cavitation of the infiltrates in the lungs (Fig. 2b), exacerbations in the sinus lesions, and the occurrence of an inflammatory orbital pseudotumor. The patient had been treated with prednisone in varying doses, cyclophosphamide (CYC, total dose 70 g orally and 5 g intravenously) and then azathioprine and methotrexate following the diagnosis. Despite the treatment, a persistent orbital tumor, joint pain and exacerbations in the paranasal sinusitis were observed each time steroids were reduced below 10 mg/day. However, there were no new infiltrations in his lungs and PR3-ANCA titers were low (PR3-ANCA 18 RU/ml, n < 20 RU/ml). In November 2019, the patient was hospitalized because of headaches, general weakness, decrease in exercise capacity, and a tear of the left eye over 2 months. He did not present fever, hemoptysis or weight loss. Physical examination revealed exophthalmos (stable compared to previous months) and there were no obvious abnormalities during lung auscultation. Laboratory findings on admission showed mild anemia (Hb 12.7 g/dl), slightly elevated inflammatory markers (CRP 7.8 mg/l, n < 5 mg/l), and a greatly increased level of PR3-ANCA (PR3 > 200 RU/ml, n < 20 RU/ml). A relapse of GPA was suspected and a chest CT scan was performed, which revealed enlarged lymph nodes in the hilus of the left lung that impressed the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, raised concerns regarding proliferation (Fig. 2c, d). Because the patient had a history of smoking 27 packets of cigarettes a year it was decided to perform bronchoscopy. This showed left lower lobe bronchial stenosis with granulomatous hypertrophy of the mucosa. Inflammatory cells, including macrophages, partial hemosiderophages and epithelial cells without atypical features, were found in the sediment from bronchoalveolar lavage. Unexpectedly, histopathology of the tissue that has been narrowing the bronchus revealed the presence of small cell lung cancer. Chemotherapy and radiotherapy were started.Fig. 2 a High-resolution CT image revealing a large nodule in the lower lobes. b High-resolution CT image revealing a cavitated nodule. c CT pulmonary window revealing enlarged lymph nodes in the hilus of the left lung that impress the bronchi to the lower lobe, which, combined with the presence of subpleural nodules, aroused suspicion of a proliferative process (2C1 axial scan, 2C2 coronal scan). d CT soft tissue window revealing a pathological mass in the hilus of the left lung (2D1 axial scan, 2D2 coronal scan)
Discussion
Since the late 1970s, the introduction of glucocorticoids and cyclophosphamide (CYC) as standard therapy in GPA has substantially improved the prognosis, thus increasing cumulative survival at 1, 2, and 5 years to 88%, 85%, and 78%, respectively [8]. However, the disease runs with remissions and exacerbations, resulting in the necessity of repeated courses of immunosuppressive treatment [3]. Alongside the improved survival rates in AAV patients, many reports suggest an increased occurrence of various malignancies [9, 10]. The increased risk of acute myeloid leukemia and bladder cancer is mainly attributed to CYC exposure and its carcinogenic effects and the toxic metabolite acrolein that becomes highly concentrated in the urine [9, 10]. The development of malignancies following CYC use is related to the duration of exposure and the cumulative doses of CYC. A high prevalence of cancer has been demonstrated in AAV patients who received cumulative CYC doses exceeding 36 g or who were treated for more than a year [11–16]. In most of the population-based studies, a pronounced increase was reported in bladder cancer, squamous cell skin cancer, and malignant lymphomas in particular [10, 12, 15–17]. Rahmattulla et al. found in their cohort of 138 patients with AAV a total of 85 malignancies in 36 individuals during a mean follow-up of 9.7 years, resulting in a 2.21-fold higher malignancy risk in comparison with the general population. They found the highest risk for non-melanoma skin cancers (NMSC), with a standardized incidence ratio of 4.23, but the incidence rates of other malignancies were not significantly increased [16]. Meta-analysis performed by Shang et al. shows that patients treated with CYC were at increased risk of late-occurring malignancies, particularly of NMSC, leukemia and bladder cancer, but not of kidney, prostate, colon and breast cancers [18]. Data from several studies suggest a standardized incidence ratio of cancer in AAV from 1.6 to 3.8 compared to that of the general population [13, 19]. An important measure in reducing cancer risk in patients with AAV has been the replacement of CYC with azathioprine for maintenance treatment. This change in practice occurred after the CYCAZAREM study in 2003 [20]. Recent studies suggest that with a reduction in CYC dosage, only NMSC risk remains increased [21].
Data regarding lung cancer in GPA patients are limited. There are some case reports and short case series in the literature [7, 22–26]. López et al. presented a patient with ANCA-positive GPA, who developed lung cancer that imitated GPA relapse. The ANCA were negative at the time of cancer diagnosis, suggesting immunological remission of vasculitis [22]. Toriyama et al. reported an interesting case of GPA with lung cancer that developed while taking long-term cyclophosphamide. The authors did not refer to ANCA status during the cancer diagnosis [23]. Our patient had a definite increase in ANCA titer which, with the presence of new infiltrations in the lungs, strongly suggested GPA relapse. Differential diagnosis of lung mass or cavitary lung disease is extensive and includes, for instance, various infections, autoimmune conditions, and primary and metastatic malignancies [27]. GPA, although rare, can also be a paraneoplastic syndrome [28]. In many published cases, it was only the prolonged detailed diagnostics, based on imaging and histopathological examinations, that made it possible to determine the proper diagnosis and appropriate treatment [29–31]. It remains currently unknown whether there is an association between solid tumors and elevated serum levels of ANCAs [32, 33].
The link between lung cancer and GPA has not yet been investigated. The scale of the problem is illustrated by data from population-based studies. Sriskandarajah et al. found, on the basis of data from 419 patients with ANCA-associated glomerulonephritis, 46 cancer cases in 41 (9.5%) patients with 7 lung cancers [34]. A study in Denmark linking the identification of cancer in 293 granulomatosis with polyangiitis patients from 1973 to 1999 who were followed through to 2010, showed 73 cancers with 5 lung cancers among them (SIR 1,1) [12]. Jardel et al. in a retrospective analysis of the French Vasculitis Study Group registry found that lung cancer was the most common cause of death due to malignancy in systemic necrotizing vasculitides [35]. Many chronic primary autoimmune diseases have been associated with an increased risk of de novo cancer development [36–39]. There was found to be a fourfold risk of lung cancer in patients from Sweden with systemic sclerosis, discoid lupus erythematosus, and polymyositis/dermatomyositis [40]. Yu et al. found an increased prevalence of lung cancer in patients with systemic sclerosis, Sjögren syndrome, lupus, and dermatomyositis, particularly in those with pulmonary involvement during the disease [41].
Detailed studies of lung cancer formation in vasculitis have not, to our knowledge, been carried out. Several potential mechanisms of increased malignancy risk in vasculitis have been suggested [42]. Evidence for CYC exposure as a lung carcinogen remains inconclusive. Cyclophosphamide is one of the immunosuppressive agents used as part of a chemotherapy regimen in lung cancer [43]. Pulmonary side effects of CYC are rare (< 1%) and are manifest either as an early-onset pneumonitis or as a late fibrosis [44]. There are no data regarding lung mass or lymphadenopathy induction by CYC.
The immune system dysfunction associated with autoimmunity may increase the risk of certain cancers [45, 46]. Dysregulation of both the innate and the adaptive immune system might have led to the observed associations between autoimmunity and cancer. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses, and the actual mechanism of the autoimmune or inflammatory disease, such as the type of cells mediating the inflammation, seems not to affect cancer risk significantly [47]. An exaggerated anti-self-tissue immune response appears to cause the damage with subsequent inflammation leading to focal and systemic malignancy [46]. Pathogenic mechanisms with continuous accumulation and the proliferation of differentiated fibroblasts in the regions of repeated epithelial injury, connected with decreased apoptosis as well as pulmonary fibrosis, seem very similar to those followed by cancer cells, featuring unrestricted cell multiplication, immortality, or rapid immigration [41]. Uncontrolled inflammation can become chronic, prompting cellular events that induce malignant cell transformation and carcinogenesis in surrounding tissues. The observation that tumors generally arise in the inflammatory tissue underlines the importance of the role of the local inflammatory mediators in carcinogenesis [41]. In AAV, inflammation at disease sites is perpetuated by necrosis of the blood vessel walls and infiltration of immune cells into damaged organs. Immune aberrations in T cell response, in terms of both the cytokine profile (Th1/Th2/Th17) and of Tregs, play a major role in the pathogenesis of GPA [48]. Interleukin (IL)-17 and IL-23 play roles in inflammation and autoimmunity and are increased in patients with ANCA-associated vasculitis [49]. Recent studies have shown that the serum IL-23 level, but not that of IL-17, is also elevated in small cell lung cancer [50, 51]. As lung cancer is not a common event in GPA patients, it seems that there might be another possible triggering factor.
Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products, occupational lung carcinogens, radiation and air pollution. Smoking is one of the environmental factors that play an important role in the genesis of aberrant immune response and the development of different inflammatory diseases and has immuno-modulatory effects in several chronic inflammatory disorders [52]. Smoking is associated with a more intensive development of inflammatory diseases and is a significant and dose-dependent risk factor for relapse. Above all, cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death [52–57].
In the patient whose case has been presented, the cumulative dose of CYC was about 75 g, which, in combination with a smoking habit, a family history of lung cancer (the patient’s sister), repeated exposure to X-rays (several lung and head-CTs were carried out during the course of GPA), could be associated with cancer development. It cannot, of course, be ruled out that the cancer as an accompanying disease was accidental in character.
Despite symptoms suggesting an exacerbation of vasculitis, such as a new mass and a high level of ANCA, it is still necessary to consider causes of pulmonary masses other than GPA relapse. It is also necessary to further evaluate the drugs used to treat GPA and their impact on the mechanisms leading to carcinogenesis. There is a continued need for alternatives to CYC that are less toxic and for cancer screening in patients with a high risk of neoplasm development [58]. Bronchoscopy with biopsy and histopathological examination are crucial in proper differential diagnosis. GPA patients require long-term follow-up to monitor the possible development of complications during the treatment.
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Author contributions
Conceptualization: AM; literature search and data analysis: AM, ŻS, SN, and JF; writing—original draft preparation: AM, SN, and ŻS; writing—review and editing: AM, SN, and ZZ; supervision: ZZ.
Funding
None.
Compliance with ethical standards
Conflict of interest
Anna Masiak, Jadwiga Fijałkowska, Szymon Nowakowski, Żaneta Smoleńska, and Zbigniew Zdrojewski declare that they have no conflict of interest.
Informed consent
The patient presented in this report gave his written informed consent prior to his inclusion and publication. | IN VARYING DOSES | DrugDosageText | CC BY | 32671469 | 19,077,216 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breech presentation'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, CALCIUM | DrugsGivenReaction | CC BY | 32672328 | 18,091,037 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Heart disease congenital'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | AZATHIOPRINE | DrugsGivenReaction | CC BY | 32672328 | 18,117,049 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, CALCIUM | DrugsGivenReaction | CC BY | 32672328 | 18,097,745 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, AZATHIOPRINE, CALCIUM, FERROUS SULFATE, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 32672328 | 19,222,337 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature baby'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, CALCIUM | DrugsGivenReaction | CC BY | 32672328 | 18,091,037 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature delivery'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, AZATHIOPRINE, CALCIUM, FERROUS SULFATE, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 32672328 | 19,222,337 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature labour'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, CALCIUM | DrugsGivenReaction | CC BY | 32672328 | 18,097,745 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature rupture of membranes'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, CALCIUM | DrugsGivenReaction | CC BY | 32672328 | 18,097,745 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Subcutaneous haematoma'. | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | ASPIRIN, AZATHIOPRINE, CALCIUM CARBONATE, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 32672328 | 18,414,674 | 2021 |
What was the administration route of drug 'ASPIRIN'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | Transplacental | DrugAdministrationRoute | CC BY | 32672328 | 18,091,037 | 2021 |
What was the administration route of drug 'AZATHIOPRINE'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | Transplacental | DrugAdministrationRoute | CC BY | 32672328 | 18,117,049 | 2021 |
What was the administration route of drug 'CALCIUM'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | Transplacental | DrugAdministrationRoute | CC BY | 32672328 | 18,091,037 | 2021 |
What was the dosage of drug 'AZATHIOPRINE'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | UNK (2.0 MG/KG) | DrugDosageText | CC BY | 32672328 | 18,414,674 | 2021 |
What was the dosage of drug 'CALCIUM CARBONATE'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | UNK (1.5 G) | DrugDosageText | CC BY | 32672328 | 18,414,674 | 2021 |
What was the dosage of drug 'FERROUS SULFATE'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY | 32672328 | 19,222,337 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | 05 MILLIGRAM, QD | DrugDosageText | CC BY | 32672328 | 18,414,674 | 2021 |
What was the outcome of reaction 'Subcutaneous haematoma'? | Twin pregnancy after kidney transplantation: case report and systematic review.
BACKGROUND
Kidney transplantation is associated with fertility restoration in more than 50% of women with chronic kidney disease. Pregnancy after transplantation may affect women's health and fetal development, with higher rates of abortion, fetal growth restriction, and neonatal deaths. Twin pregnancy is a condition of high-risk for adverse maternal and perinatal outcomes, and its occurrence in women with previous kidney transplantation is rare.
METHODS
32-year-old woman, recipient of living donor kidney transplantation, with a history of one pregnancy prior to transplantation, with current normal allograft function and no use of contraceptive method. At ten weeks of amenorrhea, ultrasound investigation showed a dichorionic diamniotic twin pregnancy. The following evaluation showed Chiari type II features in one fetus, and no detectable abnormality in the other one. There was appropriate blood pressure control with no need for an antihypertensive drug, and renal function remained normal without proteinuria. Calcium and a low dose of acetylsalicylic acid were used as preeclampsia prophylaxis. At 33 weeks of gestation, she presented premature rupture of membranes with spontaneous preterm labor. A cesarean section was performed due to the breech presentation of the first fetus. The patient persisted with normal graft function and without graft rejection during follow-up.
CONCLUSIONS
Twin pregnancies after kidney transplantation are rare, and it is most frequently associated with preterm birth. We reported a successful twin pregnancy after kidney transplantation, with good perinatal and maternal outcomes, and without graft rejection or dysfunction.
Background
Pregnancy is associated with several changes in kidney function, affecting the vascular, glomerular, and tubular components and resulting in increased renal clearance, decrease in blood pressure, and expansion of the intravascular volume 1. Advanced kidney disease disrupts the hypothalamic-pituitary-gonadal axis, reducing fertility in the absence of renal replacement therapy 2. Ovulatory cycles may begin as soon as one month after renal transplant 3, and fertility can be restored about six months after the procedure 2. Pregnancy post-transplantation may impact women’s health and fetal development, with high risk for maternal and fetal adverse events 2. The contraceptive method should be introduced before transplantation and maintained during the post-transplantation period, and it can be discontinued when it is determined that pregnancy would be relatively safe for the mother, her graft, and fetal development 3. It is recommended that women avoid pregnancy for at least one year after transplantation, due to the increased risk of potential graft dysfunction, rejection or failure, and increased risk of prematurity3.
One-third of pregnancies during transplantation ends in the first trimester, due to high rates of abortion. In the remaining cases, the occurrence of neonatal death is low, with congenital disabilities occurrence similar to that observed in healthy women 4. Small-for-date babies are frequent in pregnancies of transplant recipients and pregnancies of women with hypertension 4. Prognosis of pregnancy after kidney transplantation depends on many factors, including pre-conception kidney function, previous diagnosis and adequate control of chronic hypertension and diabetes, the incidence of opportunistic infectious diseases, and the occurrence of obstetric complications5 - 7. According to the American Society of Transplantation (AST) recommendations, pregnancy is allowable in the absence of rejection within the past year, adequate and stable graft function (serum creatinine less than 1.5 mg/dL, no or minimal proteinuria less than 500 mg/24h), no acute infections that may impact fetal growth and well-being, and maintenance of adequate immunosuppression at stable dosing3. Twin pregnancy after kidney transplantation is rare and considered an ultra-high-risk condition 8. Our study reported a successful twin pregnancy after kidney transplantation in a referral center in Brazil and performed a literature review about this issue.
Case Report
A 32-year-old woman, with chronic kidney disease (CKD) secondary to chronic glomerulonephritis, received a living donor kidney transplantation four years ago, with normal allograft function. The immunosuppressive therapy was tacrolimus 0.1 mg/kg bid, dose adjusted according to blood levels, azathioprine 2.0 mg/kg, and prednisone 5 mg/day. She had an obstetric history of one previous pregnancy before transplantation without complications, and currently not using any contraceptive method.
She presented at ten weeks amenorrhea, with pregnancy confirmed by serum human chorionic gonadotropin (hCG) test. There was no assisted fertilization treatment or hormonal use. Ultrasound showed a dichorionic diamniotic twin pregnancy with gestational age coincident to amenorrhea. Prenatal screening of infectious diseases and metabolic disorders at 12 weeks of gestational age showed no abnormalities. Renal function was normal (serum creatinine 0.78 mg/dL and urea level 27 mg/dL), without proteinuria in a 24-hour urine test (0.15 g). The patient presented normal parameters of blood test (hemoglobin of 12 g/dL, hematocrit 34.7%, platelets 212,000/mm3), normal aspartate aminotransferase and alanine aminotransferase levels (10 U/L and 13 U/L, respectively), normal serum bilirubin (1.0 mg/dL) and normal lactate dehydrogenase level (148 U/L). The patient had previous systemic arterial hypertension (SAH), but she presented normal blood pressure measurements before pregnancy in the sitting position after a five-minute rest and without antihypertensive drugs. In her first antenatal visit, she presented normal blood pressure measurement (120x80 mmHg) in the left lateral decubitus position after a five-minute rest, without any antihypertensive drugs. Because of her previous SAH, she received preeclampsia prophylaxis with a low dose of acetylsalicylic acid (100 mg) and calcium (1.5 g). The first-trimester ultrasound screening at 12 weeks was normal. The blood pressure remained stable without antihypertensive therapy. There was no change in the doses of immunosuppressive drugs, and the tacrolimus blood level remained between 3-6 ng/dL throughout the follow-up. The patient presented a reduction in the hemoglobin and hematocrit, reaching 9.6 g/dL and 29.4%, respectively, while the other laboratory parameters remained in the normal range, without the onset of proteinuria. She received iron supplementation with ferrous sulfate throughout the pregnancy.
Around 20 weeks of gestational age, an ultrasound showed multiple malformations in one of the fetuses. Such fetus had an estimated weight of 338 g, scalloping of the frontal bone (“lemon” sign), caudal displacement of the cerebellar vermis with obliteration of the cisterna magna (“banana” sign), mild ventriculomegaly, clubfeet and bifid spine with lumbosacral myelomeningocele, compatible with Chiari type II diagnosis. The other fetus had an estimated weight of 367 g without detectable abnormalities. At 28 weeks of gestational age, renal function remained stable (serum creatinine 0.79 mg/dL and urea 18mg/dL), with normal urinalysis and hematimetric parameters and negative gestational diabetes screening.
Assessment of fetal vitality at 33 weeks of pregnancy showed a non-reassuring pattern in cardiotocography test when she was referred for hospital admission. Ultrasound revealed adequate blood flow in umbilical arteries, and preeclampsia screening was negative, with mild impairment of renal function (serum creatinine 0.92 mg/dL and urea to 26 mg/dL). On the third day of hospitalization, the patient presented premature rupture of membranes, with spontaneous onset of labor within a few hours. A cesarean section was performed due to breech presentation of the first fetus. The first newborn’s weight was 2180g with an Apgar score of 9/10 at 1 and 5 minutes after childbirth, and the second newborn had the same weight and 10/10 Apgar score.
Four days after the cesarean section, a subcutaneous hematoma was diagnosed with spontaneous regression without surgical intervention. In late puerperium, the renal function returned to pre-conception values, without proteinuria. Screening for anti-human leukocyte antigens (HLA) antibodies was negative, and allograft biopsy performed in the first year post pregnancy revealed no rejection. Both children are alive and with normal growth. The child who presented malformations underwent orthopedic surgery, and remains in follow-up, with good clinical evolution and normal physical and cognitive development.
Methods of literature review
We performed a systematic review of the literature on PubMed. We searched from 1980 until December 2019, using the keywords “twin pregnancy” and “kidney transplantation”. Our search generated 33 articles. Three articles were excluded because they were written neither in English nor in Portuguese (two in French and one in Dutch). Of the remaining articles, five were excluded because the complete manuscript could not be found in any database (PubMed, BIREME, Scopus or Google Scholar); thirteen articles were excluded after abstracts were screened: two reported outcomes after liver transplantation; five had data about outcomes of renal transplantation in twin recipients; two articles had no reports of twin pregnancy; and four others were related to the aim of our systematic review [Figure 1]. We also reviewed studies with cases of Chiari II malformation related to the use of immunosuppressive drugs during pregnancy in this same period, but we did not find any report of this association.
Figure 1 Diagram for identification of studies for the systematic review.
Results
We screened 12 articles; of those, 8 were case-reports, 4 were retrospective cohorts. A total of 18 twin pregnancies were reported in the literature. Results of our systematic review are shown in Table 1.
Table 1. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation.
Author/Year/Location Ref. Number of pregnancies Number of twin pregnancies Complications in twin pregnancy
Romão (2019), Brazil 13 2 2 Triplet pregnancy with onset of hypertension and preterm birth (34 weeks) and twin pregnancy with cesarean at 37-4/7 weeks.
Gizzo (2014), Italy 14 1 1 Preterm birth (31 weeks) after onset of hypertension and proteinuria.
Farr (2014), Austria 8 13 1 Preterm birth (30 weeks) after renal function deterioring.
Rocha (2013), Portugal 10 24 1 No report of obstetrical, fetal or allograft function complications.
Kennedy (2012), Ireland 15 27 2 One of the twin pregnancy was miscarried at 10 weeks; other twin pregnancy had miscarriage of one fetus at age of 14 weeks and birth of the second fetus at age of 30 weeks.
Cheung (2010), United Kingdon 16 1 1 Preterm birth (32 weeks) after onset of hypertension with no allograft function complication.
Gutierréz (2009), Spain 17 30 3 No report of obstetrical, fetal or allograft function complications.
Khalaf (2000), United Kingdon 18 1 1 Preterm birth (30 weeks) after spontaneous premature labour.
Furman (1999), Israel 19 2 2 Preterm birth (36 and 33 weeks), the first due to fetal growth restriction and the second due to hypertension.
Vyas (1998), United States 20 1 1 Preterm birth (32 weeks) due to hypertension; the first newborn had a cardiac malformation secondary to use of azatioprine.
Prieto (1989), Spain 21 2 2 Preterm birth (both at 35 weeks), the first due to preeclampsia and the second due to spontaneous preterm labour.
Burrows (1988), United States 22 1 1 Preterm birth (33 weeks) due to preeclampsia.
Considering only the four retrospective cohorts that we analyzed, the prevalence of twin pregnancy was 10.94%. All case-reports presented an increased risk of preterm birth, with a mean gestational age of 32.6 weeks. One of the twin pregnancies progressed to complete miscarriage, while another twin pregnancy had a miscarriage of only one of the fetus. Significant complications related to allograft function were not reported.
Discussion
Adequate renal function (stated as creatinine levels lower than 1 mg/dL) is the main predictor of positive outcomes in pregnancies after kidney transplantation4 , 9. Physiological increase of blood volume and glomerular filtration rate may reduce serum levels of creatinine, which impairs its use as the only renal function marker during pregnancy 10. Changes in renal function occur in 10-18% of pregnancies after kidney transplantation, and early renal assessment and adequate treatment of the identified conditions are important in this population 7. Progression of renal function distress is highly associated with the onset of obstetric complications like preeclampsia or HELLP syndrome 4. Preterm birth is the most frequent complication associated with twin pregnancy, and all cases reported in our review were preterm 11.
Chronic hypertension and diabetes are frequently associated with CKD and may remain after kidney transplantation, which also affects pregnancy outcomes. The blood pressure target is lower than in general pregnancy, and it should be kept lower than 130x80 mmHg 2 , 10. Inflammatory activity in endothelium raises the risk of adverse effects during pregnancy, and the use of antihypertensive drugs may impact placental vascularization, with a higher occurrence of fetal growth restriction in this population 4. Due to the risk of teratogen effects of many antihypertensive drugs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), the therapeutic options for hypertension management are restricted and more challenging 2.
Most immunosuppressive drugs may cross the placental barrier, reaching fetal circulation. Calcineurin inhibitors, including cyclosporine and tacrolimus, are not associated with congenital disabilities 4. Considering this class of drugs, the use of tacrolimus reduced the occurrence of preeclampsia when compared with cyclosporine 4. Considering the antiproliferative drugs, mycophenolate is contraindicated in pregnant women because of its association with an increased risk of miscarriage during the first trimester and many possible malformations, including ears, limbs, heart, esophagus or kidney, and deformations in the upper oral tract, such as cleft lip and palate 4. Azathioprine is not associated with birth defects, although it can cause neonatal leukopenia in the first year of life4. There is limited knowledge about the potential side effects of sirolimus or everolimus in pregnancy, and they are considered contraindicated during pregnancy since its antiproliferative effect might harm the fetus and disturb the development of the unborn 4. Corticoids increase the risk of both hypertension and gestational diabetes. Daily use of more than 20 mg of prednisone may increase the risk of opportunistic infections and preterm labor. Long term use of low doses of steroids are not associated with birth defects but can be associated with thymus hypoplasia in the newborn 4 , 12.
The effect of pregnancy on immune status is controversial. There is a theoretical risk of sensitization by paternal HLA presented by the fetus. However, the occurrence of rejection during pregnancy is low due to the tolerance mechanism like HLA-G molecules, which inhibit T-lymphocytes, natural killer cells, and antigen-presenting cells 4.
The diagnosis of acute rejection is obtained through graft biopsy, but it is usually not possible during pregnancy due to the risks associated with the procedure. In suspected cases of acute rejection, high doses of corticoids may be indicated, although the safety of use of lymphocytes depleting or immunoglobulins during pregnancy is unknown 2 , 7.
Kidney allograft is usually implanted in the iliac fossa, with no mechanical influence, and under the uterus. Also, the allograft is not an obstacle to surgical delivery, and the mode of delivery may follow an obstetric indication, however, pregnancy should not exceed the 40th week 3 , 7 , 12.
Conclusion
Kidney transplantation increases obstetrical risks, and pregnancy may be planned and followed by multidisciplinary antenatal care. Contraceptive methods are essential in the pre- and post-transplant period. The gestation in transplant recipient women should be planned, and a multidisciplinary evaluation is crucial, with adequate treatment of comorbidities and adjustment of immunosuppressive therapy. Preterm birth is the most frequent complication associated with a twin pregnancy. Adequate renal function is the main predictor of good outcomes in post-transplant pregnancy, and a frequent renal function evaluation is mandatory. After pregnancy, the majority of women recover previous renal function, and immunosuppressive drugs must be adjusted. | Recovered | ReactionOutcome | CC BY | 32672328 | 18,414,674 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain lower'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,078,799 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inflammation'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intestinal obstruction'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intestinal perforation'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paradoxical drug reaction'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peritonitis'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small intestinal obstruction'. | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, PYRAZINAMIDE, RIFAMPIN | DrugsGivenReaction | CC BY-NC | 32674552 | 20,078,799 | 2021-07 |
What was the outcome of reaction 'Abdominal pain lower'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Ascites'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,078,799 | 2021-07 |
What was the outcome of reaction 'Constipation'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Inflammation'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Intestinal obstruction'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Intestinal perforation'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Paradoxical drug reaction'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Peritonitis'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Pyrexia'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,169,638 | 2021-07 |
What was the outcome of reaction 'Small intestinal obstruction'? | Intestinal Perforation as a Paradoxical Reaction to Antitubercular Therapy: A Case Report.
Paradoxical reactions to tuberculosis (TB) treatment are characterized by an initial improvement of the clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions, or by development of new lesions. Intestinal perforation in gastrointestinal TB can occur as a paradoxical reaction to antitubercular therapy. A 55-year-old man visited the outpatient department with lower abdominal pain and weight loss. He was diagnosed with intestinal TB and started antitubercular therapy. After 3 months of antitubercular therapy, a colonoscopy revealed improvement of the disease. Three days after the colonoscopy, the patient visited the emergency room complaining of abdominal pain. Abdominal computed tomography revealed extraluminal air-filled spaces in the pelvic cavity. We diagnosed a small bowel perforation and performed an emergency laparotomy and a right hemicolectomy with small bowel resection. This report describes the case of intestinal perforation presenting as a paradoxical reaction to antitubercular and provides a brief literature review.
INTRODUCTION
In 2018, extrapulmonary tuberculosis (TB) accounted for approximately 15% of all TB cases. Gastrointestinal TB accounts for 3% to 19% of cases of extrapulmonary TB [1]. Complications of gastrointestinal TB include obstruction, fistula formation, and intestinal perforation [2]. The incidence of intestinal perforation due to gastrointestinal TB is 4% to 7.6%, while the associated mortality rate is 30%. While intestinal perforation can occur before or during antitubercular therapy [3], the latter presentation is rare and is suspected to be a possible paradoxical reaction.
Paradoxical reactions to TB treatment are characterized by an initial improvement of clinical symptoms followed by clinical or radiological deterioration of existing tuberculous lesions or by the development of new lesions [4, 5]. Paradoxical reaction is identified in 6% to 30% of patients receiving antitubercular therapy [5].
We report a case of intestinal perforation that occurred while a patient with normal immunity was being treated with antitubercular drugs for intestinal TB. This report was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2020-01-017) and the written informed consent was received from the patient.
CASE REPORT
A 55-year-old man presented with a 2-month history of lower abdominal pain and diarrhea. He had lost 6 kg of weight since the symptoms started. Colonoscopy revealed transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve (Fig. 1A). Histopathological examination revealed chronic granulomatous inflammation of the ileocecal mucosa with infiltration by histocytes and thin epithelioid cells (Fig. 1B). The TB polymerase chain reaction test was negative, but the interferon gamma release assay was positive, which helped us to determine the diagnosis of intestinal TB. The patient’s chest X-ray showed increased opacity of the right upper lobe (Fig. 2A), but he had no respiratory symptoms, such as cough or expectoration. He began antitubercular therapy with a once-daily regimen of isoniazid (400 mg), rifampin (600 mg), ethambutol (800 mg), and pyrazinamide (1,500 mg).
After 4 weeks of antitubercular therapy, the patient presented with cough and expectoration. The results of both sputum smear acid-fast bacilli (AFB) examination and sputum culture were negative. Chest computed tomography (CT) showed infiltration and ill-defined centrilobular nodules with patchy opacity and multifocal tree-in-bud patterns at bilateral upper lobes, leading to the diagnosis of active pulmonary TB (Fig. 2B).
After 2 months of undergoing the 4-drug therapy, the regimen was changed to a 3-drug regimen of isoniazid (400 mg), ethambutol (800 mg), and rifampin (600 mg) daily. The patient’s symptoms of lower abdominal pain, diarrhea, cough, and expectoration were resolved, and he experienced no adverse effects apart from a mild rash.
A repeat colonoscopy was performed to evaluate treatment response after the patient completed 3 months of TB treatment. The ulcers, previously extending from the ileocecal valve till the cecum, had decreased in size. However, scars remained, associated with circular narrowing of the intestinal lumen. Localized inflammation had subsided (Fig. 3A). A microscopic examination of the ileocecal biopsy sample revealed chronic, nonspecific inflammation (Fig. 3B). We, therefore, decided to continue the patient on antitubercular drugs for a further 3 months as recommended.
Three days after the second colonoscopy, the patient came to the emergency room complaining of lower abdominal pain and constipation. On examination of his vital signs, his blood pressure, pulse rate, respiratory rate, and body temperature were 114/62 mmHg, 86 beats/min, 24 breaths/min, and 37.3°C, respectively. Signs of localized tenderness and rebound tenderness were elicited on lower abdominal palpation. Laboratory tests showed a white blood cell (WBC) count of 14,800/mm3 (with 90.3% segmented neutrophils), hemoglobin of 15.4 g/dL, platelet count of 321,000/mm3, and a C-reactive protein (CRP) of 0.7 mg/dL. Abdominal CT showed multisegmental wall thickening and luminal narrowing of the distal and terminal ileum, associated with partial small bowel obstruction, peritoneal inflammation, and complicated ascites (Fig. 4A). The patient was diagnosed with a small bowel obstruction with peritonitis. We performed bowel decompression using a Levin tube and administered antibiotics.
The patient did not report a lessening of lower abdominal pain, even on the second day of hospitalization, and developed a fever of > 38°C. Blood tests revealed that his WBC count and CRP level had increased to 20,200/mm3 and 31.3 mg/dL, respectively. A repeat abdominal CT revealed multiple, extraluminal, air-filled spaces in the pelvic cavity (Fig. 4B). We diagnosed small bowel perforation and performed an emergency laparotomy. Intraoperative examination revealed an ileal perforation at a distance of 100 cm, proximal to the ileocecal valve. Some stricturing lesions were observed from the perforation site to the ileocecal valve.
We performed an ileocecectomy (Fig. 5A); 100-cm-long distal ileum and an 11-cm-long colon, along with the IC valve, were excised. Postoperative histopathological examination of the resected bowel revealed a perforated ulcer with acute transmural suppurative inflammation (Fig. 5B).
Five days after the operation, the patient resumed oral feeding and was discharged on the 8th day after surgery. Antitubercular therapy was terminated after a further 3 months. The patient has been followed up for 2 years after the surgery and has remained asymptomatic. He has provided informed consent for the use of his medical information in this case report.
DISCUSSION
Extrapulmonary TB can affect lymph nodes, pleura, bones, the central nervous system, and the abdomen [2]. Gastrointestinal TB is the commonest presentation of abdominal TB and has been reported to account for 17% of all extrapulmonary cases.
Complications associated with gastrointestinal TB may include obstruction, perforation, fistula formation, and gastrointestinal bleeding. Risk factors for increased morbidity and mortality in patients with tuberculous intestinal perforation include delayed surgical treatment, multiple sites of perforation, concomitant corticosteroid therapy, anastomotic leaks, advanced age, and primary closure of the perforation [3, 4]. Considering the high mortality associated with intestinal TB, an operative resection of the affected portion of the intestine, followed by anastomosis, is preferred to primary closure [6]. Intestinal TB occurs mainly in the ileocecal region, with perforation commonly involving the ileal mucosa. Perforation can occur at single or multiple sites and may be associated with the formation of intestinal strictures or ulceration. As most perforations are stricture-related, small-intestinal perforations are more common than large-intestinal perforations. Perforation may occur before or after starting antitubercular therapy [3]. Intestinal perforation occurring during or after completion of antitubercular therapy can be a paradoxical reaction to treatment.
Paradoxical reactions have been observed in patients with TB affecting the nervous system, respiratory system, skin/soft tissue, lymph nodes, and the abdomen, in decreasing order of frequency. According to one report, approximately 75% of patients experience worsening of their primary lesions, and approximately 25% develop new lesions at other sites [5]. Risk factors for paradoxical reactions include extrapulmonary tuberculous lesions, a relatively low basal lymphocyte level in peripheral blood, and a sudden rise in the lymphocyte count during treatment [7].
The pathophysiological mechanism of paradoxical reaction to TB treatment is not fully understood. Increased exposure to mycobacterial antigens released from the bacilli, killed due to effective antitubercular therapy, strengthens delayed hypersensitivity of the host. Differential diagnoses of paradoxical reactions include diagnostic errors, inadequate response due to drug resistance, and poor adherence to therapy. Therefore, it is important to culture the affected tissue specimen at the time of the initial diagnosis to confirm the diagnosis and to determine the baseline level of drug resistance [2].
It is difficult to distinguish paradoxical reactions from treatment failures. When paradoxical reaction is suspected, continuing treatment is necessary. Surgeons may help determine appropriate surgical procedures for conditions such as intestinal TB, when paradoxical reactions require surgical treatment.
Our patient had 2 paradoxical reactions. The first was a paradoxical respiratory reaction. The initial chest X-ray had shown increased opacity of the right upper lobe, despite the absence of respiratory symptoms, such as cough and expectoration. He developed respiratory symptoms 4 weeks after starting antitubercular therapy, with findings of active TB on the chest CT. Some patients develop negative sputum AFB staining and culture results after completing 1 month of antitubercular therapy. Our patient experienced relief of his respiratory symptoms with concomitant improvement in his radiological findings after completing 6 months of treatment. The second paradoxical reaction was the intestinal reaction. The patient’s abdominal pain decreased after 3 months of treatment, and colonoscopy revealed an improvement in ulcerative lesions. However, the patient subsequently suffered a small bowel perforation, which required emergency surgical intervention. It was unclear whether the lesions were preexisting or new lesions because there was no test for small intestine lesions before treatment began. It is thought to be a clinical deterioration of the lesion that was already present. Since the patient had already been treated for 3 months, the TB lesions were not clearly visible in the postoperative biopsy. Blumberg et al. [8] recommended that a diagnosis of paradoxical reaction should be considered if symptomatic deterioration occurs within 3 months of starting antituberculous drugs, while that occurring 4 months or more after may be attributable to treatment failure or multidrug-resistance. Our patient experienced worsening of his clinical symptoms within 3 months, increasing the likelihood of it being a paradoxical reaction.
Table 1 summarizes case reports of intestinal perforation occurring as a paradoxical reaction [3, 4, 9-15]. The mean age of affected patients was 39 years, and 10 out of 11 were males. The primary sites affected were mostly the lung and the abdomen. It took an average of 4.1 months from the initiation of antitubercular drugs to the occurrence of perforation. Therefore, it is important to carefully monitor patients with intestinal TB for intestinal perforations undergoing treatment for intestinal TB. Most patients underwent segmental resection and right hemicolectomy. The antitubercular drugs were continued after surgery, and most patients showed good postoperative recovery except for one patient with duodenal perforation [9].
We diagnosed our patient with ileocecal TB and started antitubercular therapy. However, as the initial evaluation of his small bowel lesion was inadequate, and so we were unable to predict the risk of occurrence of a paradoxical reaction. Therefore, in patients with suspected intestinal TB, evaluation of small bowel lesions with abdominal CT, in addition to colonoscopy, may be helpful in early diagnosis and enable prompt surgical treatment of complications such as small bowel perforation.
In conclusion, this case report describes a patient who experienced a small bowel perforation as a paradoxical reaction to the treatment for intestinal TB. We recommend a thorough baseline evaluation of the small bowel be conducted to assist clinicians with the prevention, diagnosis, and management of small bowel perforations occurring as a paradoxical reaction to antitubercular therapy.
Fig. 1. (A) Photograph taken during the initial colonoscopy image showing transverse ulcerative lesions with clear borders and dirty exudates around the ileocecal valve. (B) Stained section of the ileocecal mucosa showing chronic granulomatous inflammation with infiltration by histocytes and thin epithelioid cells (H&E, ×200).
Fig. 2. (A) An image of the initial chest X-ray showing increased opacity of the right upper lobe. (B) Chest computed tomography, scan performed 4 weeks after starting antitubercular therapy, showing findings typical of active pulmonary tuberculosis, including infiltration and ill-defined centrilobular nodules with patchy opacity and bilateral multifocal tree-in-bud patterns in the upper lobes.
Fig. 3. (A) Colonoscopy image after completion of 12 weeks of antitubercular therapy showing reduced mucosal ulceration (which had previously extended from the ileocecal valve to the cecum), and an absence of inflammation, although scars with circular narrowing persist. (B) Histopathological examination of the intestinal biopsy sample (after completing 12 weeks of antitubercular therapy) showing chronic, nonspecific inflammation (H&E, ×200).
Fig. 4. (A) Abdominal computed tomography (CT) scan showing multisegmental wall thickening and luminal narrowing of the terminal and distal ileum with partial small bowel obstruction, peritonitis, and complicated ascites. (B) Repeat abdominal CT scan showing multiple, extraluminal air-filled spaces in the pelvic cavity, indicating intestinal perforation (arrow).
Fig. 5. (A) Intraoperative photograph showing suppurative inflammation on serosal surface of small bowel. (B) Luminal surface of the specimen. (C) Section of the resected bowel showing a perforated ulcer and acute, transmural, suppurative inflammation (H&E, ×40).
Table 1. Reported cases of intestinal perforation secondary to a paradoxical reaction in patients with intestinal tuberculosis (TB)
Study Age (yr) Sex HIV Status Tuberculosis TB agent used during treatmenta Time to perforation Perforation site No. of perforations Surgery Outcome
Lee et al. [3] 36 Male Negative Laryngeal, abdominal, miliary INH, RFP, EMB, PZA, MXF, CIP, AMK, STM 6 Mo Ileum 1 Laparostomy Recovered
Lee et al. [3] 26 Male Negative Pulmonary, abdominal INH, RFP, EMB, PZA 6 Mo Jejunum 1 Segmental resection Recovered
Leung et al. [4] 63 Male Negative Pulmonary INH, RFP, EMB, PZA, levofloxacin 108 Day Terminal ileum 1 Right hemicolectomy Recovered
Qureshi et al. [9] 14 Male Negative Abdominal Unknown 4 Mo Duodenum 1 Tube duodenostomy Death
Liao et al. [10] 52 Male Negative Pulmonary INH, RFP, EMB, PZA 1. 20 Day 1. Mid-jejunum 3 1. Segmental resection Recovered
2. 71 Day 2. Terminal ileum 2. Segmental resection
3. 146 Day 3. Ileocecal junction 3. Right hemicolectomy
Patel et al. [11] 26 Male Negative Pulmonary Triple therapyb 6 Mo Jejunum 1 Segmental resection Recovered
Sherpa et al. [12] 21 Male Negative Abdominal Unknown 2 Mo Distal ileum 1 Primary closure Recovered
Naveen and Mukherjee [13] 54 Male Negative Pulmonary INH, RFP, EMB, PZA 7 Mo Jejunum 1 Segmental resection Recovered
Saitou et al. [14] 61 Male Negative Pulmonary, intestinal, miliary INH, RFP, EMB, PZA 97 Day Ileocecal junction 1 Right hemicolectomy Recovered
Bellido Caparo et al. [15] 22 Female Negative Pulmonary, abdominal, ganglionar INH, RFP, EMB, PZA 3 Mo Cecum 1 Right hemicolectomy Recovered
Present case 55 Male Negative Abdominal, pulmonary INH, RFP, EMB, PZA 3 Mo Ileum 1 Ileocecectomy Recovered
HIV, human immunodeficiency virus.
a Anti-TB agents: INH, isoniazid; RFP, rifampicin; EMB, ethambutol; PZA, pyrazinamide; MXF, moxifloxacin; CIP, ciprofloxacin; AMK, amikacin; STM, streptomycin.
b INH, STM, and para-aminosalicylic acid.
No potential conflict of interest relevant to this article was reported. | Recovered | ReactionOutcome | CC BY-NC | 32674552 | 20,078,799 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Antinuclear antibody increased'. | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 32676896 | 19,097,550 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | PREDNISOLONE | DrugsGivenReaction | CC BY | 32676896 | 19,059,249 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polyarthritis'. | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 32676896 | 19,097,550 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rebound effect'. | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 32676896 | 19,097,550 | 2021-02 |
What was the administration route of drug 'PREDNISOLONE'? | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | Oral | DrugAdministrationRoute | CC BY | 32676896 | 19,059,249 | 2021-02 |
What was the outcome of reaction 'Hepatic function abnormal'? | Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is defined as primary glomerulonephritis with predominant glomerular IgA deposition. However, glomerular IgA deposition is found not only in IgAN but also in other systemic diseases like gastrointestinal and liver diseases, autoimmune disorders, neoplasia and infections [1]. It is important to differentiate primary IgAN from secondary IgAN, because therapeutic strategy is different depending on the underlying primary disease. However, it is not easy to distinguishing primary IgAN from secondary IgAN, if the patient has comorbidities which could induce secondary IgAN. Previous studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) is specifically involved in the pathogenesis of primary IgAN [2, 3]. Recently, the method of measuring serum levels of Gd-IgA1 using monoclonal antibody against Gd-IgA1 (KM55 mAb) has been established [4]. Besides, we reported that KM55 mAb could detect Gd-IgA1 deposition in glomeruli in the cases of primary IgAN, but not in other renal diseases [5]. Thus, histological analysis using KM55 mAb may be a strong tool for differentiating primary IgAN from secondary IgAN. Here, we show 4 cases which we could make definitive diagnosis by immunostaining with KM55 mAb.
Case reports
Case 1
A 44-year-old woman had presented hematuria and proteinuria from 7 years ago. She was admitted to perform renal biopsy in our hospital. Besides, she has showed PIP joints pain for several years. Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) showed positive. Thus, rheumatoid arthritis (RA) was diagnosed by rheumatologist.
Blood examination showed Cr 0.43 mg/dl, eGFR 121.8 mL/min/1.73 m2, IgG 1429 mg/dl, IgA 653 mg/dl, C3 72 mg/dl, RF 734.4 IU/ml, anti-CCP-Ab 6.2 IU/ml. Antinuclear antibodies (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), proteinase3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), anti-glomerular basement membrane antibodies (anti-GBM), and cryoglobulins were negative. Urinalysis showed urine protein–creatinine ratios (UPCR) 2.4 g/gCr, urinary red blood cells (U-RBC) 11–15/high-power field (HPF).
Light microscopic finding (LM) revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. Immunofluorescence analysis (IF) revealed mesangial deposition of IgA and C3. Mesangial and capillary deposition of IgG and IgM also noted. (Fig. 1).Fig. 1 Light microscopic findings and immunofluorescence staining of IgG, IgA, IgM, C3 and C1q in cases 1–4. All four cases showed mesangial proliferative lesions and positive for IgA and C3. PAS Periodic Acid–Schiff stain. Original magnification ×400
Based on the pathological findings, we diagnosed as IgAN. To exclude secondary IgAN caused by RA, immunostaining with KM55 mAb was performed. Finally, we diagnosed as primary IgAN due to positive staining of KM55 mAb colocalized with IgA deposit area (Fig. 2).Fig. 2 Immunofluorescence staining of IgA, KM55 and merge image in cases 1–4. Cases 1, 2 and 4 showed positive for KM55. Case 3 showed negative for KM55. Original magnification ×400
According to the diagnosis of primary IgAN, tonsillectomy with steroid pulse (TSP) therapy was performed. Urinary abnormalities has been gradually improved and achieved clinical remission (CR) afterward (Fig. 3). CR defined as three consecutive negative results over a 6-month period in urinary occult blood tests; urinary sediment red blood cell count of < 5/HPF; and urinary protein of < 0.3 g/day [6]. After TSP therapy, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).Fig. 3 Clinical courses of cases 1–4. mPSL methylprednisolone, PSL prednisolone, MTX methotrexate, QD once daily, QOD every other day, QW once a week, eGFR estimated glomerular filtration rate [mL/min/1.73 m2], UPCR urine protein–creatinine ratio [g/gCr], U-RBC urinary red blood cells, HPF high-power field, SVR sustained virological response
Table 1 Serum levels of IgA, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1/IgA ratio before and after tonsillectomy with steroid pulse (TSP) therapy (in cases 1, 2 and 4) and serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio at diagnosis (in case 3)
IgA (mg/dl) Gd-IgA1 (ng/ml) Gd-IgA1/IgA
Case 1 (Before TSP) 653 8542.2 13.1
Case 1 (After TSP) 388 4746.8 12.2
Case 2 (Before TSP) 282 7277.0 25.8
Case 2 (After TSP) 258 4911.5 19.0
Case 3 (At diagnosis) 338 3164.2 9.4
Case 4 (Before TSP) 502 8570.6 17.1
Case 4 (After TSP) 323 5063.3 15.7
Clinical symptoms of RA initially getting better by steroid therapy. However, after tapering steroid dosage, PIP joints pain has gradually getting worse without relapse of urinary abnormalities. Thus, treatment with methotrexate (MTX) was started after finishing steroid therapy. Currently, the disease activity of RA has been under control with MTX treatment and urinary findings have also maintained remission.
Case 2
A 42-year-old woman who was diagnosed as systemic lupus erythematosus (SLE) when she was 39 years old with the findings of polyarthritis, positive for ANA (1:640, homogeneous and speckled pattern) and anti-ds-DNA Ab, lymphocytopenia, and proteinuria (0.5–1.0 g/gCr). She had been followed by rheumatologist without any treatment. However, proteinuria and hematuria had been persisted. Thus, a renal biopsy was performed for definitive diagnosis.
Blood examination showed Cr 0.35 mg/dl, eGFR 177.8 mL/min/1.73m2, IgG 1214 mg/dl, IgA 282 mg/dl, C3 103 mg/dl. ANA, anti-ds-DNA. anti-SS-A, anti-SS-B, RF, and anti-CCP were positive. MPO-ANCA, PR3-ANCA, anti-GBM, and cryoglobulins were negative. Urinalysis showed UPCR 0.64 g/gCr and U-RBC > 50/HPF.
LM revealed mild mesangial cell proliferation and increase of mesangial matrix. IF showed mesangial deposition of IgA and C3, but negative for C1q that is atypical for lupus nephritis (Fig. 1). Based on the pathological findings, we could not diagnose definitively IgAN or lupus nephritis. Then, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Moreover, level of Gd-IgA1 significantly decreased (Table 1).
Disease activity of SLE had been relatively stable during steroid usage. However, after discontinuation of steroid treatment, polyarthritis exacerbated and serum level of anti-ds-DNA Ab gradually elevated. She has been followed by rheumatologist. Currently, induction of additional immunosuppression therapy is considered. Both proteinuria and hematuria have been able to maintain remission.
Case 3
A 63-year-old man had presented with proteinuria (0.5–1.0 g/gCr) from 7 years ago. Proteinuria progressed to around 5.0 g/gCr. A renal biopsy was performed for definitive diagnosis. Besides, he had hepatitis C (HCV) without any anti-viral treatment.
Blood examination showed Cr 0.74 mg/dl, eGFR 114.3 mL/min/1.73m2, IgG 1905 mg/dl, IgA 338 mg/dl, C3 120 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. HCV-RNA showed as 5.6 LogIU/mL. HCV subtyping showed type 1b. Urinalysis showed UPCR 3.6 g/gCr and U-RBC showed 1–4/HPF. Serum level of Gd-IgA1 was low, compared with cases 1, 2 and 4 (Table 1).
LM revealed mesangial cell proliferation and increase of mesangial matrix as well as endocapillary proliferation. IF showed slightly positive for IgA and C3 in mesangial area (Fig. 1). IgG also showed weakly positive in capillary area. For the presence of active inflammatory lesions, such as endocapillary proliferation, we diagnosed as active IgAN with massive proteinuria.
Initially, we considered to arrange steroid pulse therapy to treat acute lesions. However, for the complication of HCV, steroid therapy would be the risk of its activation. We decided to administer oral steroid therapy instead of steroid pulse therapy after discussing with gastroenterologist.
After informed consent, we started steroid therapy with close monitoring of liver function. However, improvement of proteinuria was limited and the liver function gradually getting worse. Thus, we stopped steroid therapy and performed immunostaining with KM55 mAb for definitive diagnosis. Finally, we diagnosed as HCV-related nephropathy (HCV-RN) due to negative staining of KM55 mAb in glomeruli (Fig. 2).
After the diagnosis of HCV-RN, we consulted gastroenterologist for HCV treatment. Antiviral therapy with daclatasvir and asunaprevir was arranged. Proteinuria has been gradually improved by the antiviral treatment (Fig. 3). HCV also achieved sustained virological response (SVR).
Case 4
A 35-year-old man presented with proteinuria and hematuria which were noted by regular health check. No abnormal urinalysis was noted until three years ago. A renal biopsy was performed for definitive diagnosis. He was diagnosed with Crohn’s disease (CD) when he was 29 years old. The disease activity of CD was stable under treatment with mesalazine and adalimumab.
Blood examination showed Cr 1.06 mg/dl, eGFR 76.6 mL/min/1.73 m2, IgG 1304 mg/dl, IgA 502 mg/dl, C3 93 mg/dl, CRP 0 mg/dl. ANA, RF, MPO-ANCA, PR3-ANCA, anti-GBM and cryoglobulins were negative. Urinalysis showed UPCR 0.56 g/gCr and U-RBC > 50/HPF.
LM revealed mesangial cell proliferation and increase of mesangial matrix. IF showed positive for IgA and C3 in mesangial area (Fig. 1). To distinguish primary IgAN and secondary IgAN with CD, immunostaining with KM55 mAb was performed and showed its positive staining colocalized with IgA (Fig. 2). Finally, we diagnosed as primary IgAN. After TSP therapy, urinary abnormalities have been gradually improved and achieved CR (Fig. 3). Furthermore, serum levels of IgA and Gd-IgA1 significantly decreased (Table 1).
Discussion
There are increasing evidences that Gd-IgA1 play a pivotal role in the pathogenesis of IgAN [7]. Elevations of serum Gd-IgA1 levels and mesangial deposition of Gd-IgA1 were reported in patients with IgAN [3, 5]. Multi-hit hypothesis which includes (Hit 1) production of Gd-IgA1, (Hit 2) IgG or IgA autoantibodies that recognize Gd-IgA1, (Hit 3) their subsequent immune complexes formation and (Hit 4) glomerular deposition was advocated as the most probable pathogenesis of IgAN [2].
Gd-IgA1 is thought to be induced by abnormal mucosal immune responses mainly at the upper respiratory tract including tonsil [8]. In fact, clinical efficacy of tonsillectomy in patients with IgAN has been reported by meta-analysis [9] and recent large retrospective cohort study with propensity score matching [10]. Besides, our group also reported decrease of serum level of Gd-IgA1 just after tonsillectomy associated with the improvement of hematuria [11].
Secondary IgAN is thought to be containing a wide disease spectrum [1]. In the clinical settings, secondary IgAN should be taken into account when systemic comorbidities exist. However, differential diagnosis of primary IgAN from secondary IgAN is not easy, because there are no specific histological features to distinguish them. Secondary IgAN can be diagnosed only by the effectiveness of treating underlying systemic comorbidities. At least, tonsillectomy do not improve secondary IgAN. Whether secondary IgAN shares the common pathogenic process with primary IgAN or not is still unclear and needs further investigation.
According to the previous report, glomerular Gd-IgA1 was specifically detected in IgAN but not in the other types of glomerular diseases [5]. Thus, if Gd-IgA1 involvement is proved by immunohistochemical analysis with KM55 mAb, abnormal mucosal immune response might be related to the pathogenic process, and tonsillectomy might be useful for disease control.
In the present cases, the case with RA, SLE and CD (cases 1, 2, and 4) showed positive for KM55 mAb and no correlation between the disease activity of systemic disease and urinary abnormalities. Thus, we diagnosed as primary IgAN. Those three cases showed improvement of urinary abnormalities by TSP therapy. To demonstrate that TSP therapy improved mesangial inflammation caused by Gd-IgA1 deposition diagnosed by KM55 immunostaining, we measured the level of Gd-IgA1 in all cases by KM55 enzyme-linked immunosorbent assay (ELISA) and showed in Table 1. It is clearly indicated that serum levels of IgA, Gd-IgA1 and Gd-IgA1/IgA ratio decreased by TSP therapy. On the other hand, the case with HCV (case 3) showed negative for KM55 mAb. Finally, we diagnosed as HCV-RN. This case showed improvement of urinary abnormalities with anti-viral therapy. All cases successfully achieved remission. Thus, immunohistochemical analysis of KM55 mAb can tell us whether Gd-IgA1 is involved in the pathogenesis or not and even help us to determine therapeutic strategy.
Most of the patients with IgAN show slowly progressive clinical course. Thus, we suggest physicians to treat the comorbidity first, if its activity was severe, even if glomerular Gd-IgA1 showed positive [5]. However, the possibility of KM55-positive secondary IgAN cannot be totally excluded, because IL-6 and IL-4 accentuated galactose deficiency of IgA1 during mucosal infections [12]. Further investigations to elucidate glomerular Gd-IgA1 in case with IgAN accompanied by comorbidities are necessary.
In conclusion, present cases suggested that immunohistochemical analysis using KM55 mAb is a strong tool for differentiation of primary IgAN from secondary IgAN, and enables us to provide appropriate treatment individually.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgment
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
All the authors declared no competing interests.
Human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the patient described in the present case. | Not recovered | ReactionOutcome | CC BY | 32676896 | 19,059,249 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aggression'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fear'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Memory impairment'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Seizure'. | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | DIAZEPAM, GLYCOPYRRONIUM, METHOHEXITAL, MIDAZOLAM, QUETIAPINE, RISPERIDONE, SODIUM CITRATE, SUCCINYLCHOLINE | DrugsGivenReaction | CC BY | 32681216 | 18,925,800 | 2021-01 |
What was the administration route of drug 'DIAZEPAM'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | Transplacental | DrugAdministrationRoute | CC BY | 32681216 | 18,981,999 | 2021-01 |
What was the administration route of drug 'GLYCOPYRROLATE'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | Transplacental | DrugAdministrationRoute | CC BY | 32681216 | 19,615,399 | 2021-01 |
What was the administration route of drug 'RISPERIDONE'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | Transplacental | DrugAdministrationRoute | CC BY | 32681216 | 18,981,999 | 2021-01 |
What was the dosage of drug 'GLYCOPYRROLATE'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | 0.2 MG | DrugDosageText | CC BY | 32681216 | 19,615,399 | 2021-01 |
What was the dosage of drug 'GLYCOPYRRONIUM'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | 0.2 MG | DrugDosageText | CC BY | 32681216 | 18,981,999 | 2021-01 |
What was the dosage of drug 'MIDAZOLAM'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | 1.5 MG | DrugDosageText | CC BY | 32681216 | 19,615,399 | 2021-01 |
What was the dosage of drug 'SODIUM CITRATE'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | 30 ML (0.3 MOLAR) | DrugDosageText | CC BY | 32681216 | 18,981,999 | 2021-01 |
What was the dosage of drug 'SUCCINYLCHOLINE'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | 1.5 MG/KG | DrugDosageText | CC BY | 32681216 | 18,981,999 | 2021-01 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | Electroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions.
BACKGROUND
Psychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.
OBJECTIVE
Description of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.
METHODS
Clinical case report and selective review of the literature with special consideration of existing systematic reviews.
CONCLUSIONS
This case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.
Hintergrund
Schwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.
Die Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.
In manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.
Die Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter Fetus/Neugeborenes
Prolongierte Anfälle Bradykardie/Arrhythmie
Uteruskontraktionen ohne Frühgeburt Frühgeburt
Abdominelle Schmerzen Abort/Totgeburt
Vaginale Blutung Kongenitale Anomalien
Plazentalösung Intrauterine Wachstumsrestriktion
Hämaturie Neonatales Atemnotsyndrom
Präeklampsie Mentale Retardierung
Sectio
In einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.
Ziel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.
Methoden
Neben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.
Fallbericht
Psychiatrie
Die 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.
Es wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.
Aufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.
Der Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.
Anästhesie
Das regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].
Ab der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).
Die Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.
Nach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].
Bei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.
Gynäkologie und Geburtshilfe
Einen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.
Aufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.
Zur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].
Hinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).
Gemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.
Neonatologie
Anders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.
Bereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.
Ergebnisse
Klinischer Fall
Im dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.
Vorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft
Basierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet Behandlungsvorschlag
Psychiatrie Aufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung
Die Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]
Interdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie
Gynäkologie/Geburtshilfe Vor Beginn der EKT-Serienbehandlung
Adäquate präpartale Versorgung:
– Anlegen bzw. Vervollständigen des Mutterpasses
– regelmäßige Vorstellung in Schwangerensprechstunde
– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)
Qualifizierter Ultraschall mit Bestimmung von
– fetalem Gewicht
– Fruchtwassermenge
– plazentarer Versorgung (Dopplersonographie)
– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)
CTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen
Lungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“
Während bzw. nach jeder EKT
Notsectiobereitschaft
CTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT
Vaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)
Anästhesiologie Sorgfältige Anamnese
Hinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)
Vor Beginn der EKT
Nüchternheitszeiten strikt einhalten
Gabe von Natriumcitrat per os
Frühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion
Gabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion
Während EKT
Leichte Linkslagerung
Suffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)
Normoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation
Engmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)
Nach EKT
Nebenwirkungsmanagement:
– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche
– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)
Neonatologie Sicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung
Nutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)
Kenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)
Benennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet
Diskussion
Unser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.
Letztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].
Aus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.
Aufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.
In Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.
Fazit für die Praxis
Die EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.
Eine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.
Die kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.
Ein abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.
Die Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
D. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. | Recovered | ReactionOutcome | CC BY | 32681216 | 19,615,399 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
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Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ACYCLOVIR, DEXAMETHASONE, ELOTUZUMAB, POMALIDOMIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 32683487 | 19,057,439 | 2021-01 |
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