Acute toxic reaction to carbamazepine: Clinical effects and serum concentrations

PEDIATRIC PHARMACOLOGY AND THERAPEUTICS

Acute toxic reaction to carbamazepine' Clinical effects and serum concentrations J a m e s Tibballs, MBBS,BMedSci(Hons) From the Intensive Care Unit, Royal Children's Hospital, Melbourne, Australia The clinical spectrum of toxic effects a n d serum concentrations after ingestion of c a r b a m a z e p i n e were studied in 82 pediatric patients. Serum c a r b a m a z e p i n e level was related to the depth of c o m a (p <0.001), convulsions (p = 0.002), hypotension (p <0.001), and the requirement for m e c h a n i c a l ventilation (p <0.001). In 10 patients in d e e p c o m a with a Glasgow Coma Scale (GCS) of 3-4, the mean serum level was 213/~mol/L (range 143 to 343); seizures, ventilatory failure, or hypotension caused by m y o c a r d i a l failure and c o n d u c t i o n defects were observed. In four of these, large doses of inotropic agents were required, one patient was treated with plasmaphaeresis, and two d i e d - - o n e of c a r d i a c failure and one of aspiration pneumonitis. In 27 patients with moderate c o m a (GCS 5-8), the mean serum level of c a r b a m a z e p i n e was 112/~mol/L (range 63 to 176); convulsions were observed in two patients in this group. In 45 patients whose conscious state was mildly depressed or normal (GCS 9-15), the mean serum level was 73/~mol/L (range 37 to 128); a d d i t i o n a l effects were drowsiness (80%), a t a x i a (53%), nystagmus (38%), vomiting (17%), and dystonia (7%). I c o n c l u d e that patients with serum c a r b a m a z e p i n e levels of a p p r o x i m a t e l y 100 ~mol/L require close observation, whereas those with levels greater than 150 ~mol/L may require intensive life support. (J PEDIATR1992,121:295-9)

Carbamazepine has become the most frequently prescribed antiepileptic medication. The drug has many additional pharmacologic actions, including sedative, anticholinergic, antiarrhythmic, muscle relaxant, antidiuretic, and antidepressant. Its structure has a close resemblance to that of the tricyclic antidepressants, it is generally regarded as a relatively safe drug; only a few deaths and cases of severe toxic reaction have been reported. This report is of a group of children poisoned with carbamazepine. The aim was to examine the spectrum of toxic effects and to relate clinical effects and outcomes to serum concentrations of the drug.

Submitted for publication July 5, 1991; accepted Feb. 28, 1992. Reprint requests: James Tibballs, MBBS, Intensive Care Unit, Royal Children's Hospital, Flemington Rd., Parkville, Victoria, Australia 3052. 9/25/37479

METHODS The study was conducted for a 10-year period (1981 to 1990) at the Royal Children's Hospital, Melbourne. Details of presentation, management, and outcome of patients with carbamazepine poisoning admitted to the intensive care unit were recorded prospectively. Details of other patients with carbamazepine poisoning admitted to the hospital, but [

GCS

Glasgow Coma Scale

I

not to the ICU, were studied retrospectively. Patients poisoned with additional substances were excluded. The study was approved by the hospital ethics committee. The neurologic, respiratory, and cardiovascular effects of poisoning were recorded. Coma was graded according to the Glasgow Coma Scale. Coincident blood samples were assayed for serum carbamazepine levels on admission to the hospital and after admission to the ICU, at intervals during management. However, regular blood sampling was not

295

296

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The Journal of Pediatrics August 1992

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Figure. Serum carbamazepine concentration (in micromolesper liter) and the occurrence of convulsions,requirement for mechanical ventilation, and occurrence of hypotension.

undertaken, nor was measurement of levels of metabolites. Statistical data were compiled with EDIT SYSTATsoftware (Baysville, Ontario, Canada) and analyzed with SYSTAT software (Systat, Inc., Evanston, Ilk). RESULTS Eighty-two patients (aged 1 to 17 years) with carbamazepine poisoning alone were admitted to the hospital. Of these, 36 were admitted to the ICU. During the same period, the number of admissions to the hospital for all intoxications was 3186, of whom 314 were admitted to the ICU. The total number of deaths from poisoning was four. Of these, two were due to carbamazepine poisoning and one each to imipramine and paracetamol poisoning. Kruskal-Wallis one-way analysis of variance revealed that the serum carbamazepine level was related to the depth of coma (p <0.001), as was also the occurrence of convulsions (p = 0.002), the requirement for mechanical ventilation (p <0.001), and the occurrence of hypotension (p <0.001) (Figure). The Lilliefors test confirmed that fhe logarithm of the serum carbamazepine concentration was normally distributed (maximum difference 0.059; p = 0.635). Forty-five patients had a GCS of 9-15. Among this group, the predominant neurologic signs were drowsiness (80%), ataxia (53%), nystagmus (38%), and dystonia (7%). Vomiting occurred in 17% of patients. Occasionally, hallucinations were present. The mean (geometric) carbamazepine level was 73 #mol/L (range 37 to 128)'.~Nine of these patients were treated with induced emesis or with gastric lavage and activated charcoal. All survived without sequelae. Twenty-seven patients taking carbamazepine had a GCS of 5-8 (moderate coma). Convulsions occurred in two

patients. Tachycardia was observed frequently. In this group the mean serum level was 112/xmol/L (range 63 to 176). Treatment consisted of intensive nursing alone or of gastric lavage and installation of activated charcoal (nine patients). All survived without sequelae. Ten patients taking carbamazepine had a GCS of 3 or 4 (deep coma). Of this group, six had seizures and eight required mechanical ventilation for respiratory failure and loss of protective airway reflexes. Four of seven who had hypotension required inotropic-vasopressor support for treatment of low cardiac output caused by poor myocardial contractility. The mean peak serum level in this group was 213 /~mol/L (range 143 to 343). Two patients died--one with left ventricular failure and the other with septicemia during extracorporeal membrane oxygenation instituted for the treatment of aspiration pneumonitis. The details of the clinical presentation, management, and outcome of the 10 severely intoxicated patients are presented in the Table. DISCUSSION Carbamazepine is a frequently prescribed anticonvulsant agent with a large therapeutic index. However, overdose or ingestion may cause serious morbidity or death. Forty-five percent of patients admitted to the hospital in this series of patients with carbamazepine poisoning had manifestations of moderate or severe toxic effects. Two deaths occurred among a total of 82 cases, one from cardiac failure and one from aspiration pneumonitis with septicemia. Only six other deaths from acute poisoning have been reported. Two of these have been attributed to aspiration pneumonitisI and one to cardiovascular collapse.2 In the remaining three, the mode of death was not specified. 3, 4 Only a few other attempts have been made to correlate

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Acute toxic reaction to carbamazepine

297

Table. Clinical presentation, peak serum carbamazepine levels, treatment, and outcome in 10 patients with severe toxic effects

Patient Age No. (yr)

Ingested dose

Clinical presentation Dystonia, myoclonus Choreoathetosis Coma (GCS 4), seizures Respiratory failure Opisthotonus Coma (GCS 4), seizures Respiratory failure Coma (GCS 4), seizures Respiratory failure Hypotension (mean BP 35 mm Hg) AV dissociation, ileus Coma (GCS 3-4), seizures Respiratory failure Hypotension (mean BP 40 mm Hg) Bradycardia CI 2.8, PCWP 35 mm Hg Pulmonary edema Coma (GCS 4), seizures Respiratory failure Hypotension (mean BP 50 mm Hg) Coma (GCS 3) Respiratory failure Hypotension Bradycardia AV dissociation Pulmonary edema Coma (GCS 4), seizures Respiratory failure Hypotension (mean BP 40 mm Hg) LVSF 15%, PCWP 20 mm Hg Pulmonary edema Coma (GCS 3-4) Respiratory failure Hypotension (mean BP 47 mm Hg) Coma (GCS 4)

1

3.5

1.3 gm

2

8.0

Unknown

3

2.5

Unknown

4

3.0

Unknown

5

5.0

Unknown

6

13.0

8-10 gm

7

2.0

Unknown

8

4.0

Unknown

9

2.5

800 mg

10

15.0

8 gm

Peak serum carbamazepine (#mol/L)

Coma (GCS 4) Hypotension (mean BP 51 mm Hg)

Treatment

Outcome

143

IPPV Gastric lavage Activated charcoal

Recovered

169

IPPV Gastric lavage Activated charcoal IPPV Dopamine, 20 #g/kg/min Adrenaline, 0.8 #g/kg/min Noradrenaline, 0.5 ~g/kg/min

Recovered

308

Recovered

343

IPPV Dopamine, 35/zg/kg/min Adrenaline, 2 izg/kg/min Gastric lavage Activated charcoal Plasmapheresis (3.5 vol)

Recovered

221

IPPV Colloid infusion Gastric lavage Activated charcoal IPPV Dopamine, 20 izg/kg/min Gastric lavage Activated charcoal Transvenous pacing

Recovered

280

IPPV Dopamine, 15 izg/kg/min Epinephrine, 1.5 izg/kg/min

Died (septicemia)

145

IPPV Gastric lavage Activated charcoal

Recovered

150

Gastric lavage Activated charcoal Colloid infusion

Recovered

300

182

Died (cardiac failure)

Recovered

IPPV, Intermittent positive-pressureventilation;AV, atrioventricular; BP, blood pressure; CI, cardiac index;PCWP, pulmonary capillary wedgepressure; LVS~,

left ventricular shortening fraction.

severity of clinical toxic effects with serum levels. In one prospective study 5 of clinical status and serum levels of 62 patients, the authors concluded that coma, seizures, and respiratory depression requiring mechanical ventilation were poorly related to serum levels. However, restratifica-

tion of their data and reanalysis suggest otherwise: subjects with serum levels up to 19.9 # g / m l (0 to 84 ~ m o l / L ) had a 4% incidence of coma, a 4% incidence of seizures, and a 4% incidence of mechanical ventilation; subjects with serum levels 20 to 29.9 ~zg/ml (85 to 168 # m o l / L ) had a 27% in-

298

Tibballs

cidence of coma, a 21% incidence of seizures, and a 12% incidence of mechanical ventilation; subjects with serum levels 40 to 59.9 #g/ml (169 to 252 #mol/L) had a 100% incidence of coma, a 33% incidence of seizures, and a 100% incidence of mechanical ventilation. Subjects with higher serum levels also remained longer in the ICU and in the hospital. Sinus tachycardia was noted frequently (33%), but no patient was hypotensive and only one had a cardiac conduction defect. Another study6 of five episodes of overdose in four subjects revealed that serum levels of 11 to 15 #g/ml (45 to 65 izmol/L) were associated with drowsiness and ataxia, and levels of 15 to 25/zg/ml (65 to 105 #mol/L) with "combativeness," hallucinations, and choreiform movements, whereas levels greater than 25 #g/ml (105 #tool/L) were associated with coma and seizures. An apparent lack of correlation between clinical effects and serum levels of carbamazepine may be attributed to additional effects of carbamazepine metabolites, particularly of 10,11-epoxide, which may have intrinsic anticonvulsant activity7 and which has a longer half-life of elimination than the parent compound after overdose. 8 Moreover, coma after carbamazepine overdose may be cyclic9, 10 because of delayed absorption. Carbamazepine is not generally regarded as a cardiotoxic drug, but there are several case reports in which therapeutic doses caused bradycardia and complete heart block.11, 12 Congestive cardiac failure 13 and aggravation of heart block 14 have also been recognized as a consequence of regular therapy. In several cases of deliberate self-poisoning, disturbances of conduction have been recognized as prolongations of the PR interval, QRS complex, and QT interval.15, 16 Severe hypotension has been reported on several occasions,15, ~6 and in one fatal case hypotension was refractory to infusion of large doses of catecholamines2; the mechanism of hypotension was probably left ventricular failure, because elevated pulmonary capillary wedge pressure was also observed. In another case, acute pulmonary edema in association with severe hypotension was reported. 17 In several cases in this series, hypotension and pulmonary edema were associated with a reduced left ventricular shortening fraction, low cardiac output, and elevated pulmonary capillary wedge pressure, indicating that hypotension was indeed due to depression of myocardial contractility. Conduction defects were also observed. Treatment of an acute toxic reaction is largely supportive, with the use of gastric lavage and of activated charcoal to adsorb the drug and to hasten elimination from the enterohepatic circulation and intestinaY~cosa. 18 For adults intoxicated with carbamazepine and other drugs, intermittent doses of activated charcoal are used, 19 whereas for children a continuous instillation may be associated with a lower incidence of vomiting.2~ If intestinal ileus is n o t present, we administer 1 to 2 gm/kg initiallyl followed by

The Journal of Pediatrics August 1992

0.25 gm/kg every 4 hours for 16 hours 21 or 0.25 gm/kg hourly22 via nasogastric tube. Invasive methods to remove carbamazepine from the body have been reported. Charcoal hemoperfusion is moderately effective.l 5, 16, 23-25However, hemoperfusion may be associated with thrombocytopenia and disturbances of serum electrolyte and glucose levels. For the removal of drugs such as carbamazepine, which are highly protein bound26 and have a low volume of distribution,27 we prefer the use of plasmapheresis, which is as efficacious as charcoal hemoperfusion28 and, moreover, devoid of the problems of thrombocytopenia, although a balanced solution of electrolytes, proteins, and glucose must be replaced in a volume identical to that of the filtrate removed. I recommend that patients who have serum carbamazepine concentrations of approximately 100/zmol/L be monitored closely and treated with gastric lavage or activated charcoal or both. Patients with serum levels of approximately 150 #mol/L or greater may requireintensive life support and may need to undergo invasive methods to remove the toxin if conventional supportive therapy is inadequate. The assistance of Dr. Frank Shann with the statistical analysis is gratefully acknowledged. REFERENCES

1. Denning DW, Matheson L, Bryson SM, Streete J, Berry D J, Henry JA. Death due to carbamazepine self-poisoning:remedies reviewed. Hum Toxicol 1985;4:255-60. 2. Fisher RS, Cysyk B. A fatal overdose of carbamazepine: case report and review of literature. Clin Toxicol 1988;26:477-86. 3. Hundt HKL, Aucamp AK, Muller FO. Pharmacokiaetic aspects of carbamazepine and its two major metabolites in plasma during overdosage. Hum Toxicol 1983;2:607-14. 4. Baselt RC. Disposition of toxic drugs and chemicals in man. 2nd ed. Davis, California: Biomedical Publications, 1982: 113-7. 5. SpillerHA, Krenzelok EP, Cookson E. Carbamazepine overdoses: a prospee~ive study of serum levels and toxicity. Clin Toxicol 1990;28:445-58. 6. Weaver DF, Camfield P, Fraser A. Massive carbamazepine overdose: clinical and pharmacologicalobservationsin fiveepisodes. Neurology 1988;38:755-9. 7. Eichelbaum M, Bertilsson L, Lund L, Palmer L, Sjoqvist F. Plasma levels of carbamazepine and carbamazepine-10,11epoxide during treatment of epilepsy. Eur J Clin Pharmacol 1976;9:417-21. 8. Pynnonen S, Sillanpaa M, Frey H, et al. Carbamazepine and 10,11-epoxy carbamazepine levels in children. Proc Eur Soc Toxicol 1977;18:192-4. 9. Sullivan JB, Rumack BH, Peterson RG. Acute carbamazepine toxicity resulting from overdose. Neurology 1981;31:621-4. 10. De Zeeuw RA, Westenberg HGM. An unusual case of carbamazepine poisoning with a near-fatal relapse after two days. Clin Toxicol 1979;14:263-9. 11. Hamilton DV. Carbamazepine and heart block [Letter]. Lancet 1978;1:1365.

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A c u t e toxic reaction to carbamazepine

12. Herzberg L. Carbamazepine and bradycardia [Letter]. Lancet 1978;1:1097-8. 13. Terrence CF, Fromm G. Congestive heart failure during carbamazepine therapy. Ann Neurol 1980;8:200-1. 14. Bearmann B, Edhag O, Vallin H. Advanced heart block aggravated by carbamazepine. Br Heart J 1975;37:668-71. 15. Leslie P J, Heyworth R, Prescott LF. Cardiac complications of carbamazepine intoxication: treatment by haemoperfusion. BMJ 1983;286:1018. 16. Gary NE, Byra WM, Eisinger RP. Carbamazepine poisoning: treatment by hemoperfusion. Nephron 1981;27:202-3. 17. Kitson GE, Wauchab TD. Pulmonary oedema following carbamazepine overdose. Anaesthesia 1988;43:967-9. 18. Boldy DAR, Heath A, Ruddock S, Vale JA, Prescott LF. Activated charcoal for carbamazepine poisoning [Letter]. Lancet 1987;1:1027. 19. McLuckie A, Forbes AM, Ilett KF. Role of repeated doses of oral activated charcoal in the treatment of acute intoxications. Anaesth Intensive Care 1990;18:375-84. 20. Ohning BL, Reed MD, Blumer JL. Continuous nasogastric administration of activated charcoal for the treatment of theophylline intoxication. Pediatr Pharmacol 1986;5:241-5.

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21. Lilley B, Nolan T, Tibballs J. Paediatric pharmacopoeia. 10th ed. Melbourne: Royal Children's Hospital, 1989. 22. Shann F, Duncan A. Drug doses in paediatrics. 6th ed. Melbourne: Royal Children's Hospital, 1991. 23. Chart KM, Aguanno J J, Jansen R, Dietzler DN. Charcoal hemoperfusion for treatment of carbamazepine poisoning. Clin Chem 1987;27:1300-2. 24. De Groot G, van Heijst ANP, Maes RAA. Charcoal hemoperfusion in the treatment of two cases of acute carbamazepine poisoning. Clin Toxicol 1984;22:349-62. 25. Nilsson C, Sterner G, Idvall J. Charcoal hemoperfusion for treatment of serious carbamazepine poisoning. Acta Med Scand 1984;216:137-40. 26. Rawlins MD, Collste P, Bertilsson L, Palmer L. Distribution and elimination kinetics of earbamazepine in man. Eur J Clin Pharmacol 1975;8:9l-6. 27. Rey E, d'Athis P, deLauture D, et al. Pharmacokinetics of carbamazepine in the neonate and in the child. Int J Clin Pharmacol Biopharm 1979;17:90-6. 28. Laussen P, Shann F, Butt W, Tibbatls J. Use of plasmapheresis in acute theophylline toxicity. Crit Care Med 1991; 19:28890.

Clinical and laboratory observations Randomized, controlled trial of antibiotic therapy for Escherichia coil O 57:H7 enteritis Frangois Proulx, MD, Jean P. Turgeon, MD, FRCP(C), Gilles Delage, MD, MSc, FRCP(C), L u c e t t e

Lafleur, MD, FRCP(C), a n d Luc Chicoine, MD, FRCP(C)

From the Departments of Pediatrics and of Microbiology and Immunology, Sainte-Justine Hospital, Universit~ de Montr6al, Montreal, Canada

We undertook a prospective, controlled study to evaluate the effect of trimethoprim-sulfamethoxazole in children with proven Escherichia coli O157:H7 enteritis on the duration of symptoms, on fecal excretion of pathogen, and on the risk of progression to hemolytic-uremic syndrome. There was no statistically significant effect of treatment on progression of symptoms, fecal pathogen excretion, or the incidence of HUS (2/22 vs 4/25; p = 0.67). Our results suggest that a multicentric trial using rapid diagnostic methods to permit early randomization should be carried out. (J PEDIATR1992;121:299-303) Submitted for publication Dec. 10, 1991; accepted Feb. 25, 1992. 9/26/37450

Reprint requests: Francois Proulx, MD, Department of Pediatrics, Sainte-Justine-Hospital, 3175, chemin C6te Sainte-Catherine, Montr6al (Quebec), Canada H3T IC5.