Clinical Pharmacology

"Adverse Drug Event of the month"

CARBAMAZEPINE POISONING IN A CHILD-A preventable adverse drug reaction.

Case report:
A blood sample of two and half year old male child was sent to the Therapeutic Drug Monitoring OPD of KEM hospital for measurement of serum levels of the antiepileptic Carbamazepine. The patient was apparently alright few hours before admission when he accidentally ingested a few tablets of Carbamazepine of 100mg strength, exact number of which was not known. The patient's sister was a known epileptic. Tablets were kept within reach of the child, which he accidentally consumed while playing. Patient became unconscious within 30 minutes following this episode and was taken to B J Wadia pediatric hospital. At admission patient was unconscious and was not responding to oral commands. There was no history of nausea, vomiting, headache, diplopia, drowsiness or ataxia. There was no significant past or family history or history of any other concomitant illness. Child was the third of three siblings, born by full term normal delivery and was vaccinated till date

Clinical Examination
On CNS examination child was drowsy with Glasgow coma scale of E2M4V3 (eye opening in response to loud noise, flexion of limbs, uttering inappropriate words).Reflexes were exaggerated. Other systemic examination was normal.

Management
Patient was treated with gastric lavage and other symptomatic treatment. Oxygen was administered for initial two hours. Patient was drowsy for 12 hours and regained consciousness subsequently. Patient's stay in the ward was uneventful and he was discharged on third day. On discharge patient's general condition was fair. Vital parameters were stable and there was no neurological deficit.

Discussion
Carbamazepine (CBZ) is an iminostilbene derivative chemically related to tricyclic antidepressants. It has a carbonyl group at C 5 position, which is essential for its potent antiseizure activity. CBZ is used as an antiepileptic in treatment of generalized tonic clonic seizures as well as simple and complex partial seizures. It is also used for patients with manic-depressive illness, postherpetic and trigeminal neuralgia and phantom limb pain (1).

Carbamazepine poisoning can result from accidental or suicidal ingestion. Other causes of CBZ poisoning include iatrogenic overdose, dosage errors and interaction with other drugs. More than 50% of CBZ poisoning cases occur in patients less than 19 years of age. (2) Accidental ingestions are common in children younger than 6 years of age, while suicidal ingestion typically occurs in adolescents. In younger children accidental ingestion of CBZ tablets prescribed for a family member is the most common cause of poisoning (3).

Symptoms of CBZ poisoning usually appear within few hours of ingestion but rarely it may take 24 hours for symptoms to appear. Nausea, vomiting, dizziness, headache, ataxia drowsiness, and diplopia are common symptoms resulting from ingestion of small doses of CBZ.However severe intoxication may produce coma, seizures, respiratory depression and hypotension. Its anticholinergic effect may lead to delayed gastric emptying and decreased intestinal motility, which may further increase its gastrointestinal absorption. In a retrospective study of CBZ poisoning in children carried out at toxicology center, Israel, nystagmus and drowsiness were found to be the most common symptoms of presentation followed by ataxia. (3) When an unconscious child is brought to emergency unit possibility of such poisoning should be looked for. Differential diagnosis for such cases includes postictal state in a known case of epilepsy, trauma, infection, space occupying lesions or suspected child abuse.

Other than routine hematological and biochemical investigations estimation of Serum Carbamazepine level forms the most important diagnostic criteria for diagnosing CBZ poisoning .It can help in predicting prognosis of the case as well. In a study carried out at Regional Poison Center, Kentucky, USA, serum CBZ levels of more than 28 mg/ml were associated with serious toxicities like dystonia, coma and apnoea and death was reported in pediatric patient with serum CBZ level of 54mg/ml (4) CBZ is extensively metabolized in the liver to its active metabolite epoxide and excreted mainly in urine. Toxicity may result from CBZ itself or its active epoxide metabolite. Even though plasma half-life of epoxide is shorter than CBZ, measuring epoxide metabolite might prove to be useful. (5) In this child epoxide levels were estimated and were found to be 39 % of total serum CBZ concentration.( 9.06 ug/ml)

No antidote exists for CBZ poisoning and the treatment is symptomatic. Securing airway, breathing and circulation forms first line of treatment. Therapeutic emesis is not recommended because of risk of aspiration in comatose patients. Gastric lavage followed by administration of activated charcoal prevents further absorption of the drug from gastro intestinal tract. Activated charcoal hemoperfusion has come up as novel therapy for CBZ poisoning, where activated charcoal competes with the protein binding sites for CBZ. (2) Severely toxic patients require admission in intensive care units. Rarely ventilatory support is required for patients with respiratory depression.

Poisoning with CBZ in children is a tragic accident and can result in disastrous consequences like death. Such medicines should be stored at places, which are not accessible to children. To avoid iatrogenic poisoning in children prescribed CBZ as an antiepileptic serum levels of the drug should be monitored at regular intervals. Parents and other family members of patients taking antiepileptic drugs should be vigilant to prevent such accidents from happening.

References
1. Mcnamara J D:Drugs effective in treatment of epilepsies.In:Hadmen J,Limbird L E(Edi in chief),Molinoff P B, Ruddon R W (Eds),Alfred Goodman Gilman. Pharmacological basis Of Therapeutics.9th edition McGraw Hill Companies, USA 1996,Pp461-487

2. Author-Girish Deshpande.Last updated on 29 Jan 2000.Available from www.emedicine.com

3. Lifshitz M, Gavrilov V, Sofu S. Signs and symptoms of carbamazepine overdose in young children.Pediatr Emerg Care 2000;16;26-27

4. Matos M E, Burns M M, Shannon M W.False positive tricyclic antidepressant drug screen Results leading to diagnosis of carbamazepine intoxication.Pediatrics 2000;105:66-67

5. In:Dollery C,Boobis A,Rawlins M,Thomas S,Wilkins M(Eds)Therapeutic Drugs 2nd Edition .UK:Churchill Livingston Company,1986-Pp


Department of Clinical Pharmacology
Seth G S Medical College and KEM Hospital.
Department of Pediatrics,
B J Wadia Pediatric Hospital, Parel.