AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Girish G Deshpande, MD, MBBS, FAAP, Assistant Professor, Department of Pediatrics, Division of Critical Care Medicine, Children's Hospital of Illinois at OSF St Francis Medical Center
Girish G Deshpande is a member of the following medical societies: American Academy of Pediatrics
Editors: William T Zempsky, MD, Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Author and Editor Disclosure
Synonyms and related keywords:
carbamazepine overdose, carbamazepine poisoning, acute carbamazepine poisoning, accidental carbamazepine poisoning, Tegretol, Tegretol overdose, Tegretol toxicity, Carbatrol, Epitol, trigeminal neuralgias, tonic-clonic epilepsy, partial epilepsy, manic depression, postherpetic neuralgia, phantom limb pain, respiratory depression, seizures, hypotension, GI hypomotility, hyperthermia, neuroleptic malignant syndrome, status epilepticus, transient ophthalmoplegia, chemical pancreatitis, neutropenia, thrombocytopenia, aplastic anemia, immunoglobulin deficiency, aspiration pneumonitis, severe hepatitis
Background
Carbamazepine (Tegretol) has been used for treatment of trigeminal neuralgias since 1960. Since carbamazepine received approval for use as an antiepileptic agent in the United States in 1974, it became widely used for the management of partial or tonic-clonic epilepsy. Carbamazepine is also used as a treatment for patients with manic-depressive illness, postherpetic neuralgia, or phantom limb pain. Some of the available dosage forms for carbamazepine include 100- and 200-mg oral tablets and a 100-mg/5-mL oral suspension. The therapeutic plasma concentration is 4-12 mg/L. A peak plasma level is achieved in 6-24 hours. Controlled-release formulation could result in peak levels as late as 4 days after administration.1 The volume of distribution is 1-2 L/kg. Carbamazepine is approximately 75-80% protein bound, and approximately 2-3% is excreted unchanged in the urine. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10,11-epoxide. The serum concentration of the epoxide metabolite is approximately 20% in children and 10-15% in adults. Autoinduction of microsomal enzyme results in a shorter carbamazepine half-life (10-20 h) in patients who use the drug long-term compared with those with a short-term exposure (31-35 h). The autoinduction process takes about 4 weeks. In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide. Inhibitors of hepatic microsomal enzymes such as erythromycin, clarithromycin, cimetidine, and propoxyphene increase carbamazepine levels.
Pathophysiology
Carbamazepine is a complex drug that has both anticonvulsant properties in therapeutic doses and a proconvulsant property in overdose situations with supratherapeutic serum levels. Carbamazepine is chemically and stereospatially related to the tricyclic antidepressant (TCA) imipramine; it is spatially similar to phenytoin. The therapeutic anticonvulsant mechanism of carbamazepine is similar to phenytoin and is believed to be primarily related to the blockade of presynaptic voltage-gated sodium channels.
Blockage of sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. It also inhibits N-methyl-D-aspartate (NMDA) receptors and CNS adenosine receptors. Carbamazepine also has powerful anticholinergic properties through inhibition of the muscarinic and nicotinic acetylcholine receptors. The seizures are largely secondary to a central anticholinergic syndrome. The coma and respiratory depression associated with overdose may be related to sodium channel suppression of neurotransmission. Carbamazepine causes antagonism at the adenosine subtype A1 receptor and agonism at the adenosine subtype A2 receptor. In lower therapeutic doses, this may be partially responsible for the anticonvulsant effect, whereas, in overdose situations, it may increase sedation or precipitate coma. Cardiac arrhythmias due to carbamazepine are related to the sodium channel effects and the anticholinergic effects. In therapeutic doses, the cardiovascular sodium channels are only minimally affected, and carbamazepine does not appear to be proarrhythmic. However, in overdose situations, carbamazepine produces sodium channel blockade effects similar to those of TCAs.
Frequency
United States
Because of widespread use of carbamazepine in patients with pediatric epilepsy, the incidence of carbamazepine poisoning is increasing in all age groups. In 1997, the American Association of Poison Control Centers recorded 7151 cases of carbamazepine intoxication.2
Mortality/Morbidity
- In 2004, among 4845 exposures to carbamazepine, 232 patients had a major outcome, and 4 deaths were reported.2
- Complications of severe poisoning include coma, respiratory depression, seizures, hypotension, and GI hypomotility.
- Cardiac toxicity is uncommon in children, especially in those who have a structurally normal heart.
Sex
- No specific sex predilection has been noted.
Age
- Of 4845 cases of carbamazepine toxicity reported by the American Association of Poison Control Centers in 2004, a total of 1157 involved persons younger than 6 years.2
- Most pediatric patients are younger than 6 years.
History
- Ingestion history
- Accidental ingestions are common in children younger than 6 years; suicidal ingestions typically occur in adolescents.
- Other causes of carbamazepine poisoning include iatrogenic overdose; dosage errors; and interactions with drugs such as erythromycin, cimetidine, isoniazid, and propoxyphene. All these drugs increase the levels of carbamazepine by competitively inhibiting its metabolism.
- The medication source is usually the patient himself or herself or another family member who is taking carbamazepine for seizure control or the treatment of other illness.
- Symptom history
- Symptoms usually appear within 6 hours of ingestion but may be delayed as long as 24 hours after the ingestion. Case reports indicate the possibility of delayed absorption, which causes levels to peak as late as 72 hours.
- Mild ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations.
- Severe intoxications may produce coma, seizures, respiratory depression, and hypotension.
Physical
Carbamazepine toxicity should be considered in any child who presents with seizures, apnea, or an unexplained change in mental status, particularly when the child has access to the drug. The serum concentration may not be correlated with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.
- Vital signs
- Neurologic effects
- Common neurologic effects include ataxia, slurred speech, nystagmus, dystonia and other extrapyramidal movements, and various degrees of CNS depression. Seizures are common in children with an epileptic disorder.
- In severe cases, coma, status epilepticus, or isolated seizures may occur.
- Neuroleptic malignant syndrome and transient ophthalmoplegia are also associated with carbamazepine overdose.
- Syndrome of inappropriate antidiuretic hormone secretion has also been reported.
- Respiratory effects
- Respiratory depression or apnea that requires mechanical ventilation may be observed within first 24 hours of the patient's presentation.
- Pulmonary edema or aspiration pneumonia may occur.
- Cardiovascular effects
- Cardiovascular effects are rarely observed in children.
- Hypotension, bradycardia, and conduction disorders may occur in those with an abnormal myocardium or a preexisting conduction defect.
- GI and hepatic effects
- Anticholinergic effects include delayed gastric emptying and decreased intestinal motility.
- With acute carbamazepine toxicity, chemical pancreatitis without accompanying pain or abnormalities may be present.
- Hematologic effects
- Neutropenia, thrombocytopenia, and aplastic anemia may occur with therapeutic doses or chronic intoxication but not after an acute overdose. Carbamazepine has also been reported to have induced immunoglobulin deficiency in some cases in therapeutic doses;3 however, this has not been reported in acute intoxication.
- Thrombocytopenia or aplastic anemia can result in bleeding; however, this effect is never seen with acute poisoning.
- Fatalities: Death may result from apnea, status epilepticus,4 aspiration pneumonitis, severe hepatitis, or aplastic anemia.
Other Problems to be Considered
- Acute change in mental status: In patients who have a history of seizures while taking carbamazepine, the postictal state (after an unwitnessed seizure) and an acute mental status change due to carbamazepine overdose are difficult to differentiate. Always consider other causes of coma in a child with no prior history of illness. Such other causes include trauma, suspected child abuse, infections, CNS tumors, and intoxication.
- Arrhythmia
- Seizures: In patients taking long-term carbamazepine therapy for epilepsy, identify the cause of the current seizure. A seizure could be due to subtherapeutic drug levels, breakthrough seizures with therapeutic drug levels, or carbamazepine toxicity. Other causes must also be considered; these include trauma, hypoglycemia, electrolyte disturbances, brain tumors, CNS infections, or new-onset epilepsy.
Lab Studies
- The workup in a patient with suspected poisoning should include comprehensive serum and urine drug screening; (ie, the procedure) with analysis of the following:
- Alcohol panel if alcohol toxicity is suspected, particularly in adolescents
- Serum electrolyte levels, including calcium, magnesium, phosphate, serum bicarbonate, BUN, and serum creatinine levels
- A serum and urine drug screen may not detect carbamazepine; therefore, the serum carbamazepine level should also be determined if the patient has access to carbamazepine. Structural similarity between carbamazepine and TCAs may cause false-positive results with immunoassay for TCAs.
- Because carbamazepine absorption varies, the serum concentration may not peak for as long as 24-72 hours. With controlled-release formulation, levels may continue to rise until 4 days postingestion.
- Initial serum levels of more than 35 mg/L (127 µmol/L) suggest serious toxicity.5 However, lower initial serum levels do not indicate a benign course; thus, serial monitoring is required.
- The serum concentration may not be correlated with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.
- Toxicity may result from carbamazepine itself or its active epoxide metabolite. However, measuring epoxide levels along with the carbamazepine level provides no additional advantage.
- Elevated liver enzyme levels, hepatitis, and hyperammonemia may occur with chronic overdose.
- The CBC count and platelet count should be obtained.
Imaging Studies
- With acute carbamazepine toxicity, ultrasonography may reveal chemical pancreatitis without accompanying pain or abnormalities.
Other Tests
- Perform a 12-lead ECG in patients with suspected poisoning.
- Continuous EEG recordings in a case with unconsciousness, absent brainstem reflexes, and stimulus-sensitive multifocal myoclonus revealed a burst-suppression pattern, with bursts containing only generalized spikes accompanying myoclonic activity.6 After treatment, EEG became more continuous and rhythmic without epileptiform discharges and with declining serum carbamazepine levels.
- Sectional hair analysis: Carbamazepine is incorporated and retained in hair, depending on the blood levels. Sectional hair analysis helps investigators unmask chronic nature of poisoning.7
Medical Care
- General and supportive measures
- Rapid and thorough evaluation of the patient's status is crucial; pay particular attention to the patient's level of sensorium, his or her ability to maintain an airway, and his or her respiratory and hemodynamic status.
- Patients with severe poisoning require admission to the intensive care unit. Examples of such patients include those who are comatose on arrival to the facility and those with a deteriorating mental status, hypotension, seizures, or respiratory irregularities (eg, respiratory depression, apnea).
- Therapeutic emesis is not recommended because rapid deterioration in neurostatus may occur.
- Patients with a deep coma, apnea, or respiratory depression may require intubation and mechanical ventilation.
- Patients with hypotension may need isotonic fluid boluses or inotropic support.
- All patients require continuous cardiac monitoring for cardiac arrhythmia.
- Administration of multiple-dose activated charcoal
- After the patient's airway, breathing, and circulation are stabilized, therapy with multiple-dose activated charcoal should be started, with doses administered every 4 hours via a nasogastric tube after initial stomach lavage.
- A significant amount of carbamazepine is excreted in the bile. Enterally administered activated charcoal can be used to prevent the primary absorption and reabsorption of carbamazepine, which can be excreted in the bile.
- Serious carbamazepine poisoning is often complicated by drug-induced gastrointestinal hypomotility. Severe ileus may interfere with the administration of multiple-dose charcoal and with decontamination of the GI tract. GI hypomotility may result in ongoing drug absorption and prolongation of symptoms.
- Charcoal hemoperfusion
- Charcoal hemoperfusion has been used to treat patients with life-threatening carbamazepine poisoning.8 Activated charcoal imbedded in the hemoperfusion cartridge competes with plasma proteins for binding of the drug.
- Hemoperfusion is limited to the removal of substances from the blood compartment; therefore, patients receiving drugs with a large volume of distribution may require prolonged hemoperfusion.
- Charcoal hemoperfusion may have a more important role in patients with acute toxicity because of the low intrinsic clearance (see Background).
- Hemoperfusion may effectively remove the parent drug and its epoxide metabolite.
- Charcoal hemoperfusion is an important adjuvant therapy in patients with life-threatening carbamazepine poisoning complicated by drug-induced gastrointestinal hypomotility.
- Repeat hemoperfusion treatments may by necessary until GI motility returns to its previous level.
- To the author's knowledge, no written guidelines address the use of charcoal hemoperfusion in carbamazepine poisoning. Hence, a common-sense approach is to use charcoal hemoperfusion in the following situations: (1) when associated GI hypomotility or ileus is present and makes the use of activated charcoal ineffective, (2) when the patient's clinical status is deteriorating despite the administration of enteric activated charcoal, and (3) when the patient has a severe life-threatening intoxication that causes deep coma, seizures, or respiratory depression. In this last situation, the patient usually has an associated ileus, and/or rapid progression is possible.
- Dialysis
- Hemodialysis and peritoneal dialysis are ineffective in eliminating carbamazepine from the serum because of the drug's insolubility in water, high protein binding, and relatively large volume of distribution. However, Askenazi et al reported a 10-year old girl with carbamazepine poisoning who was treated successfully using albumin-enhanced continuous venovenous hemodialysis.9
- Yildiz et al recently reported successful use of continuous venovenous hemodiafiltration (CVVHDF) for the treatment of carbamazepine poisoning in a 2-year old patient after ingestion of controlled-release tablets.10 Yildiz et al claim that, although more difficult and more expensive, CVVHDF combines both diffusion and convection principles, thus enhancing the clearance of the drug.
- Bek et al used conventional low-flux hemodialysis in the management of acute carbamazepine overdose in 2 adolescent patients.11 They conclude that standard low-flux hemodialysis may be used for treatment of mild carbamazepine overdose or when hemoperfusion is not available.
Consultations
- If the patient's history suggests suicidal intent, consult a child psychiatrist.
- In all cases involving an accidental ingestion, personnel from social services or child protective services should be notified to evaluate the patient's home situation.
- Consultation with a toxicologist or with poison control center personnel should be considered.
Drug Category: Decontamination agents
Consider activated charcoal decontamination in any patient who presents within 4 hours of ingestion.
| Drug Name | Activated charcoal (Actidose-Aqua, Liqui-Char, Insta-Char) |
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| Description | Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Prevents absorption by adsorbing drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Does not dissolve in water.
For maximum effect, administer within 30 min after poison ingestion. |
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| Adult Dose | 25-100 g, 1 g/kg, or 10 times the weight of ingested poison given PO as susp in 4-8 oz of water |
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| Pediatric Dose | <1 year: Not recommended
>1 year: Administer as in adults |
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| Contraindications | Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies |
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| Interactions | May inactivate syrup of ipecac if used concomitantly; effectiveness of other medications decrease with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties of activated charcoal) |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black |
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Further Inpatient Care
Discharge patient if the following conditions are met:
- The patient is symptom-free and the carbamazepine level has decreased to less than 4-8 mg/L.
- An exception to the previous condition is a patient who is taking carbamazepine for seizure control. This patient may be discharged with a therapeutic serum level of carbamazepine or another substituted anticonvulsant.
- The patient may be discharged from the hospital by personnel from social services or child protective services or by a psychiatrist if the case required the notification of these professionals.
Further Outpatient Care
- Patients should follow up with their primary care provider within 24-48 hours after their discharge.
- The physician should reevaluate the patient's condition and discuss the prevention of future episodes.
Deterrence/Prevention
- A discussion with the patient's parents concerning the safe storage of medications is essential.
- Parents should be provided the toll-free telephone number for the American Association of Poison Control Centers (800-222-1222).
Patient Education
Medical/Legal Pitfalls
When patients with suspected carbamazepine poisoning are treated, the following services should be notified:
- The American Association of Poison Control Centers: This organization maintains a nationwide database of all the poisoning cases. Contacting the regional or state poison control center in cases of carbamazepine poisoning helps in maintaining the accuracy of this database and also helps in managing the case according to current guidelines. Information from this database can also help in ensuring that patients receive the necessary follow-up care.
- Social services: Once the patient is admitted to the hospital, social services should be contacted to evaluate the patient's home situation. Social services personnel may later notify child protection services if needed.
- Child protection services: If the patient's history strongly suggests a disturbed home environment that may have resulted in the neglect of the child, notifying child protection services may be prudent. However, in most cases, a consultation with social services personnel is sufficient.
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Toxicity, Carbamazepine excerpt Article Last Updated: Feb 13, 2008
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