Carbamazepine Toxicity

Carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus. Carbamazepine is absorbed slowly and distributed erratically following oral administration. It enters the brain rapidly because of its high lipid solubility.

Continuous electroencephalographic (EEG) recordings in a case of carbamazepine toxicity with unconsciousness, absent brainstem reflexes, and stimulus-sensitive multifocal myoclonus revealed a burst-suppression pattern, with bursts containing only generalized spikes accompanying myoclonic activity.[10] After treatment, with declining serum carbamazepine levels, EEG became more continuous and rhythmic without epileptiform discharges.

Carbamazepine is metabolized primarily in the liver by oxidative enzymes, then is conjugated with glucuronic acid, and finally is excreted in the urine. Its metabolite, carbamazepine-10,11-epoxide, is active and may achieve up to 50% concentration of the parent compound.

The elimination of carbamazepine increases over the first few weeks because of autoinduction. Carbamazepine also enhances the metabolism of phenytoin, causing its levels to fall. Erythromycin, isoniazid, and propoxyphene (withdrawn from the US market) inhibit the hepatic metabolism of carbamazepine; therefore, the dose of carbamazepine may need to be adjusted in patients taking multiple medications.

Carbamazepine induces the hepatic cytochrome P-450 system and its half-life decreases with long-term administration. The enhanced cytochrome P-450 system increases metabolism of other antiepileptic drugs.

Carbamazepine toxicity may result from acute overdose or long-term therapy. Therapeutic levels are 4-12 mg/L, but individual variation exists. Patients on multiple anticonvulsants may not tolerate high levels and can be maintained at 4-8 mg/L, while others can achieve levels of 8-12 mg/L without adverse effects.  Ataxia and nystagmus may occur at levels greater than 10 mg/L. Cardiovascular effects are usually seen at levels greater than 12 mg/L; interference with action potentials in Purkinje fibers and the His bundle may lead to atrioventricular blocks and arrhythmias.[11]  

Severe toxicity occurs at levels of 40 mg/L.  If carbamazepine is combined with other agents such as benzodiazepines or antidepressants, severe toxicity can occur at 30mg/L. Alcohol heightens the toxic effects as well and can cause death when treatment with activated charcoal is not sufficient.[12]

Other drug-drug interactions are known to occur. Vander et al reported a case of carbamazepine toxicity that occurred after administration of oxybutynin and an increase in the dose of dantrolene.[13]  The combination of these drugs elevated the level of carbamazepine, leading to toxicity.

According to the American Association of Poison Control Centers' National Poison Data System, 1062 carbamazepine single exposures were reported in 2021. Of those, 768 were treated in a health care facility.[14]

In addition, 1942 single exposures to oxcarbazepine were reported in 2021. Oxcarbazepine is structural derivative of carbamazepine. It is metabolized to 10-monohydrate derivate (MHD), which is the pharmacologically effective compound. Of those cases, 1048 were treated in a health care facility.[14]

Of cases reported in 2021, 81% of carbamazepine exposures (856 cases) and 42% of oxcarbazepine exposures (820 cases) occurred in patients age 20 years and older. Only 8% (87 cases) of carbamazepine exposures and 18% (344 cases) of oxcarbazepine exposures occurred in children younger than 6 years.[14] Pediatric patients with carbamazepine ingestion are at higher risk for dystonic reactions, coma, and apnea if serum levels exceed 28 mg/L. However, children eliminate the drug more rapidly than adults.

Increased risk for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis has been linked to carriage of HLA-B*1502, which is common in Han-Chinese, Thai, and Malaysian populations.[8] High prevalence of the HLA-B*1502 phenotype has also been found among populations in India.[15] ​In a study of cutaneous adverse drug reactions in northern India, HLA-B*5701 and HLA-DRB1*0701, but not HLA-B*1502, were associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.[16] The US Food and Drug Administration has recommended screening for the HLA-B*1502 allele before starting carbamazepine therapy in patients of Asian ancestry.[8]

Patients may experience altered levels of consciousness for several days following acute carbamazepine overdose. Their clinical status should improve as the plasma levels of the drug fall. Complications of carbamazepine toxicity may include the following:

• Coma
• Stevens-Johnson syndrome
• Syndrome of inappropriate antidiuretic hormone (SIADH)
• Elevated liver function test results
• Pulmonary edema
• Pancytopenia
• Anuria

Montgomery et al reported that severity of symptoms at the time of initial contact with the poison control center correlates with outcome severity for children and adults. However, the amount of time between ingestion and poison control center contact did not alter the correlation between initial severity of symptoms and final outcome severity. Carbamazepine levels greater than 85 mg/L were associated with severe toxicity.[17]

The American Association of Poison Control Centers reported that of the 1062 single exposures to carbamazepine in 2021, there was no significant outcome in 152 cases, major outcomes in 61 cases, and no deaths; of the 1942 single exposures to oxcarbazepine, there was no significant outcome in 376 cases, major outcomes in 42 cases, and no deaths.[14] A review of oxcarbazepine exposures reported to National Poison Data System from 2000 to 2012 found that less than 1% of cases resulted in severe outcomes. Of the 18,867 total cases, 68% of those with major outcomes, and all five deaths, were due to intentional exposure (ie, suicide attempt).[18]

van Optstal et al reported a case in which a patient ingested more than 100 tablets of oxcarbazepine. The serum level of the parent compound was 10-fold higher than the therapeutic dosage of 31.6 mg/L. However, the concentration of the pharmacologically active metabolite 10-monohydroxy derivate (MHD) was only 2-fold higher. MHD levels peaked 7 hours after intake. The patient survived without an adverse outcome. The authors concluded that since oxcarbazepine is a prodrug, formation of the active MHD metabolite is a rate-limiting process contributing to low overall toxicity of this drug.[19]

Carefully explain the proper method of taking anticonvulsants to avoid adverse reactions. Educate parents and caregivers to keep all medications and poisons in a locked cabinet or on high shelves to prevent pediatric accidental ingestions.

Instruct patients and parents to ensure that suspensions of carbamazepine should be shaken vigorously before administration. Otherwise, the drug settles in its container and early doses will contain less carbamazepine and subsequent underdosing will occur; later doses may contain more drug and lead to toxicity.

For patient education information, see Carbamazepine and Poison Proofing Your Home.

Symptom history

Carbamazepine toxicity should be considered in the differential diagnosis of patients presenting with ataxia. Query about the following:

• Whether the patient is carbamazepine naive or has been taking carbamazepine on a long-term basis
• Time of ingestion
• Drug formulation (immediate vs extended release)
• Approximate dose ingested

Signs and symptoms of carbamazepine toxicity may include the following:

• Drowsiness
• Slurred speech
• Ataxia
• Hallucinations
• Nausea, vomiting
• Tremors
• Seizures
• Oliguria
• Blurred vision
• Bullous skin lesions

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 always directly correlate with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.

Symptoms usually appear within 6 hours after ingestion but significant symptoms may be delayed for as long as 24 hours. Case reports indicate the possibility of delayed absorption, which causes levels to peak as late as 72 hours. Overdose of controlled-release formulations of carbamazepine can result in delayed presentations of toxicity; levels may not peak for 96 hours from the time of ingestion.[20]

Mild toxic ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations. Infrequently,  hyperglycemia may be present.[21]

Severe intoxications may produce hypotension, respiratory depression, seizures, and coma. Neurologic symptoms are the most common manifestations seen with severe overdoses. For example, a case report describes a 7-year-old boy presenting to the emergency department in a coma after ingesting the equivalent of 100 mg/kg of carbamazepine.[22]

Ingestion history

In children younger than 6 years, ingestions of carbamazepine are commonly unintentional. Suicidal ingestions typically occur in adolescents.

Other causes of carbamazepine poisoning include iatrogenic overdose; dosage errors; and interactions with drugs such as erythromycin, cimetidine, and isoniazid. All these drugs increase the levels of carbamazepine by competitively inhibiting its metabolism.

The medication source is usually the patient or another family member who is taking carbamazepine for seizure control or the treatment of other illness.

An important cause of toxicity in children who are using the suspension is failure to adequately shake the bottle. Because the drug settles to the bottom of the bottle, if the full bottle is not shaken, the patient actually receives a low dose of the drug, which may lead to subtherapeutic levels and seizures. However, if the child is subsequently given doses of the drug from the bottom of the unshaken bottle, toxicity may occur because the active drug has been concentrated there.

Vital signs

Tachycardia is common with carbamazepine toxicity.  Hypothermia may occur after an acute overdose and may last as long as 10 hours. 

Neurologic effects

Common neurologic effects include ataxia, slurred speech, nystagmus, dystonia and other extrapyramidal movements, and various degrees of central nervous system depression. A waxing and waning delirium is commonly seen. Seizures are common in children with an underlying epileptic disorder. In severe cases, coma and status epilepticus may occur.

Syndrome of inappropriate antidiuretic hormone secretion has also been reported, though this complication is much more common with long-term use.[23, 24]

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. Fulminant interstitial pneumonitis may also be noted.[25]

Cardiovascular effects

Cardiovascular effects are rarely observed in children. Hypotension, bradycardia, and conduction disorders may occur in patients with an abnormal myocardium or a preexisting conduction defect. A 2:1 atrioventricular (AV) block due to carbamazepine has been reported, which may occur even at therapeutic serum carbamazepine levels, and can be reversible after discontinuation of carbamazepine therapy.[26]

Gastrointestinal and hepatic effects

Antimuscarinic effects include delayed gastric emptying and decreased intestinal motility.

With acute carbamazepine toxicity, chemical pancreatitis without accompanying pain or abnormalities may be present.

Hepatitis and, rarely, liver failure may occur. This is usually due to an idiosyncratic reaction rather than an overdose. Studies in mice demonstrate that liver injury due to carbamazepine is probably due to metabolic activation of enzymes followed by the stimulation of immune responses. Prostaglandin E administration appeared to ameliorate the liver toxicity caused by carbamazepine in mice.[27]

Hematologic effects

Neutropenia, agranulocytosis, thrombocytopenia, and aplastic anemia may occur with therapeutic doses or chronic intoxication but not after an acute overdose. Carbamazepine in therapeutic doses has also been reported to have induced immunoglobulin deficiency in some cases;[28] however, this has not been reported in acute intoxication.

Thrombocytopenia or aplastic anemia can result in bleeding. However, this effect is rarely seen with acute poisoning.

Dermatologic effects

Dermatologic effects are due to idiosyncratic reactions rather than to an overdose of carbamazepine. Severe cutaneous adverse reactions such as the following may occur:

• Toxic epidermal necrolysis ^[29]
• Hypersensitivity syndrome ^[30]
• Stevens-Johnson syndrome  ^[8]
• Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome ^{[31, 32]}

Patients of Asian descent, especially Han Chinese, are particularly at risk for severe cutaneous adverse reactions. This sensitivity is linked to carriage of the HLA-B*1502 allele. The US Food and Drug Administration has recommended screening for the HLA-B*1502 allele before starting carbamazepine therapy in patients of Asian ancestry.[8] In Europeans, the HLA-A*3101 allele has been associated with carbamazepine-induced hypersensitivity reactions, but this is much less common than that seen in Asians who have the HLA-B*1502 allele.[33]

Endocrine effects

Long-term use of carbamazepine may decrease free T4 levels. Usually the body compensates by increasing thyrotropin levels. Therefore, thyroid function tests should be monitored in patients on carbamazepine, and thyroid hormone supplementation can be given if clinically indicated.[34]

Hyponatremia

Hyponatremia is not usually seen after acute overdoses but is known complication of chronic use.  There are several risk factors for hyponatremia associated with carbamazepine use:  age greater than 40 years, concomitant use of drugs associated with hyponatremia, menstruation, psychiatric conditions, surgery, (psychogenic) polydipsia, and female gender. Symptoms such as unsteadiness, dizziness, difficulty concentrating, reduced attention span, mild confusion, and lethargy should alert the physician to check the sodium levels. In patients with multiple risk factors, hyponatremia may occur much faster and can even cause life-threatening symptoms. In such cases, preventive fluid restriction can be of great value.[9]

Fatalities

Death may result from any of the following:

• Apnea
• Status epilepticus
• Aspiration pneumonitis
• Severe hepatitis
• Aplastic anemia

The workup in a patient with suspected carbamazepine poisoning should include appropriate comprehensive serum and urine drug screening, plus analysis of the following:

• Alcohol level, if alcohol toxicity is suspected.
• Serum electrolyte levels, including glucose, calcium, magnesium, phosphate, serum bicarbonate, blood urea nitrogen (BUN), and serum creatinine levels; hyponatremia can be seen with long-term use ^[35]  but rarely is noted in acute overdose.
• Liver function tests, because elevated liver enzyme levels, hepatitis, and hyperammonemia may be noted with chronic toxicity

Serum drug testing should be based on the history of ingestion and/or the patient’s toxidrome.

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 tricyclic antidepressants (TCAs) may cause false-positive results with immunoassay for TCAs. Patients who are taking carbamazepine should have therapeutic drug monitoring using serum carbamazepine levels.[36]

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. In fact, the initial carbamazepine level may be misleading. For this reason, serial measurements documenting a declining carbamazepine level and prolonged observation are recommended when managing these overdoses.[37]

Initial serum levels of more than 35 mg/L (127 µmol/L) suggest serious toxicity. However, lower initial serum levels do not necessarily indicate a benign course and the patient still needs to be closely monitored for signs and symptoms of significant toxicity.

The serum concentration may not always directly correlate with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not only 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.

The complete blood cell count (CBC) with a differential should be obtained. Rarely, hematologic adverse effects, including agranulocytosis, thrombocytopenia, and aplastic anemia, have been reported with long-term carbamazepine use.[38]

Although in utero exposure to carbamazepine has not been associated with adverse neuropsychological function, it has been associated with reduced verbal abilities.Therefore, a urine pregnancy test should be obtained on adolescent girls and women and if they are pregnant they should be counseled as to the possible effects of carbamazepine on the development of the fetus.[39]

Obtain an abdominal radiograph, because patients with rising serum levels may have a bezoar of undigested tablets that may be visualized radiographically.

Obtain a chest radiograph if crackles or rales are heard on physical examination and pulmonary edema is suspected or to confirm endotracheal (ET) placement if respiratory depression occurs.

Computed tomography of the head maybe warranted as part of evaluation for altered mental status.

With acute carbamazepine toxicity, ultrasonography may reveal chemical pancreatitis. These patients may have no accompanying pain or other signs and symptoms.

Obtain a 12-lead electrocardiogram (ECG). Abnormalties found may include the following[11] :

• QRS widening
• Sinus tachycardia
• Varying degrees of atrioventricular block
• QT prolongation

Carbamazepine is incorporated and retained in hair, depending on the blood levels. Sectional hair analysis can help investigators determine if chronic poisoning is an issue.[40]

Prehospital care may include the following:

• Obtain intravenous (IV) access
• Place the patient on a cardiac monitor
• Administer IV fluids if the patient is hypotensive
• Administer activated charcoal if the patient has intact mental status and is able to protect the airway

All patients should be monitored for at least 6 hours.  Those that develop symptoms will require further monitoring till they return to baseline.  Those that are completely asymptomatic 6 hours from the exposure can be medically cleared. Rapid and thorough evaluation of the patient's status is crucial; pay particular attention to the patient's level of sensorium, the ability to maintain an airway, and the respiratory and hemodynamic status.

For carbamazepine toxicity, the following emergency department care may be indicated[41] :

• Place the patient on a cardiac monitor
• Administer intravenous fluids as needed for hypotension
• Administer a benzodiazepine (eg, lorazepam, diazepam) intravenously to control seizures; intramuscular administration can be used if vascular access cannot be achieved
• Gastric lavage may be helpful if performed within 1 hour of ingestion
• Protect the patient’s airway by placing the patient in left lateral decubitus position or by intubating
• Induction of emesis is not recommended because of the risk of CNS depression and seizures
• Administer activated charcoal if the patient is able to protect his or her airway
• Multiple doses of activated charcoal (1 g/kg) can be administered every 2-4 hours to enhance total body clearance and elimination in the patient with significant toxicity
• A saline cathartic or sorbitol may be given with the first dose of charcoal, although evidence for their effectiveness is lacking. Do not repeat activated charcoal administration if ileus is present
• Perform whole-bowel irrigation (WBI) after ingestion of extended-release drug formulation: Adults and adolescents are treated with 1.5-2 L/h (20-30 mL/min) of polyethylene glycol electrolyte lavage solution (PEG-ELS); small children are given 0.5 L/h (25 mL/kg/h)
• Administer sodium bicarbonate when the QRS complex is wider than 100 msec due to carbamazepine toxicity (sodium channel blockade)

Patients with severe poisoning require admission to the ICU. 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).

The clinician should be aware of the marginal clinical effect of extracorporal carbamazepine removal. High-efficiency hemodialysis and venovenous hemodialysis may have a similar effect as charcoal hemoperfusion. Peritoneal dialysis is not useful for carbamazepine removal.

Monitor carbamazepine plasma levels to make sure that they are decreasing and correlating with the clinical picture.  Admit the patient to the monitored setting with cardiac telemetry. Transfer the patient if appropriate monitoring facilities or critical care areas are not available.

Discharge patients with carbamazepine toxicity if the following conditions are met[41] :

• The patient is symptom free and the carbamazepine level has decreased to less than 4-8 mg/L. Obviously, patients with significant toxicity should be admitted and patients with life threatening or potentially life-threatening signs and/or symptoms should be admitted to an ICU.

• An exception to decreasing the carbamazepine level to a subtherapeutic level is in the patient who is taking carbamazepine for seizure control. These patients may be discharged with a therapeutic serum level of carbamazepine or another substituted anticonvulsant.

• After being “medically cleared," the patient should not be discharged from the hospital until personnel from social services or child protective services or a psychiatrist agrees, if the case required the notification of these professionals.

Activated charcoal and lavage

After the patient's airway, breathing, and circulation are stabilized, therapy with multiple-dose activated charcoal can be considered and should be directed by a medical toxicologist or poison control center. Multi-dose activated charcoal may be of benefit due to the enterohepatic circulation that occurs with carbamazepine overdose. Carbamazepine is one of several important drugs that have enterohepatic circulation (others are phenobarbital and theophylline), which allows treatment of overdose with multiple doses of charcoal, even after all of the drug has been absorbed. This procedure is often referred to as "gut dialysis" because drug levels may rapidly fall after this treatment.

Multi-dose activated charcoal should only be given in cases where there airway is secure. In patients with an impaired gag reflex, this will require insertion of a nasogastric tube after the airway has been protected by endotracheal intubation. In patients with unsecured airways, multi-dose activated charcoal should not be given. Sorbitol should not be used.

It is important to note that serious carbamazepine poisoning is often complicated by drug-induced gastrointestinal (GI) 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.

Whole bowel irrigation

Whole bowel irrigation may be used to treat carbamazepine overdoses with sustained-released preparations or in patients who had a massive ingestion. It can also be used if the formation of concretions or pharmacobezoars is suspected. If the carbamazepine level is not decreasing or is even rising despite repeated doses of activated charcoal, the use of whole bowel irrigation should be strongly considered. The use of whole bowel irrigation should be guided by a medical toxicologist or poison control center.

Whole bowel irrigation uses preparations that contain polyethylene glycol (PEG), such as Colyte or Go-lightly. PEG decreases the amount of the toxin in the digestive tract without causing dehydration or electrolyte depletion. The dose is 20-40 mL/kg/h until the patient has clear diarrhea. It is contraindicated in children younger than 9 months and in patients with an acute abdominal problem. In young children, the PEG solution should not be cooled, as that could result in hypothermia.[42]

Charcoal hemoperfusion

Charcoal hemoperfusion has been used to treat patients with life-threatening carbamazepine poisoning. 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. Hemoperfusion may effectively remove the parent drug and its epoxide metabolite; thus, 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:

• Associated GI hypomotility or ileus is present and makes the use of activated charcoal ineffective
• The patient's clinical status is deteriorating despite the administration of enteric activated charcoal
• The patient has a severe life-threatening intoxication that causes deep coma, seizures, arrhythmias, and/or respiratory depression; such patients are at risk for rapid deterioration and death

Dialysis

Peritoneal dialysis is ineffective in eliminating carbamazepine from the serum because of the drug's insolubility in water, high protein binding, and relatively large volume of distribution. It had been thought that hemodialysis is also ineffective in treating carbamazepine toxicity for the same reasons. However, case reports have documented successful management of severe carbamazepine toxicity with hemodialysis.

Harder et al reported a case in an adult with acute carbamazepine overdose who was successfully treated with hemodialysis followed by continuous venovenous hemodialysis. The patient’s clinical status and her levels of carbamazepine and its epoxide metabolite markedly and rapidly improved with this treatment.[43]

Ram Prabahar et al successfully treated an adult with severe carbamazepine toxicity using “simple hemodialysis” because hemoperfusion was not available at their facility. Their report also included a review of the available literature on this subject. They concluded that hemodialysis was an effective and relatively safe way of managing severe carbamazepine toxicity, especially when charcoal hemoperfusion is not available.[44]

A systematic review of extracorporeal treatment of carbemazepine poisoning by Ghannoum et al concluded that intermittent hemodialysis is the preferred extracorporeal treatment, but intermittent hemoperfusion or continuous renal replacement therapies are alternatives if hemodialysis is not available.[45]

Ghannoum et al recommend extracorporeal treatment for patients with multiple seizures refractory to treatment or with life-threatening dysrhythmias. They suggest it for patients with prolonged coma or respiratory depression requiring mechanical ventilation and for those with significant, persistent toxicity, particularly when multiple-dose activated charcoal and supportive measures fail to reduce carbamazepine concentrations. Extracorporeal treatment should be continued until clinical improvement becomes apparent or the serum carbamazepine concentration falls below 10 mg/L.[45]

Successful treatment with continuous renal replacement therapy (CRRT) using continuous venovenous hemofiltration (CVVH) has been reported.[46]

Consult a medical toxicologist or a certified poison control center. Nephrology consultation is indicated if charcoal hemoperfusion is being considered.

If the patient's history suggests suicidal intent, consult a psychiatrist. In all cases involving an accidental ingestion in a child, personnel from social services or child protective services should be notified to evaluate the patient's home situation.

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.

The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup performed a systematic review and provided the following clinical recommendations for ECTR in carbamazepine poisoning[45] :

• ECTR is suggested in severe carbamazepine poisoning.

• ECTR is recommended if multiple seizures occur and are refractory to treatment, or if life-threatening dysrhythmias occur.

• ECTR is suggested if prolonged coma or respiratory depression requiring mechanical ventilation is present or if significant toxicity persists, particularly when carbamazepine concentrations rise or remain elevated, despite using multiple-dose activated charcoal (MDAC) and supportive measures.

• ECTR should be continued until clinical improvement is apparent or the serum carbamazepine concentration is below 10 mg/L.

• Intermittent hemodialysis is the preferred ECTR, but both intermittent hemoperfusion or continuous renal replacement therapies are alternatives if hemodialysis is not available.

• MDAC therapy should be continued during ECTR.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Other than activated charcoal, no antidotes are available.

Activated charcoal

Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingestion of poison. May administer as aqueous suspension or combine with cathartic (usually sorbitol 70%) in the presence of active bowel sounds.

Repeat dose, if necessary (without cathartic), to adsorb large pill masses or drug packages.

With superactivated forms, use of doses of 0.5 g/kg PO may be possible.

Lorazepam (Ativan)

DOC for treatment of status epilepticus because persists in the CNS longer than diazepam. Rate of injection should not exceed 2 mg/min. May be administered IM if unable to obtain vascular access.

Monitoring patient's blood pressure after administering dose is important. Adjust prn.

Diazepam (Valium, Diastat, Diazepam Intensol)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.

Midazolam

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Sodium bicarbonate

Used to correct arrhythmias if patient is diagnosed with bicarbonate-responsive acidosis, hyperkalemia, or overdose resulting in an acidotic state. Routine use for arrhythmia is not recommended.

Polyethylene glycol-electrolyte solution (Colyte, GoLytely, MoviPrep, NuLytely)

Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.