MANAGEMENT OF CARBAMAZEPINE OVERDOSE IN THE INTENSIVE CARE UNIT
Ahmet Akyol MD, Hülya Ulusoy MD, Filiz Karip MD, ?brahim Özen MD
Department of Anesthesiology and Critical Care, KTU, Faculty of Medicine, Trabzon, Turkey
We describe the use of multiple doses activated charcoal in an 18-year-old female who developed coma due to an intentional carbamazepine overdose (peak drug level of 37.14 mcg/ml ; therapeutic range: 8-12 mcg/ml). Without intervention, the half-life of drug elimination is 25 to 60 hours in patients who are naive to carbamazepine 12 to 20 hours in adolescence on chronic carbamazepine therapy. The patient recovered rapidly and was discharged from hospital 3 days from the time of ingestion with no complications or neurologic impairment. Because the cost-benefit analysis was also favorable relative to other therapeutic options, multiple doses activated charcoal may be optimal treatment of toxic level (drug level below 40 mcg/ml) ingestion of carbamazepine.
Keys words: Carbamazepine; overdose; activated charcoal; critical care
The differential diagnosis of altered mental status in an adult is broad. It can be difficult to eliminate trauma, ingestion, or infection as the cause in any presentation of alteration of consciousness. Carbamazepine intoxication is common in the pediatric and adult population. Because of its availability, carbamazepine is a drug commonly involved in accidental and intentional overdoses. Carbamazepine, approved by the Food and Drug Administration (FDA) in 1968, is indicated as first-line therapy for simple partial, complex partial, and general tonic-clonic seizures. Carbamazepine is also approved by the FDA for trigeminal neuralgia, and of-label indications include bipolar disorder, neuropathic pain, and attention-deficit/hyperactivity disorder (1). Because this drug is present in many households, there is a high incidence of accidental as well as intentional poisoning. Acute carbamazepine toxicity presents with cardiac, respiratory, and neurological effects. Cardiac effect can include hypertension, hypotension, tachycardia, and cardiac conduction delays. Respiratory depression requiring mechanical ventilation is extremely common, and other neurological signs include loss of consciousness, seizures, ataxia, choreoathetosis, myoclonus, motor restlessness, opisthotonus, mydriasis, and nystagmus (2). The observed toxicity increases as plasma carbamazepine concentrations increase above the therapeutic range; however, an individual adult’s prognosis is unpredictable. Some comatose patients demonstrate complete recovery, whereas 5% to 38% of patients die (3). Patients with serum carbamazepine levels equal to or above 40 mcg/ml are significantly associated with an increased risk of serious complications such as coma, seizures, respiratory failure and cardiac conduction defects (4).
Carbamazepine distribution and metabolism are complex. It is reasonably bioavailable and rapidly absorbed from the gastrointestinal tract, leading to peak drug concentrations in 1 to 3 hours. Carbamazepine is highly bound to plasma proteins (75-80%) with moderately large volume of distribution and has a half-life between 12 and 20 hours. Hepatic metabolism is the major route of elimination, with renal excretion accounting for only 1% to 3% of its elimination. When patients are started on carbamazepine, hepatic cytochrome p450 (CYP3A4) induction occurs over 2 to 3 weeks. This induction reduces the plasma half-life of the drug from 25 to 65 hours to 12 to 20 hours. Consequently, patients who are naive to carbamazepine can overdose on much lower dose. Once p450 induction has occurred, peak levels are usually achieved 1.5 hours after administration (5). Carbamazepine ingestion management is generally supportive. Patients receive endotracheal intubation and mechanical ventilation as well as intravenous volume expansion and pressors to maintain hemodynamic stability.
Several modalities have been proposed to enhance drug clearance of carbamazepine using hemodialysis circuits. Because carbamazepine is highly protein-bound and has a resultant large volume of distribution, conventional hemodialysis and peritoneal dialysis have not been efficacious in acute carbamazepine toxicity (6). Many authors recommend charcoal hemoperfusion for enhanced clearance in patients who are intubated or severely impaired after carbamazepine toxicity (7).
An 18-year-old female was brought to the emergency service, after her mother found her unresponsive at home. One month before admission she was started on carbamazepine for a newly diagnosed depression. She had been taking carbamazepine 200 mg, twice a day and did not have any drug levels checked before the admission. After an argument in her home, the patient intentionally took 35 pills (200 mg tablets) carbamazepine. The time of ingestion was estimated at 4 hours before arrival to the emergency service. She had one episode of emesis, but no pill fragments were present.
On physical examination, her blood pressure was 110/65 mmHg, heart rate was 82 per minute, respiratory rate was 15 per minute, temperature was 37.4 oC, SpO2 was 98% on room air. Glasgow Coma Score was 8. Her pupils were 3 mm bilaterally and reactive to light. She had a regular heart rate and rhythm. Her abdomen was not distended and she had no peripheral edema. Respiration was spontaneous and adequate. There were no obvious signs of trauma. Her cardiac and pulmonary examinations were normal. A head computed tomography scan and electrocardiogram were normal.
Initial laboratory analysis, 4 hours after ingestion (totally 7 g carbamazepine), showed a drug level of 37.14 mcg /ml (therapeutic range: 8-12 mcg /ml). Her complete blood count, electrolytes, liver function tests, arterial blood gases, and urinalysis were normal. (Hb: 12.9 mg/dl; Hct: 39%; sodium:141 mmol/L; potassium:3.4 mmol/L; chloride:105mmol/L; glucose: 97 mg/dl; blood urea nitrogen:14 mg/dl; creatinine:0.6 mg/dl; ionized calcium: 1.18 mmol/L; SGOT:16 U/L; SGPT:10 U/L; arterial pH : 7.41)
Activated charcoal (Char-flo Aqueous base 50 g/240 ml, Ballard, USA) was given via a nasogastric tube after gastric lavage.
The patient was admitted to the critical care unit, then, applied full supportive care in a monitored setting and oxygen 4 L/min by face mask. At this time the arterial blood gas analysis, under oxygen 4 L/min by face mask, showed a pH:7.41, pO2 :102 mmHg, pCO2:36.5 mmHg, HCO3:24.1 mmol/L.
The carbamazepine level was 13.47 mcg /ml on second day. Psychiatry consult was involved, and supportive care continued. Until we observed therapeutic drug level, given multiple doses activated charcoal with routine supportive strategies.
On the third hospital day, the patient transferred to the psychiatry department with a therapeutic carbamazepine level which was 9 mcg/ml. She was subsequently discharged from the hospital with outpatient psychiatry follow-up.
This case illustrates some of the difficulties of managing life-threatening toxic ingestion with agents that are highly protein-bound. Delays in seeking or reaching treatment and or diagnosis will attenuate the utility of bowel decontamination procedures. Carbamazepine is most commonly used for prevention of seizures, analgesia for trigeminal neuralgia and affective disorders, particularly bipolar disorder (8). Coma, somnolence, and cerebellar syndrome were the most common symptoms in overdose, with an increased incidence of seizures and respiratory depression in the lethal overdose group (9). There should be a low threshold for intubation in patients with borderline mental status because of frequent emesis and neurological compromise (10). Serum drug levels below 40 mcg/ml do not appear to accurately predict the severity of toxicity (8). However, cardiovascular and respiratory monitoring are essential. Repeat doses of activated charcoal therapy may useful by increasing the clearance of enterohepatic circulation. The half-life of serum carbamazepine can be significantly shortened by multiple doses of activated charcoal (2). Multiple doses of activated charcoal have been shown to be useful in enhancing the elimination of carbamazepine by binding the drug and preventing primary absorption as well as increasing biliary excretion (11). Unfortunately, the efficacy of activated charcoal is reduced dramatically when given above one hour postingestion (12).
Drug elimination by other methods is clearly needed to decrease the morbidity and mortality of carbamazepine intoxication.
The pharmacokinetic properties of carbamazepine play a role in determining management strategies. Management is largely supportive, through avoidance of drug interactions, large doses of activated charcoal, careful airway management and correction of electrolyte disturbances (2). Our patient was comatose and had critically high drug levels that had responded to multiple administrations of activated charcoal. Charcoal hemoperfusion is effective and may be considered for severe intoxication refractory to standard therapies (8).
Manifestations of carbamazepine overdoses reviewed from the literature were similar to those of tricyclic-anticholinergic overdose, with coma, hypotension, respiratory depression, cardiac arrhythmia,
abnormal movements and seizures. Management should consist of vigorous gastric lavage and installation of activated charcoal, full supportive care in a monitored setting and consideration of early charcoal hemoperfusion, before the patient become hypotensive (10).
Serum carbamazepine levels below 40 mcg/ml do not appear to accurately predict the severity of toxicity.
Finally, management of Carbamazepine overdose (drug level below 40 mcg/ml) are supportive care, large doses of activated charcoal, careful airway management, and correction of electrolyte disturbances.
Ahmet Akyol MD,
Department of Anesthesiology and Critical Care,
Karadeniz Technical University, Faculty of Medicine,
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