Clinical Toxicology, 35(3), 321-324 (1997)

Fatal Bupropion Overdose

Carson R. Harris; John Gualtieri; Gerrald Stark

St. Paul-Ramsey Medical Center, St. Paul (CRH, GS); Minnesota Regional Pokon Center, Bloomington (CRH. JG), Minnesota

ABSTRACT

Backeround : Bupropion is a unique monocyclic antidepressant that has been known to cause seizures in high therapeutic doses and in acute overdoses. Death due to ingestion, however, is a rare occurrence. Case Remrt: We report a case of a 26-year-old man who ingested 23 g bupropion, developed seizures and hypoxia, and presented in cardiac arrest. The patient was resuscitated in the emergency department, but died 4 d after supportive intensive care. Conclusions: Bupropion overdose may lead to recurrent sehres, hypoxia and death. Aggressive management of severe bupropion overdose is recommended.

INTRODUCTION

Bupropion (Wellbutrin*) is a propiophenone with a chemical structure similar to phenylethylamine derived compounds such as amphetamine. It is a relatively new antidepressant for which a mechanism of action has not been elucidated. In significant acute overdoses, sinus tachycardia, tremors, and seizures are the expected effects and occur between 1 and 4 h after ingestion.' No major cardiovascular toxicity or deaths were noted in a review of 58 pure bupropion overdoses by Spiller and colleague^.^ Few cases of cardiac arrest have been reported in the

recent l i terat~re .~-~ We report the case of a fatal overdose involving bupropion that presented to our institution.

Case Report

A 26-year-old male with a history of depression and cocaine abuse was transported to the Emergency Department (ED) in cardiac arrest after an apparent overdose of his antidepressant medications. He had taken the medication approximately 2 h prior to the paramedics' arrival at his house. A local crisis center worker, who talked to the patient on the phone was told by the patient that he had taken an

Correspondence: Dr. Carson Harris, Emergency Medicine Department, Ramsey Medical Center, St. Paul, MN 55101- 2595. Tel: 6 12/22 1-33 1 1; Fax: 6 12/22 1-8756; Email: harri037@maroon. tc .umn.edu

321

Copyright 1997 by Marcel Dekker, Inc.

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322 Harris, Gualtieri, and Stark

overdose and had only two hours left to live, called the ambulance. When police and medics arrived at the patient’s home, they noted him to be lethargic and within 5 min of their arrival, the patient had a general i i clonic seizure. Empty pill bottles labeled bupropion and paroxetine were found at the scene.

In the postictal state, medics noted that the patient had a BP 160/88, P 13O/min, and R 32/min. An IV line was placed and oxygen was administered. While being transported to the ambulance the patient had an episode of emesis and then experienced another clonic seizure. Treatment with 5 mg diazepam and 50 mEq sodium bicarbonate IV (suggested by the Prehospital Base Station Wysician) failed to stop the seizure activity. He developed a bradycardia of 32 bpm and rapidly progressed to asystole. Prehospital resuscitation included attempts at endotracheal intubation and CombitubeO placement by medics. When this was unsuccessful, a nasopharyngeal airway was placed and the patient was ventilated with Bag-ValveMask. One mg boluses of epinephrine and atropine were administered with return of a pulseless wide complex ECG rhythm at 20 bpm. Repeat doses of epinephrine and atropine failed to increase the heart rate or generate a blood pressure (BP).

On arrival to the ED approximately 2 h 35 min postingestion, the patient had no spontaneous respirations and the monitor revealed asystole. Cardiac ultrasound examination showed no cardiac motion. Resuscitation efforts were continued with endotracheal intubation, central line placement, and administration of epinephrine, atropine, and sodium bicarbonate. Eight minutes after the patient’s arrival in the ED a palpable pulse was noted. A BP of 13/60 was obtained with a sinus tachycardia of 130 bpm. However, 10 min later the patient’s BP began to decrease. With the administration of a total of 1500 mL normal saline, and infusions of dopamine and norepinephrine his systolic pressure was maintained at 80. A nasogastric tube was placed in the stomach followed by instillation of 50 g activated charcoal with sorbitol.

The initial arterial blood gases (AF3Gs) during ED resuscitation revealed a pH of 6.75, K O 2 133 mm Hg, PO2 244 mm Hg. Repeat ABGs after sodium bicarbonate therapy showed pH 7.03, K O 2 73 mm Hg, PO2 384 mm Hg. With adjustments of the

ventilator settings a third ABG revealed pH 7.28, K O 2 51 mm Hg, poZ. 102 mm Hg. Other laboratory results obtained in the ED revealed a sodium of 146 mEq/L, potassium 2.6 mEq/L, chloride 104 mEq/L, carbon dioxide 16 mEq/L, glucose 153 mg/dL (85 mmol/L), urea nitrogen 5 mg/& (1.78 mmol/L), and creatinine 1.5 mg/dL (1 32.6 pmol/L). The magnesium and calcium levels were within normal range 2.6 mg/dL (1.07 mmol/L), 9.2 mg/& (2.30 mmol/L), respectively, but phosphate levels were < 1 mg/dL (C0.32 mmol/L). The CBC revealed a WBC of 18,500/mm3, hemoglobin 13.4 g/dL (134 g/L), hematocrit 42.3% (0.423 vol fraction), and platelet count of 214,0001 mm3. The ethanol, ethylene glycol, and methanol screens were negative. No illicit drugs, such as stimulants, hallucinogens, or narcotics were detected on rapid urine drug screening. The comprehensive serum and urine toxicology screens for over-the- counter and prescription drugs were positive only for benzodiazepines. The lithium concentration was 0.4 mEq/L and paroxetine was < 5 ng/mL (C15 nmol/L) on serum obtained at initial presentation.

A bupropion level obtained approximately 18 h after the patient’s arrival to the ED was 446 ng/mL (laboratory therapeutic levels are between 50 and 100 ng/mL) . The hydroxy-bupropion metabolite level was 3212 ng/mL. Subsequent levels of bupropion and the hydroxybupropion metabolite obtained 3 1 h after ED arrival were 135 ng/mL and 3109 ng/mL, respectively.

During the first day of hospitalization, the patient exhibited some eye-opening activity without external stimuli. The pupils were 7 mm and minimally reactive. On the second hospital day and subsequent days until his death, the patient was unresponsive. EEG and neurologic evaluations were consistent with a poor prognosis. On the fourth hospital day the patient was declared brain dead and disconnected from life supports with family members in attendance.

It was estimated that the patient had ingested 23 g bupropion based on the date that the prescription was filled and the number of pills dispensed.

DISCUSSION

Bupropion is a monocyclic antidepressant with a chemical structure similar to amphetamine and

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Bupropion Death 323

diethylpropion. Its therapeutic efficacy is reported to be comparable to the tricyclic antide~ressants.~ No serotonergic effect is noted, nor monamine oxidase inhibition. It was initially approved for use in the US for the treatment of depression in 1986, but was voluntarily withdrawn from the market because of a high incidence of seizures occurring at therapeutic doses. The drug was reintroduced in 1989 with new dosing schedule recommending maximum daily dosage of less than 450 mg/d.

Spiller and colleagues retrospectively reported 58 cases of pure bupropion ingestions. Seizures were noted in 21%. The time of seizure onset ranged from 1 to 8 h. Mixed overdoses involving bupropion and benzodiazepines did not show a protective effect of the benzodiazepines in preventing seizures.2 Our patient had an apparent seizure at 2 to 3 h following ingestion. He had recurrent seizures that did not respond to IV diazepam.

Cardiovascular effects of bupropion seen in the majority of overdoses have been limited to sinus tachycardia and hypotension.6 In the above study it was concluded that major cardiovascular toxicity was nonexistent. Our case began with tachycardia but progressed to a bradycardia and asystole arrest. The patient developed severe hypoxia and respiratory acidosis during the initial phase of his resuscitation that led to his death. Interestingly, in a study done by Glassman and Preude’homme, patients with a diagnosis of depression and with preexisting cardiac disease (including conduction disturbances) had little or no exacerbation of their underlying arrhythmia or ventricular function while taking bupropion?

Friel and colleagues reported three fatalities associated with bupropion. Two of these cases were found to have other drugs present (carbamazepine, thioridazine, and diphenhydramine). The third case was noted to have a positive urine screen for benzodiazepine but none was detected in the postmortem blood samples.3 There was very little clinical information provided in their report regarding the circumstances of the overdoses, and the largest amount ingested was estimated to be less than 10 g. The concentrations of bupropion in the postmortem blood ranged from 4OOO ng/mL to 13,000 ~~g/rnL.~-’ Our case is the first that we are aware of that provide concentration levels of the drug prior to the occurrence of death. Our concentrations are considerably lower but the

difference may relate to postmortem changes in drug distribution. Toxicologic screening in our patient revealed only bupropion in the blood samples. An empty bottle of paroxetine was found at the scene, but blood paroxetine at 18 h was essentially negative ( < 5 ng/mL).

Another interesting finding in our patient was the severe hypophosphatemia at C 1 .O mEq. Hypophos- phatemia has been noted in critically ill patients and in patients with brain Because phosphate is an intracellular ion, the significance of serum levels is not known. Low phosphate frequently occurs after brain death and may be associated with intmcellular transfer rather than depletion. There have been conflicting reports whether hypophosphatemia has significant cardiovascular consequences. Ognibene and colleagues found that a serum phosphate less than 2.6 mg/dL (0.84 mmol/L) is a significant predictor of ventricular tach cardia in patients with acute myocardial infarction!’ They recommended a more close scrutiny of the phosphate concentration in patients with chest pain. Riou and associates studied the effects of hypophosphatemia on myo- cardial function of brain-dead patients and concluded that there was no significant relationship W e e n phosphate concentrations and left ventricular ejection fraction area.’ The relationship of bupropion to this profound electrolyte disturbance is unknown. Our patient did receive catecholamines and sodium bicarbonate, both of which have been associated with the development of hypophosphatemia.’ Because of the extremely poor prognosis in our patient and the wishes of the family, there were no aggressive attempts to replace the phosphate or continue supportive care.

Our patient also had hypokalemia with a serum potassium of 2.6 mEq/L. Hypokalemia was reported in association with bupropion overdose by Spiller et aL2 The significance of this finding and whether or not it has any predictive value in fatal bupropion overdose is yet to be determined.

Although a major consequence of acute bupropion overdoses is the production of seizures, the possibility of a fatal outcome exists with massive overdose. Patients with overdose who present in status epilepticus should be aggressively managed and closely monitored for the development of cardiac dysrhythmias , acid-base and electrolyte imbalance, and cardiac arrest.

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324 Harris, Gualtieri, and Stark

Although early and successful airway may have affected the patient's outcome, it is difficult to say whether prehospital conditions and unknown variables, such as lighting and ambulance movement, had any effect on intubation success. The patient had a mesomorphic body habitus and was not considered obese. Intubation in the ED was performed by the Senior Staff and noted to be easy.

This patient developed seizures after his overdose of 23 g bupropion and subsequently deteriorated with a fatal cardiac dysrhythmia. It is the first case, to our knowledge, where bupropion and metabolite concentrations were obtained in the antemortem state. We recommend that patients ingesting what is considered a sizable overdose of bupropion should be admitted to an intensive care setting with continuous cardiac monitoring. Aggressive airway management is paramount to resuscitation efforts in such critical cases presenting with seizures or in cardiac arrest. It is important to be aware that brady-asystole arrest is a likely consequence of significant bupropion overdose resulting in seizure and hypoxia.

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REFERENCES

Rumack BH, Ekins BR. Bupropion therapeuticltoxic class. In: Poisindex Information System. Rumack BH, ed. Denver: Micromedex Inc, Edition expires 11130f95.

2.

3.

4.

5.

6.

7.

8.

9.

Spiller HA, Ramoska EA, Krenzelok EP, et d . Bupropion overdose: a 3-year multicenter retro- spective analysis. Am J Emerg Med 1994;12:4345. Friel PN, Logan BK, Fligner CL. Three fatal drug overdoses involving bupropion. J Anal Toxic01 1993;17:436438. Rohrig TP, Ray NG. Tissue distribution of bupropion in a fatal overdose. JAnal Tm'col1992;16:343-345. Ramcharitar V, Levine BS, Goldberger BA, Caplan YH. Bupropion and alcohol fatal intoxication: case report. Forensic Sci lnt 1992;56151-156. Van Wyck Fleet J, Manberg PJ, Miller LL, et d. Overview of clinically significant adverse reactions to bupropion. J a i n Psychiafry 1983;44: 191-196. Glassman AH, Preud'homme XA. Review of the cardiovascular effects of heterocyclic antidepressants. J Clin Psychiatry 1993;54:16-22. Riou B, Kalfon P, Arock M, Goarin JP, Saada M, Viars P. Cardiovascular consequences of severe hypophosphataemia in brain4ead patients. Br J Anaesth 1995;74:424429. Brown GR, Greenwood JK. Drug- and nutrition- induced hypophosphatemia: mechanisms and relevance in the critically ill. Ann Phurmacother 1994;23:626- 632.

10. Ognibene A, Ciniglio R, Greifenstein A, et d . Ventricular tachycardia in acute myocardial infarction: the role of hypophosphatemia. South Med J 1994;87:65-69.

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