Cardiogenic shock and status epilepticus after massive bupropion overdose

Abstract

Background. To describe a profound cardiac dysfunction and a status epilepticus after a massive bupropion overdose. Case report. A 35-year-old man was admitted in coma following the deliberate ingestion of 12 g of bupropion. The course was marked by the rapid onset of severe and prolonged status epilepticus and cardiogenic shock. Plasma bupropion level determined four hours after the estimated time of ingestion was 1.4 mg/L. All clinical features resolved completely in response to symptomatic treatment. Conclusion. Several cases of bupropion overdose, with sinus tachycardia and seizures rapidly corrected by symptomatic treatment, have been reported in the literature. To our knowledge, this case of overdose with bupropion alone, at very high doses, is the first to describe clinical features comprising severe and prolonged status epilepticus and direct cardiotoxicity with the development of cardiogenic shock documented by echocardiogram.

Keywords: :

• Overdose
• Bupropion
• Cardiogenic shock
• Status epilepticus

Bupropion is an atypical antidepressant marketed for the treatment of severe depression, anxiety disorders accompanying alcoholism and bipolar disorder; and, more recently, smoking cessation (1–3). Bupropion is a monocyclic antidepressant belonging to the aminoketone class, structurally related to amphetamines. It is a selective inhibitor of dopamine, norepinephrine and serotonin reuptake. It also possesses anticholinergic activity. Its mechanism of action in smoking cessation remains unknown. We report a case of deliberate overdose with 12 g of bupropion associated with status epilepticus and severe cardiac dysfunction. As there were no specific intervention and measurement, the hospital ethics committee approved this case report without informed consent.

Case report

A 35-year-old man was admitted to the intensive care unit with toxic coma following deliberate ingestion of eighty 150 mg sustained-release tablets (12 g) of bupropion. The past medical history included schizophrenia since the age of 22 years and an estimated five packets of cigarettes per day. His usual therapy comprised zopiclone and olanzapine. Treatment with bupropion was recently initiated to facilitate smoking cessation. The patient was found at home 90 minutes after the estimated time of drug ingestion. He presented in a deep coma (Glasgow Coma Score 3) with no localizing signs, a bilateral symetric and reactive mydriasis, and moderate hypotension (BP 95/60 mmHg). His temperature was 37.5°C. The initial electrocardiogram showed only a sinus tachycardia at 96 beats/minute. Tracheal intubation was performed after celocurine and etomidate administration. The patient was then admitted to the intensive care unit (ICU). The initial clinical state and electrocardiogram on ICU admission remained unchanged. The blood cell count, electrolytes, blood gas, liver function tests were within normal ranges). Qualitative screening for tricyclic antidepressants, benzodiazepines, opioids and carbamates and blood ethanol level were negative. Management comprised continuation of mechanical ventilation and administration of 100 g of activated charcoal by a nasogastric tube.

Two hours after admission, the patient developed generalized seizures, recurring despite administration of clonazepam (1 mg bolus followed by continuous infusion of 3 mg/day) followed by phenobarbital (10 mg/kg bolus over 20 minutes, followed by continuous intravenous infusion of 10 mg/kg/day). Due to persistence of these generalized seizures, thiopental was administered at a dose of 3.5 mg/kg/h, which allowed clinical and electroencephalographic control of the status epilepticus. Absence of cerebral lesions was verified by computed tomography on the second day after admission. Thiopental was stopped on the third day with a therapeutic plasma phenobarbital level of 27.3 mg/L (therapeutic range 15 and 30 mg/L). The seizures recurred immediately after stopping thiopental, requiring resumption of thiopental at a dose of 3.2 mg/kg/h for six days. Status epilepticus was accompanied by a moderate elevation of creatine phosphokinase (CPK) not exceeding 3,400 IU/mL (17 times the upper limit of normal). Thiopental was progressively withdrawn with the addition of phenobarbital and valproic acid at therapeutic doses, monitored by plasma assays. No clinical recurrence was observed and EEG monitoring demonstrated the absence of subclinical seizures. Treatment with phenobarbital and valproic acid was continued for seven days.

Three hours after ingestion, the patient developed hypotension with a systolic blood pressure less than 90 mmHg, which was persistent despite plasma expansion with 1500 mL crystalloids, 500 mL colloids, and dopamine infusion at a rate of 5 μg/kg/min followed by norepinephrine at a rate of 0.3 μg/kg/min. Ultrasound examination confirmed cardiogenic shock with global alteration of cardiac function, systolic dysfunction with right ventricular hypokinesia associated with homogeneous left ventricular hypokinesia without ventricular dilatation. The shortening fraction was severely reduced and was estimated to be between 12% and 17%. Cardiac output was estimated to be 2.8 L/min. In the light of these results, dobutamine was administrated up to a dosage of 30 μg/kg/min and norepinephrine was gradually stopped, resulting in restoration of normal cardiac output, confirmed by esophageal Doppler, after twenty to thirty minutes. Twelve hours after admission, the patient developed an atrioventricular conduction disorder with nodal rhythm and premature junctional complexes, and prolonged corrected QT of 467 ms. Cardiac rhythm spontaneously returned to sinus rhythm after 24 hours of dobutamine and QT interval returned to normal in two days. The echocardiogram performed on the following day (second day after admission) showed a global improvement of right and left systolic function. Dobutamine was then rapidly decreased to 5 μg/kg/min, while monitoring cardiac output by esophageal Doppler, and was continued at this same dosage until the sixth day.

At 12 hours after admission, the patient developed hyperthermia with a temperature of 41.4°C in the absence of signs of sepsis and without muscle rigidity. All routine bacteriological samples remained negative. Hyperthermia persisted for 24 hours despite external cooling techniques combined with paracetamol injection (1 g × 2 doses in 12 hours). Normothermia was restored 24 hours after resolving of seizure.

At 48 hours after admission, the laboratory assessment demonstrated hepatic cytolysis with elevation of aspartate aminotransferase (AST) to 10 times the upper limit of normal and alanine aminotransferase (ALT) to 14 times the upper limit of normal, with no elevation of bilirubin. Liver transaminase levels returned to normal after one week.

Although the patient regained conscious after discontinuation of thiopental, extubation was not possible before the tenth day due to the development of ventilator-associated pneumonia. The patient was discharged from the intensive care unit 20 days after admission, with no clinical abnormalities. In view of the unusual features of the poisoning, quantitative bupropion assays were performed by HPLC-DAD using liquid-liquid alkaline extraction of plasma by hexane-iso-amylic alcohol 98-2 and then back extraction by 0.02N hydrochloric acid. Five bupropion levels were determined during the first 48 hours of hopitalization (Table 1). In all plasma and urine samples, three bupropion metabolites were also detected. Zopiclone and olanzapine were measured in the first plasma sample at 0.7 and 0.2 mg/L (therapeutic level below 0.1 mg/L for both). The time course of events is represented in Figure 1.

Table 1. Course of quantitative plasma and urine assays of bupropion during the first 48 hours of hospitalization

	H4	H18	H24	H36	H48
Plasma bupropion (mg/L)	1.40	0.25	0.16	0.07	0.05
Urinary bupropion (mg/L)	30	15	35	40	5.5

Therapeutic plasma level: 0.05 to 0.1 mg/L.

Fig. 1. Time course of events.

Discussion

This clinical case report describes the effects after an estimated 12 g bupropion overdose. The dose was estimated by family members and the physician and paramedics present at home. All the packages were near the patient and were empty.

To our knowledge, this is the first reported case of a patient who survived such a massive bupropion overdose. In most published cases, the ingested dose was much lower and was responsible for less severe clinical effects (4): generalized seizures easily controlled by benzodiazepines (5–7), sinus tachycardia (5,8–10), conduction disorders with widening of the QRS complex (11), and prolongation of the QT interval (12–14). These effects return to baseline within several hours (5,10,15). Peak plasma values are reached within three hours of ingestion, the mean elimination half-life is 21 hours, and bupropion is extensively metabolised by multiple pathways, with no single pathway predominating (16).

This case presents some differences from previous reports. Generalized seizures progressed to severe status epilepticus that was only controlled by continuous infusion of thiopental sodium. A high initial concentration of zopiclone did not prevent these seizures. A severe hyperthermia refractory to standard treatment modalities appeared at the time of status epilepticus and resolved shortly after the status epilepticus was controlled; the major generalized seizures may be the main cause for this hyperthermia as no infectious process was identified and the fever resolved without any antibiotic treatment. One of the outstanding features of this case is the development of cardiogenic shock, documented by echocardiogram and esophageal Doppler, with global impairment of cardiac function and development of arrhythmia with nodal rhythm and premature junctional complexes. Cardiogenic shock persisted for 48 hours before complete restoration of cardiac function allowed rapid tapering and withdrawal of dobutamine over five days. Finally, this patient with no history of liver disease, developed evidence of hepatic cytolysis during the first 48 hours of hospitalization, with elevation of hepatic transaminases up to 10- and 14-fold the upper normal limit. This complication is often encountered, as the development of moderate hepatic cytolysis is one of the known adverse effects of bupropion (17).

Quantitative bupropion assays (Table 1) confirmed the massive overdose with serum levels more than 15 times therapeutic levels (0.05 to 0.1 mg/L). The status epilepticus appears to be mainly attributable to bupropion. From a pharmacological point of view, onset of status epilepticus corresponded to the peak of serum bupropion concentration (between 2 and 3 hours after drug ingestion). The severity of the status epilepticus and the difficulties encountered to control it are probably related to the massive dose of ingested bupropion and subsequent high cerebral concentrations. In published data, cerebrospinal fluid concentrations are 10- to 25-fold higher than blood concentration (18–20). Hyperthermia cannot be attributed to malignant hyperthermia, because succinylcholine had been administered more than 12 hours before onset of fever. This hyperthermia could be attributed to a bupropion-induced serotonin syndrome, although a possible role of the patient's long-term treatment by neuroleptic drugs cannot be excluded

Massive overdoses are responsible for rapid death from asystolic cardiorespiratory arrest usually due to long intervals between the time of ingestion and the time of initial management (13,21). Cardiogenic shock can probably be explained by the short interval prior to management, allowing early and effective cardiovascular intensive care in a ventilated patient. The physiopathology of this myocardial dysfunction remains unknown. However, one must consider that the patient received other myocardial depressant agents, such as benzodiazepines and barbiturates, used in high doses to treat seizures

Finally, one must consider that bupropion was the main toxic drug involved. Qualitative screening for tricyclic antidepressants, benzodiazepines, opioids and carbamates and blood ethanol were negative. Etomidate, used to facilitate tracheal intubation, didn't contribute to the onset of seizures (more than three hours elaped between etomidate administration and the onset of seizures). Olanzapine (plasma concentrations twice the upper limit of therapeutic level) may have increased the toxicity of the bupropion overdose, but it cannot be considered as the main cause for the observed abnormalities; there are cases of olanzapine intoxication with similar plasma levels causing no clinical nor biological disturbances (22,23). Olanzapine, zopiclone, hypotension, low cardiac output, status epilepticus, and hyperthermia can contribute to hepatic cytolysis, which cannot be attributed to other hepatotoxic treatments (the patient received only 1 g × 2 doses in 12 hours paracetamol, and valproic acid was initiated at a time when liver function tests were normalized).

Conclusion

Several cases of bupropion overdose, with sinus tachycardia and seizures rapidly corrected by symptomatic treatment, have been reported in the literature. To our knowledge, this case of overdose with bupropion alone, at very high doses, is the first to describe clinical features comprising severe and prolonged status epilepticus and direct cardiotoxicity with the development of cardiogenic shock documented by echocardiogram. All clinical features resolved completely in response to symptomatic treatment, probably part as a result of early management after bupropion ingestion.