TRANYLCYPROMINE INTOXICATION WITH MALIGNANT HYPERTHERMIA, DELIRIUM, AND THROMBOCYTOPENIA

Ed J.M. Pennings, PhD^1,2, Robbert J. Verkes MD², Jan de Koning MD³, Johan J.M. Bommelé⁴, G. Sebastiaan I.M. Jansen PhD⁴, and Pieter Vermeij PhD¹ Affiliations: ¹Department of Clinical Pharmacy and Toxicology, ²Department of Psychiatry, ³Department of General Internal Medicine, Leiden University Medical Centre, Leiden, the Netherlands; ⁴Psychiatric Hospital Bloemendaal, Monster, the Netherlands. Key words: tranylcypromine, hyperthermia, thrombocytopenia, serotonin, monoamine oxidase, intoxication. Correspondence: Dr E.J.M. Pennings, Leiden University Medical Centre, Toxicology Laboratory, L1-P, P.O. Box 9600 2300 RC Leiden, The Netherlands, + 31 71 5262202 fax: 5266759

Introduction

Tranylcypromine is an irreversible monoamine oxidase (MAO) inhibitor used in the treatment of therapy-resistant depression and atypical depression.¹ Here we describe a case of an almost fatal intoxication in a male after ingestion of 4 g of tranylcypromine.

Case

A 41-year-old Caucasian divorced male was incidentally found in coma along with a note indicating that he had taken 400 10-mg tablets of tranylcypromine with the intent to commit suicide. The man, in whom a narcissistic personality disorder had been diagnosed, was known with persisting suicidal thoughts for over 20 years. He had been recently treated clinically for a major depressive episode. Pharmacotherapy with nortriptyline alone, and with lithium addition, had been unsuccessful. Tranylcypromine was started, and a dose of 50 mg two times a day resulted in a partial remission of the depressive symptoms. Four weeks before the suicide attempt mentioned above, he had attempted suicide for the first time with an overdose of nitrazepam. There was no history of alcohol or substance abuse.

On arrival in the hospital, approximately 8 hours after the ingestion of the tranylcypromine overdose, the patient was comatose (Glasgow coma scale score 3). The temperature was 35.6° C, the pulse was 143/min, the respirations were shallow at 40 breaths per minute; and the blood pressure was 123/68. Coarse rhonchi were heard over all lung fields. The blood gas analysis was follows: pH 7.33, pCO₂ 7.7 kPa, pO₂ 8.4 kPa, bicarbonate 30 mmol/L, oxygen-saturation 90%.

Because of respiratory insufficiency, the patient was intubated and mechanically ventilated. In the first hours after admission he developed chills and fever which were attributed to an infectious complication of the insertion of a suprapubic bladder catheter. Intravenous benzylpenicillin was started. Blood cultures appeared positive for Streptococcus sanguinis the next day. During the night, diffuse muscular contractions and tremors started to occur. Epilepsy was excluded by monitoring brain activity by electroencephalography. The next morning (day 2) the patient developed a malignant hyperthermia syndrome with shaking of the whole body and a rise in body temperature from 39.6° C to 41.6° C in about 1 hour. The hyperthermia was treated successfully by spraying cold water over the body and fanning, and by administration of the Ca²⁺ release blocker dantrolene at 2.5 mg/kg intravenously (total dose 160 mg). Hypotension ensued, which was treated with colloids and noradrenaline (0.1 ?g/kg/min) under Swan-Ganz catheter monitoring. An initially low serum potassium level of 3.3 mmol/L was corrected by intravenous potassium chloride. Other electrolytes and liver function tests were normal. Creatine phosphokinase activity in blood rose to 419 U/L on day 3. A transient impairment of renal function was noted. After regaining consciousness and extubation (day 3), the patient was disoriented in time and place, unable to sustain attention, and showed impaired memory, incoherent thoughts and ataxia. He was agitated, paranoid with inadequate affect. Vivid visual hallucinations were present. Haloperidol 5 mg two times a day was given for the treatment of the delirium. The delirium and ataxia resolved in 7 days.

Methods

Tranylcypromine Concentrations in Blood: Tranylcypromine concentrations were determined in blood serum samples by capillary gas chromatography after derivatization with heptafluorobutyric anhydride (HFAA).² Briefly, to 2 mL of serum, p-methylamphetamine was added as the internal standard followed by the addition of 100 µL 5 M sodium hydroxide and 5 mL hexane for extraction of compounds. After mixing and centrifugation, the organic layer was transferred into a glass tube, 40 µL pure HFAA was added, and the tube was sealed with a ground-glass stopper. The mixture was allowed to react for 15 minutes at 70 ° C and then cooled to room temperature. The organic phase was washed by mixing it for 40 seconds with 1 mL of 5 M sodium hydroxide. After centrifugation, the organic phase was concentrated at room temperature under a gentle stream of nitrogen until a volume of approximately 50 µL remained. Of this residue, 30 µL was transferred into an injection vial, and 1.2 µL was injected into the gas chromatograph equipped with a fused-silica capillary column (CP-Sil-5CB) and a nitrogen/phosphorus detector.The injector was operated in the splitless mode. The column temperature program was as follows: 80° C to 140° C (10° C/min); holding time 1 minute; 140° C to 200° C (30° C/min); and holding time 2 minutes. Calibration graphs were contructed with known amounts of tranylcypromine and amphetamine added to blank serum samples. The tranylcypromine concentration in the blood sample taken on admission was 19880 ng/mL. This value is more than 1000-fold the concentration we have found at dosages of 50 mg two times a day (7 - 14 ng/mL, trough value, i.e. 12 hours post-dose). This value is approximately 300 and 600 times, respectively, the concentrations of 61.0 ng/mL (median for nonresponders) and 29.2 ng/mL (median for responders) reported³ in a clinical study with maximum daily doses 60 mg (actual doses not stated) and with tranylcypromine concentrations determined 5 hours postdose. The concentrations found in blood samples on the following days were as follows: 1140 ng/mL (day 2); 28 ng/mL (day 3); 6 ng/mL (day 4); 1 ng/mL (day 8). To confirm the suggestion⁴ that amphetamines are metabolic products of tranylcypromine, we also searched for the presence of amphetamine in the serum samples by the same method. Amphetamine was not found.

Serotonergic Parameters in Blood: The course of thrombocyte number, MAO activity in whole blood⁵, and serotonin concentration in whole blood⁶ are shown in Figure 1. On admission (day 1), MAO activity was absent (reference range 18-57 U/L). Thrombocyte numbers (x 10⁹/L) on consecutive days were as follows: 198 (on admission); 141 (day 2); 72 (day 3); 64 (day 4); 42 (day 6); 34 (day 7); 43 (day 8); 139 (day 9); 325 (day 10); 554 (day 15); 444 (day 20); and 292 (day 50). Thrombocytopenia developed on the second day (reference range 150-350 x 10⁹/L), and blood serotonin concentration decreased below the reference range (0.5-1.6 ?mol/L) on the fourth day. Disseminated intravascular coagulation was excluded. Thrombocyte number, serotonin concentration and MAO activity recovered during a period of 9 to 10 days. The thrombocyte number and the serotonin concentration transiently increased to above the reference range and returned to normal after about 50 days.

Discussion