Protracted deep coma after bromazepam poisoning

International Journal of Clinical Pharmacology and Therapeutics, Vol. 47 – No. n/2009 (nnn-nnn)

Protracted deep coma after bromazepam poisoning Case Report ©2009 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965

K. Lakhal1, S. Pallancher1, J.-C. Mathieu-Daude2, P. Harry3 and X. Capdevila1 1Réanimation

Polyvalente, Département d’Anesthésie-Réanimation A, 2Service de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, Centre Hospitalier Universitaire de Montpellier, and 3Centre Antipoison des régions Centre et Pays de la Loire, Centre Hospitalier Universitaire d’Angers, France Bromazepam-induced protracted coma

Key words anti-anxiety agents/poisoning – bromazepam/ poisoning – zolpidem/ poisoning – suicide, attempted – time factors – charcoal – intestinal dialysis – drug-drug interaction – esomeprazole – cytochrome – CYP2C19

Abstract. Background: Bromazepam intoxication is very common but surprisingly rarely reported. Case description: We describe the case of a 73-year-old woman who suffered from a prolonged coma after acute self poisoning with bromazepam (serum concentration of 2,000 ng/ml at admission, 2 – 10 hours after ingestion of up to 180 mg) and zolpidem (900 ng/ml at admission). Only the former lasted at toxic concentrations. Recovery of consciousness allowed extubation on Day 16. Repeat-dose activated charcoal (25 g every 6 h from Day 14 to 16) resulted in minimal effects on bromazepam grossly estimated kinetics. Conclusion: Despite its relatively low theoretic half-life, bromazepam may induce a prolonged life-threatening coma, even in the absence of renal or hepatic failure.

Introduction

Received March 11, 2009; accepted September 7, 2009 Correspondence to K. Lakhal, MD Réanimation Polyvalente, Département d’Anesthésie-Réanimation A, Hôpital Lapeyronie, Centre Hospitalier Universitaire, 34000 Montpellier, France [email protected]

Bromazepam, a widely used anxiolytic benzodiazepine, is one of the most frequently prescribed medications in Europe [Villa et al. 2007] and is the most frequently involved drug in acute self poisonings admitted to French emergency departments [Staikowsky et al. 2005]. Surprisingly, few case reports of bromazepam intoxication are available. Pure benzodiazepine or benzodiazepine-like drugs overdose rarely causes deep coma requiring mechanical ventilation and, even if, total recovery classically occurs within a few hours or days [Gaudreault et al. 1991, Michaud et al. 2001]. We depict a case of protracted sedation requiring 16 days of mechanical ventilation after bromazepam intoxication.

Case description A 73-year-old Caucasian woman (58 kg, 160 cm) was found unconscious, lying in her bed, surrounded by tablets.

Her medical history contained essential hypertension, diabetes mellitus, chronic atrial fibrillation, asymptomatic lacuna cerebri and ischemic embolic stroke 9 years earlier without sequela. Treatment comprised fluindione, amiodarone, dipyramidole, amlodipine, ramipril, gliclazide, atorvastatin, betahistine and zolpidem (10 mg per day). A once-a-day consumption of bromazepam was interrupted a few months earlier, as she was started on zolpidem. In the emergency department, altered consciousness was noted (Glasgow Coma Scale of 7) along with bradypnea (10/min) without hypothermia, pupillary abnormality or circulatory failure. The electrocardiogram exhibited sinus bradycardia (47/min), a prolonged but constant PR-interval (280 ms) and narrow QRS complexes. INR was 3.5. Intravenous flumazenil (0.3 mg followed by a 0.3 mg/h infusion) allowed an improvement in consciousness. However, an aspiration pneumonia made tracheal intubation necessary (etomidate 0.3 mg/kg, suxamethonium 1.3 mg/kg, fentanyl 3.5 µg/kg). Blood toxicological analysis of samples taken at hospital admission was negative for alcohol (enzymatic assay) and tricyclic antidepressant (immunoenzymatic assay). Liquid chromatography-mass spectrometry screening revealed bromazepam (2,000 ng/ml, therapeutic range 80 – 170 ng/ml) and zolpidem (900 ng/ml, therapeutic range 80 – 150 ng/ml). No other toxic substances were investigated. The ingestion-to-admission delay was estimated to be 2 – 10 hours. An empty package of each involved drug was found (total maximum intake of 180 and 140 mg of bromazepam and zolpidem, respectively). Aspiration pneumonia resolved in 3 days but, unexpectedly, the patient remained in an

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Figure 1. Evolution of serum bromazepam and zolpidem concentration during the ICU stay. The intestinal dialysis was not associated with a marked decrease in serum bromazepam elimination half-life. Half-life = apparent elimination half-life calculated between 2 serum concentrations. Intestinal dialysis = administration of 25 g/6 h of activated charcoal for 48 h.

areflective, hypotonic deep coma (Ramsay Scale 6, Glasgow Coma Scale 3) for several days. Brain CT-scan was unchanged as compared with that performed 3 years earlier. During the ICU stay, along with enteral feeding, the administered drugs were: unfractioned heparin, amiodarone (200 mg per day), insulin, enteral esomeprazole (20 mg per day) and an 8 days antimicrobial course (cefotaxime 1 g/8 h and metronidazole 500 mg/8 h). Serum glucose, electrolytes, oxygen and carbon dioxide were constantly kept in a normal range. At Day 2, a diagnostic injection of flumazenil (1 mg) led to a transient recovery and strongly suggested the role of bromazepam and/or zolpidem in the neurological impairment. Flumazenil was not continuously infused because this strategy is associated with an important extra cost [Guglielminotti et al. 1999] and is neither risk-free [nnn 1992, Mathieu-Nolf et al. 2001] nor impacts on patient’s outcome [Mathieu-Nolf et al. 2001]. A persistent high serum bromazepam concentration was measured during the ICU stay whereas zolpidem concentration declined in predictable first order fashion (Figure 1).

Measured creatinine clearance was constantly above 69 ml/min. Routine liver function tests remained in a normal range as did thyroid hormones. Serum proteins ranged from 39 to 62 g/l. From Day 14 to 16, repeated administration of activated charcoal through the gastric tube (25 g/6 h) [Malgorn et al. 2004], did not produce a marked change in bromazepam elimination half-life (Figure 1). No side-effect was observed except decreased intestinal transit. The patient regained consciousness and was extubated on Day 16. Clinical examination was then normal, except a mild confusional state. The patient was discharged from the ICU a few days later, without any neurologic residual effect.

Discussion We report the case of an acute self co-ingestion of a benzodiazepine (bromazepam), and a benzodiazepine-like drug (zolpidem), causing a prolonged coma requiring mechanical ventilation. Zolpidem is a hypnosedative benzodiazepine-like drug belonging to the imidazopyridine class. Its elimination half-life is remarkably short, close to 2.5 hours but probably longer in the elderly [Chouinard et al. 1999]. It is extensively metabolized in inactive metabolites. Because zolpidem and bromazepam have similar effects on the central nervous system through the same receptor complex, and are both reversed by flumazenil, distinguishing each drug involvement in the initial coma may be challenging. However, the faster decrease in serum zolpidem level strongly suggested that the prolonged sedation was only due to bromazepam intoxication. After ingestion, benzodiazepines are rapidly and almost totally absorbed. They undergo an intense hepatic metabolism [Gaudreault et al. 1991]. Contrary to zolpidem, bromazepam has an active metabolite (3-hydroxy-bromazepam), which has not been measured in our patient, even if it may also have contributed to our patient sedation. Bromazepam elimination half-life in healthy young subjects ranges between 10 to 30 hours [Kaplan et al. 1976, Ochs et al. 1987] but

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may be higher in the elderly [Ochs et al. 1987] or after massive ingestion [Megarbane and Baud 2002]. However, Koyama et al. [Koyama 2003] reported a mean elimination half-life of 29 ± 4 hours after acute poisoning, i.e. close to non-overdose values. Interestingly, the mean serum bromazepam level at admission was similar to that of our patient (1,871 ng/ml and 2,000 ng/ml, respectively) but, in our case, the bromazepam apparent elimination halflife was initially close to 150 hours. Some reports about deep coma induced by benzodiazepine poisoning are available. Surprisingly, despite the high incidence of bromazepam poisoning, reports of bromazepaminduced prolonged sedation are particularly scarce. Rudolf et al. [1998] reported the case of a 68-year-old woman who required 12 days of mechanical ventilation because of respiratory and brain-stem reflex impairment caused by a bromazepam overdose. Interestingly, serum bromazepam level at admission was three-fold that of our patient. Tas et al. [1986] described an overdose with 200 – 300 mg of bromazepam with a peak concentration of 5,800 ng/ml on the first day which decreased to 1,800 ng/ml on the Day 7. Importantly, other co-ingestants could have contributed to the protracted coma. Moreover, a persistent gastrointestinal burden of the drug may be another strong explanation to the apparent prolongation of elimination, as suggested by the small spike in serum concentration seen on Day 13 (Figure 1). Interestingly, as reported in a clonazepam-induced prolonged comatose state [Guglielminotti et al. 1999], the slow elimination of bromazepam in our patient may be due to impaired hepatic isoenzyme of cytochrome P450 (CYP) activity, which is the major metabolic pathway of bromazepam [Kaplan et al. 1976]. Indeed, bromazepam clearance is decreased by interaction of non-specific inhibitors of CYP [Ochs et al. 1987, van Harten et al. 1992]. Remarkably, the responsible isoenzyme of CYP in bromazepam metabolism has not yet been clarified [Oda et al. 2003]. Our patient may be a “poor metabolizer” because of constitutional lack of the concerned CYP isoenzyme activity. For example, 3 – 6% of the Caucasian [Jacqz et al. 1988] and 19 – 23% of the Japanese populations [Horai et al. 1989] lack of CYP2C19 [Gerson and Triadafilopoulos 2001]. Further, the re-

sponsible isoenzyme of CYP may have been inhibited by a coadministered medication during the patient’s ICU stay e.g. esomeprazole, the S-isomer of omeprazole, which is a CYP2C19, CYP3A4 and CYP2C9 inhibitor [Li et al. 2004]. CYP3A4 and CYP2C9 inhibition doesn’t alter bromazepam kinetics [Oda et al. 2003, Ohtani et al. 2002]. Further, drug-drug interactions with esomeprazole are considered as mainly induced by CYP2C19 inhibition [Gerson and Triadafilopoulos 2001, Liu et al. 2005]. Therefore one may hypothesize that, as for diazepam [Robinson and Horn 2003] or clorazepate [Maslin et al. 2005], the metabolism of bromazepam involves CYP2C19 and that it may be altered by the co-prescribed esomeprazole. Cases of loss of vigilance or prolonged sedation due to the interaction between clorazepate and esomeprazole were reported [Achim 2000, Maslin et al. 2005]. To our knowledge, this is the first report of a possible similar interaction involving the widely used bromazepam. Among the other co-administered drugs, amiodarone (consumed for many years by our patient) and especially its main metabolite, desethylamiodarone, moderately decrease the activity of a wide range of CYP isoenzymes [Ohyama et al. 2000] and may have interacted in a synergistic manner with esomeprazole in decreasing bromazepam clearance. Metronidazole [Haas et al. 2001], cefotaxim or heparin seem unlikely to interact with CYP. The above-mentioned hypotheses, constitutional or induced low CYP isoenzyme activity, may coexist as the inhibiting role of esomeprazole is more patent among poor metabolizers [Gerson and Triadafilopoulos 2001, Klotz et al. 2004]. Zolpidem hepatic biotransformation by several CYP isoenzymes [Hesse et al. 2003] could explain that esomeprazole did not affect its pharmacokinetics. Moreover, zolpidem itself is unlikely to inhibit CYP activity [von Moltke et al. 2002]. In an attempt to enhance bromazepam clearance, intestinal dialysis was carried out by repeat-dose activated charcoal [Arimori and Nakano 1986, Harry and Gamelin 2006]. Thus, the large amount of serum free bromazepam (probably higher in hypoproteinemic ICU patients than the 30% observed in

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healthy volunteers) makes it available for diffusion toward the gut for charcoal adsorption across the gastrointestinal membrane barrier. A successful effect of late intestinal dialysis has been described in diazepam [Traeger and Haug 1986] and clorazepam [Dorrington et al. 2003, Malgorn et al. 2004] poisoning but this strategy was never reported in bromazepam intoxication. However, despite the fact that extubation was possible after intestinal dialysis, bromazepam elimination halflife did not seem to be markedly altered by intestinal dialysis. Nevertheless, a more extensive toxicological analysis is required to confirm this possible lack of effect especially for higher bromazepam serum level than seen in our patient at Day 14.

Conclusion Bromazepam may induce protracted sedation. The influence of drug-drug interaction and intestinal dialysis on bromazepam elimination half-life deserves further study.

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