Salbutamol misuse or abuse with fatal outcome: A case-report

Abstract

Salbutamol is a short-acting agonist of the β₂ adrenergic receptors sometimes misused or abused, which can result in various cardiovascular adverse effects. We report one case of fatal salbutamol misuse or abuse in a 36-year-old poorly controlled female asthmatic patient with a past medical history of alcoholism and a recent smoking cessation. She died shortly after hospital admission following acute dyspnea and sudden collapse at home. Toxicological analyses evidenced salbutamol overdose, and necropsy showed acute lung edema and marked dysplasia of the right ventricle and revealed the patient was pregnant. The involvement of an initial disorder of the ventricular rhythm leading to cardiac failure is suggested by the presence of several combined pro-arrhythmogenic factors, such as arrhythmogenic right ventricle dysplasia, hypoxemia related to bronchospasm and salbutamol overdose.

Introduction

Salbutamol is a short-acting agonist of the β₂ adrenergic receptors, which has been reported to be involved in several cases of abuse by inhalation. ^1–3 Although the pursuit of psychoactive effects related to the propellant gases was the first hypothesis suggested to account for the reported misuse or abuse of salbutamol, nowadays the direct role of salbutamol is held to be the leading cause of such misuse or abuse. Psychic dependence can result from excessive use of salbutamol due to poor control of asthma. ⁴ Moreover, neuropsychiatric effects of salbutamol including antidepressive properties and hallucinations have been described, ^5–7 which can be the basis for reported abuse in healthy human subjects seeking the stimulatory or exhilarating effects of high doses (e.g. 10−15 puffs in a row). ⁸ Whatever the actual motivations, the misuse or abuse of salbutamol metered dose inhaler or other delivery devices is a matter of current concern. ⁹ We report one fatal case in a poorly controlled female asthmatic patient who evidenced salbutamol misuse or abuse. The death occurred in a context of acute dyspnea and sudden collapse, whereas actual salbutamol overdose was evidenced in a patient who presented several combined risk factors predisposing to the expression of salbutamol toxicity including arrhythmogenic right ventricle dysplasia, hypoxemia related to bronchospasm and pregnancy.

Case report

A 36-year-old woman with a past medical history of alcoholism and recent smoking cessation was being treated for asthma since childhood with a combination of the corticosteroid derivative fluticasone and the long-acting β₂ adrenergic agonist salmeterol (Seretide 250^©, GlaxoSmithKline, Marly-Le-Roi Cedex, France) by inhalation. In addition, she had a prescription of salbutamol (Ventoline aerosol^©, GlaxoSmithKline) for the symptomatic management of acute worsening episodes. She had been hospitalized on several occasions for severe asthma attacks and was considered to poorly adhere to her prescribed treatment, especially with a known misuse or abuse of salbutamol for which she had been repeatedly warned by her doctor and her pharmacist. Indeed, her pharmacist refused to dispense the drug on many occasions because of her too frequent demands. On July 2007, she was prescribed methylprednisolone and clarithromycin to treat acute bronchitis. In the afternoon of September 8, 2007, she had an asthma attack, which improved without medical care. Later on at 8 p.m., she complained of acute dyspnea, which was severe enough to require the assistance of the mobile emergency medical care unit that found her unconscious with asystolia. She immediately received heart massage, intubation and intravenous adrenalin (total dose = 6 mg), which enabled recovery of the cardiac activity with supraventricular tachycardia (heart rate between 109 and 211 bpm). Both her respiratory status (despite oxygen flow rate of 15 L/min) and hemodynamics (systolic blood pressure = 70−75 mm Hg) remained very fragile. She was admitted to the emergency department at 11 p.m. and shortly thereafter, she had cardiac arrest on 2 occasions. The second cardiac arrest could not be corrected despite the administration of 3 mg and then 2 mg of adrenalin. She was considered to be deceased at 11.30 p.m. Because of the rapid death after admission, no biochemistry analysis was performed. The post-mortem chest X-ray showed diffuse whitening of the lung fields. The initial qualitative toxicological analyses using liquid chromatography with photodiode array detection (LC-DAD) did not reveal any informative findings: no medicinal or toxic substances including ethanol were evidenced in her plasma. In contrast, relatively high levels of methylprednisolone and minute amounts of prednisolone and triamcinolone were detected in her urines, but no illicit recreative substances including cannabis, opiates, cocaine and amphetamine. However, salbutamol was detected in her urines and this later finding was confirmed by further analysis using liquid chromatography coupled to tandem mass spectrometry (LC-MS). Her measured levels of salbutamol were 40 ng/mL in the blood and 587 ng/mL in the urines. The histopathological examination confirmed the presence of extensive lung edema with sero-edematous and hemorrhagic alveolitis. Mild enlarged myocardium (heart weight = 360 g) was found with a macroscopic aspect of dysplasia of the right ventricle confirmed by microscopic findings, which evidenced a full thickness substitution of the right ventricle myocardium by fatty tissue. Left ventricle was normal. Arrhythmogenic right ventricular dysplasia (ARVD) was diagnosed. In addition, liver lesions typically associated with heart failure and marked steatosis, and hemorrhagic congestion of the spleen and kidneys were noted. Finally, the examination found that she was pregnant at 4 months of gestation. The cause of her death was diagnosed to be due to salbutamol overdose in a setting of arrhythmogenic dysplasia of the right ventricle.

Discussion

Salbutamol, a selective β₂ adrenergic agonist, can induce adverse cardiac effects including sinus tachycardia, ventricular and supraventricular tachycardia and myocardial ischemia, especially in cases of acute overdose, chronic abuse or intravenous injection. ^10–13 Indeed, even though β₁ adrenergic receptors predominate in the myocardium, β₂ adrenergic receptors are also present, which explains why β₂ adrenergic agonists can exert inotropic and chronotropic effects potentially leading to various cardiovascular adverse events including cardiac rhythm disturbances. It is noteworthy that several case reports of acute lung edema in pregnant women following the oral and/or intravenous administration of β₂ adrenergic agonists for tocolytic indications have been published. The underlying mechanism is still debated, but the hydric overload resulting from pregnancy is considered to be a predisposing factor. ^14,15

In this patient, the diagnosis of salbutamol overdose was confirmed by toxicological analyses. According to the International Association of Forensic Toxicologists (TIAFT), the therapeutic range of blood salbutamol levels is between 4 and 18 ng/mL, with toxic levels above 30 ng/mL and lethal levels above 160 ng/mL. ¹⁶ The blood level of 40 ng/mL measured in this patient, however, is in agreement with other forensic data, ¹⁷ and the urine level of 587 ng/mL confirmed a massive intake of salbutamol. Indeed, urine salbutamol levels have been found to be below 250 ng/mL in human subjects following the inhalation of 200 µg of salbutamol every 8 hours for 3 days, ¹⁸ and below 500 ng/mL in the vast majority of subjects following the inhalation of 1600 µg of salbutamol over the last 24 hours (including a dose of 800 µg during the last 4 hours). ¹⁹

Salbutamol overdose, associated with arrhythmogenic right ventricular dysplasia in a particular setting of hypoxia resulting from bronchospasm, is suggested to be a key contributing factor to the fatal outcome in this patient, even though a lethal asthma attack or cardiac failure related to ARVD with subsequent pulmonary edema cannot be excluded. No history of pre-existing cardiac disease was clearly identified, but a relative later alluded to the patient's cardiac problems. Salbutamol overdose can indeed be suspected to have caused inaugural ventricular dysrhythmia with subsequent heart failure. The initial clinical pattern (acute dyspnea and rapid collapse) was consistent with acute cardiac attack, which was supported with necropsy findings. Finally, the possibility that hydric overload as a consequence of pregnancy also played a role in the early development of acute lung edema leading to hypoxia and precipitating ventricular rhythm disturbances cannot be excluded.