DISSCUSSION
Our patient presented with a fatal ventricular arrhythmia in the setting of volatile hydrocarbon inhalation, potentially compounded by concomitant catecholaminergic stimulation due to methamphetamine use. To our knowledge, this represents the first clinical description of torsade de pointes associated with volatile hydrocarbon inhalation, though sudden death has been associated with this practice. Despite prior reports of sudden death, no definitive rhythm documentation has been published (1-3). Tetrafluoroethane is used as a propellant for wine cork removers and gas dusters, whose intended use is to remove debris and dust particles from computer keyboards. These products are not FDA regulated and are widely available. Volatile inhalant abuse is performed by sniffing (e.g. sniffing glue), bagging, or huffing. Bagging is performed by breathing the vapor directly from a plastic or paper bag to augment the concentration of inhaled fumes. Huffing is perhaps the most potent form of abuse as it is performed by soaking a cloth in the hydrocarbon and holding it over the nose and mouth in order to maximize the intoxicant concentration (4). These inhalants are abused as an inexpensive alternative to typical drugs of abuse. Most inhalants affect the central nervous system and lead to euphoria, often accompanied by slurred or distorted speech, lack of coordination, dizziness, and hallucination.
While the use of volatile inhalants is associated with both cardiotoxicity and sudden death (1), less is known about the cardiovascular properties of these agents. The air conditioning gas, Freon, for example, has been associated with sudden death, but an arrhythmic etiology has not been described (3). However, a few cases of ventricular fibrillation occurring with trichloroethylene (4) and butane (5) suggest that these agents may promote malignant ventricular arrhythmias. Specifically, cardiac sensitization to catecholamines is a recognized result of exposure to halogenated hydrocarbons solvents, including aerosol propellant (6), which was the putative culprit in the present case. Commercially available volatile chemicals are analogous to the general anesthetics. At physiologically relevant concentrations they interact with the primary repolarizing cardiac potassium ion channel, known as the human cardiac ether a‘ go-go–related gene (hERG), which encodes Ikr, the delayed-rectifier potassium ion current. At higher concentrations, these chemicals may also interact with the slowly activating delayed rectifier potassium channels (IKs), as well as calcium and sodium channels (6).
The compound used in the current case, tetrafluoroethane, has not been extensively studied with regard to electrophysiologic properties. Nevertheless, the molecule is structurally similar to trichloromethane (aka, Chlorophorm) which is an archetypical volatile anesthetic. Chlorophorm is a colorless, sweet-smelling, dense liquid infamously associated with sinister criminal actions whereby a chloroform-soaked rag is applied to the nose and mouth to render victims unconscious. Arrhythmogenesis is presumed secondary to Ikr blockade with an inhibitory concentration required to block 50% (IC50) approximately 5 mmol/L (7). Other anesthetics such as halothane and sevoflurane exhibit only modest Ikr blockade at supratherapeutic concentrations, yet may lead to IKs blockade (8). In the present case, we speculate that volatile hydrocarbon inhalation led to delayed repolarization given prolonged QTc on admission. This coupled with enhanced automaticity and triggered activity (early afterdepolarizations) created the substrate for arrhythmia (6) whereby we speculate that concurrent amphetamine use represented the trigger.
Amphetamines are well known to increase catecholamine concentrations, both centrally and peripherally, by stimulating their release, blocking their reuptake, and inhibiting their metabolism by monoamine oxidase (9). Clinically, this results in tachycardia, vasoconstriction, and hypertension (10). The most common clinical presentations in amphetamine users include chest pain, tachyarrhythmias, palpitations, elevated blood pressure, and myocardial injury, mediated through a confluence of increased myocardial oxygen demand secondary to enhanced chronotropy, wall stress, and afterload, with a simultaneous reduction in coronary blood flow due to intense vasoconstriction. The clinical scenario in the present case, however, was not consistent with a primary ischemic etiology, given normal global and segmental left ventricular systolic function.
In the case of our patient, amphetamines likely served as the catalyst for fatal arrhythmia as they are known to be associated with sudden cardiac death due to malignant ventricular arrhythmias in susceptible individuals (10), but are not definitively known to prolong the QTc-interval in humans. Although one study found an association between methamphetamine use and QTc-prolongation (11), confounding factors may have contributed. Nonetheless, studies in rats suggest that this effect may be due to the inhibition of transient outward potassium current and the inward rectifying potassium current via its effects on the L-type calcium channel (12). This effect, in conjunction with volatile hydrocarbons that block Ikr, may be synergistically cardiotoxic.
The present case reveals a fatal malignant ventricular arrhythmia, which occurred in the setting of concomitant methamphetamine and inhalational hydrocarbon intoxication. We concede that a causal connection between huffing and torsade de pointes cannot be definitively made given concomitant methamphetamine use. Moreover, because this patient only recovered brainstem reflexes, serial ECG was not performed, which precludes a diagnosis of congenital long QT syndrome.
Nevertheless, there are no reports of torsade de pointes clearly and directly related to amphetamines, or the medications used to treat attention deficit disorder (13). In support of this, methamphetamine is not considered a potent Ikr -blocker and was more likely a triggering factor rather than a QTc-prolonging drug (14). Amphetamines, therefore, have a theoretical risk of causing arrhythmias in predisposed patients given their inherent sympathomimetic properties. Nonetheless, using a validated score for drug-associated adverse events, the association between huffing and torsade de pointes is considered probable (15), particularly in light of the temporal association with sudden cardiac death. Importantly, although isolated “huffing” intoxication is rare in the developed world, it may be used to augment the physiologic high associated with more expensive drugs of abuse in certain low-income patient populations.
In summary, this case highlights the fatal synergistic effects of increased catecholamines in the setting of prolonged QTc due to blockade of the delayed potassium rectifying channel (IKr). In the appropriate setting, clinicians should consider this compound in the differential diagnosis of patients with idiopathic ventricular fibrillation or torsade de pointes in the setting of intoxication. A prompt search for key historical clues such as paper bags or canisters may be helpful. In addition, an assiduous effort to rapidly correct underlying metabolic abnormalities associated with prolonged QTc has the potential to improve patient outcomes.