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.