In 1937, Meek et al. (1937) refined the experimental protocol of Levy and used dogs as the experimental animal. They also demonstrated an increased sensitivity of the heart to hydrocarbons (cyclopropane) when inhalation was accompanied by intravenous injections of epinephrine. On the basis of those studies, the potential hazard associated with administering hydrocarbon anesthetic agents followed by epinephrine became clearly recognized.
As a result of those and later studies on the ability of anesthetic agents to produce cardiac arrhythmia in the presence of exogenous epinephrine, it became evident that hydrocarbons, both halogenated and nonhalogenated, alone or in combination with injected epinephrine could sensitize the myocardium to produce cardiac arrhythmia. The hydrocarbon concentrations required to produce such sensitization ranged from 0.5% to 90% in air.
Although cardiac arrhythmia presents a risk to anesthetized patients, it was not until the 1960s, when chlorofluorocarbons (CFCs) began to be used as aerosol propellants in consumer products, that cardiac sensitization received more toxicologic consideration. CFC propellants were sniffed to reach light anesthesia, that is, to get “high”; and there were 65 reported deaths from such abuse (Bass 1970; Reinhardt et al. 1971). Such deaths occurred during or shortly after inhalation of high concentrations of the aerosols and were generally accompanied by physical or other stress. The deaths were thought to be due to ventricular fibrillation resulting from cardiac sensitization caused by the combination of inhalation of high concentrations of aerosol propellants and high blood concentrations of endogenous epinephrine produced by excitement. At autopsy, there were no unusual pathologic findings, and no anatomic changes were seen in the heart, brain, or other organs. Cardiac sensitization as the cause of death was typically based on circumstantial evidence at the scene—the position of the body and empty aerosol cans and a lack of autopsy findings that might otherwise be responsible for the death.
Such abuse was of concern to the CFC manufacturers, who began to develop a toxicologic method that could determine the cardiac-sensitization potential of the chemicals. Reinhardt et al. (1971) and Clark and Tinston (1973) worked on identifying an appropriate animal model and determining appropriate doses of exogenous epinephrine to simulate circulating blood epinephrine.
As CFCs have been phased out over the last 2 decades in compliance with the Montreal Protocol, the search for effective alternatives has focused on using cardiac sensitization as a mechanism for ranking the human health risk posed by the alternative chemicals. In some applications, the exposures are very brief, lasting several seconds to a few minutes.