Some Observations on the Etiology of the Fulminant Hyperthermia—Stress Syndrome

SOME OBSERVATIONS ON THE ETIOLOGY OF THE FULMINANT HYPERTHERMIA-STRESS SYNDROME CHARLES H. WILLIAMS* The fulminant hyperthermia-stress syndrome (malignant hyperpyrexia , malignant hyperthermia, porcine stress syndrome) is an inborn error of metabolism (genetic disease) that affects man [1], swine [2-6], dogs [7], cats [8], and horses [9, 10]. The disease syndrome occurred as early as 1922 in man [11], but it was Denborough's article about the familial nature of the problem that sparked new interest in the etiology of the disease [12]. A number of review articles have appeared which document the extensive incidence of fulminant hyperthermia in man as a worldwide syndrome [13-15]. The usual rate of occurrence is 1:10,000-1:15,000 in a normal hospital population exposed to anesthesia [16], however, Dr. W. G. Locher of Wausau, Wisconsin, reports a 1:1,000 rate of occurrence in the Wausau Hospital due to a localized concentration of the genetic carriers of the defect [1 1]. The syndrome consists of a tachycardia [17-19], a fulminating body temperature (up to 44.4° C in man [17] and 48.2° C in swine [20]), severe metabolic and respiratory acidosis as the result of the rapid accumulation of lactate in the blood [18], serious serum electrolyte changes with marked hyperkalemia in the terminal period [16, 17], and involuntary skeletal muscle rigor in 75 percent of the human cases [17]. Mortality rates are greater than 70 percent in man [16]. The syndrome is usually triggered in man by the administration of a potent inhalational anesthetic such as halothane and/or muscle relaxants , especially the depolarizing type such as succinylcholine, during a surgical procedure [16]. Cases have also been reported during dental anesthesia [21, 22]. The recent report of a stress susceptible clan offulminant hyperthermia people in Nebraska [10] demonstrates that the syndrome in man parallels the identical syndrome we have been studying in swine since we identified our first susceptible pig in July 1970. The porcine stress syndrome (PSS) was described by Topel et al. as an *Departments of Medicine and Biochemistry, University of Missouri, and Harry S. Truman Memorial Veterans Administration Hospital, Columbia, Missouri 65201. I thank Ms. Velma Fischbeck for typing the manuscript and Wayne Meyer for the illustration. 120 I Charles H. Williams · Fulminant Hyperthermia Stress inability of susceptible swine to endure the usual environmental stressors , such as handling, hauling, moving, high ambient temperature, breeding activity, or fighting for social order [19]. Subsequently several other groups reported a similar stress susceptibility occurring in several breeds of swine [4, 23, 24]. Prior to 1968 several meat-science laboratories had been studying a metabolic change that occurred in the carcass after slaughter to produce muscle that was pale, soft, and exudative (PSE) [25, 26]. The main biochemical changes which occurred in defective animal carcasses appeared to be (1) a high rate of glycolysis that rapidly depleted muscle glycogen [27], (2) the rapid acidification by lactate of the muscle at high temperature [28], and (3) a denaturing of muscle proteins which decreased their water-binding capacity [29]. We now know that the fulminant hyperthermia-stress syndrome pig produces the pale, soft, exudative carcasses [30]. Other groups have reached the same conclusion [31, 32]. The pale, soft, exudative (PSE) carcasses are derived from animals that are hypermetabolic in vivo [30]. The development of PSE muscle in the carcass is a function of(1) the amount of glycogen stored in the muscle, (2) rate of anaerobic glycolysis, and (3) rate of carcass cooling. Those animals which are fed so that a maximum amount of glycogen is stored, who have an accelerated rate of metabolism in vivo, and with heavily muscled hams and loins will have the most severely PSE affected carcasses. Normal or affected animals that are held off feed, which depletes glycogen stores, should not produce PSE muscle. They may produce a high pH carcass which results in "dark cutting" muscle. Genetic Basis of the Syndrome Fulminant hyperthermia has been reported to be transmitted as a dominant gene with "reduced penetrance" and "variable expressivity" in humans [32]. We have raised 249 animals derived from the original herd boars (Lucky Strike, Hyland's Flash, and Hyland's Distinction). Extended...