Advanced Research on Malignant Hyperthermia: A Runaway Thermogenic Futile Cycle at the Sodium Channel Level

Malignant Hyperthermia (“MH”)—the rapid onset of extremely high fever with muscle rigidity—is
caused by a runaway heat production futile cycle mediated via the sodium channels at the myoneural
receptor sites. MH is not triggered by non-depolarizing muscle relaxants; however, depolarizing
muscle relaxants may trigger it [1]. Here we present a de novo hypothesis of how MH is triggered and
develops. We believe that the acetylcholine receptor/sodium channels in the muscles of MH
susceptible pigs initiate MH by allowing an increased flux of sodium ions when it is depolarized by
acetylcholine or other depolarizing agents, such as succinylcholine and Halothane. Our theory is
consistent with our observations of the effects of general anesthetics over twenty years.
Succinylcholine is a depolarizing agent that is a potent MH trigger. Acetylcholine, the natural
depolarizing muscle activator, may trigger MH if the susceptible patient or animal is exposed to
sufficient stress, i.e., during strenuous activity, such as transport, fighting, breeding, etc. Halothane
apparently destabilizes the myoneural sodium channels, which rapidly induces MH. The increased
sodium channel activity releases heat with cascades that further releases of heat which results in the
rapid onset of MH. MH susceptible pigs have increased action potential amplitudes at their myoneural
junctions that are abnormally long in duration. This increased activity is thought to induce hypertrophy
of muscle mass, increase metabolic rate, and cause other physical manifestations. When slaughtered,
this increased metabolic activity causes the rapid post mortem release of heat in the muscles of MH
susceptible pigs and, at the same time, the accumulation of low acidity, all of which denatures the
muscle proteins to result in a pale, soft, exudative, pork meat considered to be of lesser quality for
human consumption. The potency of inhalation anesthetics as a MH triggers varies widely. The
inhalation anesthetic Halothane is a strong trigger of MH, causing MH within minutes of exposure. In
contrast, the anesthetic Sevoflurane is a very weak trigger of MH, requiring several hours of inhalation
exposure to trigger MH. Because of this, changing from Halothane to Sevoflurane as the general
anesthetic of choice for surgeries in hospitals in the Greater Kansas City area during 1994 to 2006 led
to an 11-fold decrease in the incidence of MH, from 1:50,000 to 1:550,000 [2]. One non-depolarizing
muscle relaxant, Organon 9426 (“Rocuronium”) temporarily prevents MH in MH susceptible pigs when
they are given sufficient dosages of it before being challenged with either Halothane or
succinylcholine. Binding Rocuronium to the myoneural receptor sites apparently stabilizes them,
thereby preventing increased sodium channel activity, and resulting MH. However, other nondepolarizing
muscle relaxants do not have this protective effect— for examples Vecuronium, Arduan,
and Organon 9616 do not. Uncoupling of mitochondria is not the source of accelerated heat
production in MH susceptible pigs, as heart, liver, and skeletal muscle mitochondria isolated from MH
susceptible pigs are all competent.