Death frequently occurs with a 70-80% mortality during a fulminant malignant hyperthermia (MH) episode if the syndrome is not treated rapidly. Environmental, exertional, and health stressors (ie. a cold, the flu, etc.) have been documented to correlate with the hypermetabolic symptoms associated with MH. Detecting the MH-susceptible (MHS) trait is important to the military, since a significant population of the military are exposed to environmentally and physically stressful conditions. MHS can be a medically disqualifying condition, but enlistees may not know they are MHS prior to an initiating event.
Malignant hyperthermia (MH) is an uncommon, autosomal dominantly inherited disorder of calcium handling in skeletal muscle mainly caused by mutations in a gene coding for the type 1 ryanodine receptor (RyR1). RYR1 functions as a calcium ion channel in the sarcoplasmic reticulum (SR) membrane regulating the release of calcium from the SR. Until challenged by “triggering” inhalational anesthetics and/or succinylcholine, patients with MH, many of whom are physically fit, are asymptomatic. Triggering anesthetics can cause a life-threatening, fulminant episode of MH. Such episodes are characterized by hypermetabolism, with variable signs and symptoms including tachycardia, hypercarbia rhabdomyolysis, hyperthermia and, if untreated, death. Dantrolene, a compound that blocks the release of calcium from the SR via the RYR1, can provide effective treatment of such episodes. Without treatment, mortality from acute MH episodes exceeds 70% but with modern intraoperative monitoring and the administration of dantrolene, the death rate had decreased to less than 7%.
INNOVATION & DISCOVERIES
For more than 20 years we have we have provided MH related consultations, diagnostic services, and research advances.
Our research was instrumental in developing the caffeine halothane contracture test (CHCT) which remains the only validated diagnostic for MH in North America.
The long term goal of our research is to develop a non-invasive bioassay to detect MH susceptibility. MH is primarily unmasked using inhalational anesthetics (halothane, sevoflurane, isoflurane) and/or the neuromuscular blocking agent succinylcholine. Currently, no non-invasive assay is available to validly detect the MHS trait, whose prevalence is estimated to be 1 in 2,000 – 1 in 10,000 within the general population.
We are currently collaborating with researchers from University of Southern Florida and University of New Mexico to evaluate how sympathomimetic stressors affect the intracellular Ca2+ dynamics differently within MHS human b-lymphocytes compared to MH non-susceptible (MHN) b-lymphocytes. Recently, our findings suggest norepinephrine sensitizes the MHS b-lymphocytes to altered intracellular Ca2+ flux. These findings support case reports documenting non-anesthetic induced MH events. This research will advance the research into how the environment and stress may induce MH symptoms.