Knowledge on rare diseases and orphan drugs

The incidence of MH reactions ranges from 1/5000 to 1/50,000-100,000 anesthesias. However, the genetic prevalence of the genetic abnormalities may be as great as 1/400 individuals. A significant male preponderance has been reported.

Clinical symptoms of MH are highly variable, ranging from self limiting courses with mild or moderate symptoms to fulminant MH crises. The classic signs of MH include marked hyperthermia, tachycardia, supraventricular and ventricular arrhythmia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, isolated masseter spasm or generalized muscle rigidity and rhabdomyolysis, all of which are related to a hypermetabolic response. In untreated patients, multiorgan failure (including acute renal failure) and circulatory collapse are the end-stage of the disease.

In most cases, MH is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the ryanodine receptor gene (RYR1), located on chromosome 19q13.1, and at least 34 are causal for MH. The pathophysiologic changes of MH are due to an uncontrolled rise in myoplasmic calcium, which activates biochemical processes related to muscle activation. As a result of ATP depletion, muscle membrane integrity is compromised, leading to hyperkalemia and rhabdomyolysis. MH events are mainly triggered by volatile anesthetics and succinylcholine. Extremely rarely stresses such as exercise, emotion and heat may trigger a reaction.

An early diagnostic clue is elevation of end-expired carbon dioxide. Arterial blood gas analyses reveal a combination of respiratory and metabolic acidosis with negative base excess, lactemia, hypercapnia, and hypoxemia. Diagnostic testing relies on assessing the in-vitro contracture response of biopsied muscle to halothane and caffeine. Other drugs such as ryanodine and 4-chloro-m-cresol have also been used but are not part of a standard protocol. A diagnosis of MH is given when contracture forces exceed the given threshold after exposure to these substances. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be increasing useful for identifying those at risk.

The differential diagnosis of a fulminant MH crisis includes sporadic pheochromocytoma, serotonin syndrome, neuroleptic malignant syndrome, anaphylactic reaction, thyroid crisis and sepsis.

MH is inherited autosomal dominantly. Genetic counseling is possible in families with a known disease causing mutation.

Dantrolene sodium is a specific antagonist of the pathophysiologic changes in MH and should be available wherever general anesthesia is administered. When MH is suspected, administration of triggering agents should be ceased immediately and anesthesia continued with intravenous propofol, opiods and/or sedatives. During an MH crisis, dantrolene should be administered at a dosage of 2.5 mg/kg, every 5-10 minutes until patient is stabilized. Volume resuscitation and administration of vasopressors might be needed to stabilize hemodynamics. Cooling (with cold intravenous fluids, topical ice or special cooling blankets) is essential as high temperatures exacerbate an established MH reaction.

The syndrome is likely to be fatal if untreated but thanks to the dramatic progress in understanding the clinical manifestations and pathophysiology of the syndrome, the mortality from MH has dropped from over 80%, thirty years ago, to less than 5% at present.

Last update: February 2015 - Expert reviewer(s): Dr Neil POLLOCK - Dr Henry ROSENBERG - Dr Kathryn STOWELL