Malignant hyperthermia

Harvey K Rosenbaum MD (Dr. Rosenbaum of the David Geffen School of Medicine at the University of California, Los Angeles has no relevant financial relationships to disclose.)
Dorothea Hall MD (Dr. Hall of the UCLA Department of Anesthesiology has no relevant financial relationships to disclose.)
Emma Ciafaloni MD, editor. (Dr. Ciafaloni of the University of Rochester received consulting fees from Marathon and a research grant from Sarepta.)
Originally released September 6, 1993; last updated June 5, 2017; expires June 5, 2020

This article includes discussion of malignant hyperthermia, malignant hyperpyrexia, anesthetic-induced myopathy, masseter muscle rigidity (masseter spasm), and genetically mediated, nonanesthetic triggered rhabdomyolysis +/- hypermetabolism. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Malignant hyperthermia is a pharmacogenetic disease that typically manifests during or immediately following general anesthesia. The authors discuss the disease and its diagnosis, including genetic testing. The primary mode of inheritance is autosomal dominant, although malignant hyperthermia does not always occur with each anesthetic exposure. Nonanesthesia-related cases of severe rhabdomyolysis in predisposed individuals linked to hereditary neuromuscular disorders are reported in the literature with increasing frequency.

Without early identification and treatment, mortality is 70+%; thus, early diagnosis and treatment are lifesaving. However, early symptoms can be mistaken for inadequate anesthesia or for a febrile reaction of any cause. Thus, treatment must be started before the definitive diagnosis, although many patients who are treated may, in fact, not have this disease. Diagnosis is best confirmed by the caffeine halothane contracture test, which is performed at a limited number of centers and requires fresh muscle tissue. Genetic testing is available at a few centers in the United States. Although progress is being made, molecular genetic testing has limited sensitivity and is being used to confirm susceptibility to malignant hyperthermia rather than to clear patients of the diagnosis. Patients who are susceptible to malignant hyperthermia may receive general or regional anesthesia, but the anesthetic must be trigger-free, consisting of regional and local anesthetics or IV agents with or without nitrous oxide. The muscle relaxant succinylcholine and all potent inhalational agents carry a risk of triggering malignant hyperthermia in these patients. Reports of non-anesthetic-associated rhabdomyolysis, with or without hyperthermia, have been associated with malignant hyperthermia susceptible contracture tests or malignant hyperthermia-associated RYR1 mutations (Dlamini et al 2013; Molenaar et al 2014). These patients represent a smaller subset of malignant hyperthermia susceptible individuals, given that most patients with anesthetic-induced malignant hyperthermia do not develop life-threatening hyperthermia or rhabdomyolysis with exercise or heat exposure.

Key points

 

• Malignant hyperthermia is a hypermetabolic response to potent inhalational agents and/or succinylcholine that can lead to death.

 

• Most patients have no signs or symptoms prior to the event.

 

• Dominant inheritance is mostly of RYR1 mutations.

 

• Exertional myalgia and rhabdomyolysis may be associated with RYR1 mutations or other genetic variants in individuals or families without a history of anesthetic-induced malignant hyperthermia.

 

RYR1 variants of unknown significance are not uncommon in an unselected population (ie, no history of malignant hyperthermia or myopathy).

 

• Early recognition, discontinuing triggers, treatment with dantrolene, and symptomatic therapy are critical.

 

• Adequate temperature monitoring has been associated with preventing death in analysis of malignant hyperthermia cases.

 

• For the known malignant hyperthermia-susceptible patient, general anesthesia is safe as long as known triggering agents are avoided.

 

• Family members must be identified to alert them about the potential risk.

Historical note and terminology

Malignant hyperthermia is a rare but potentially lethal complication of anesthesia. This syndrome was first identified in Australia in 1960. The proband had survived an anesthetic-induced syndrome characterized by hypotension, cyanosis, tachycardia, hyperthermia, and postoperative difficulty with movement. A family history of anesthesia-related deaths (10 of 24 relatives receiving anesthetics) suggested that this syndrome was an inherited disorder (Denborough et al 1962). An analogous syndrome occurs in various strains of pigs and is referred to as malignant hyperthermia, porcine stress syndrome, or pale, soft, exudative pork syndrome. Similar disorders have also been described in horses, dogs, and cats. Mice with knock-in of abnormal RyR1 have been produced and allow a better understanding of the syndrome (Yang 2006; Loy et al 2012; Eltit et al 2013). Malignant hyperthermia is associated with exposure to volatile anesthetics or depolarizing neuromuscular blockers such as succinylcholine (triggering agents) in otherwise normal patients (Miller 1998; Rosenberg et al 2009; Zhou et al 2009). The observation that an in vitro contracture occurred in a muscle bundle in response to low doses of caffeine or halothane in individuals susceptible to malignant hyperthermia formed the basis for a diagnostic test and suggested that skeletal muscle was the target tissue.

Dantrolene was first synthesized in 1967 and accidentally found to have antispasmodic properties. Extensive work by Keith Ellis, a research scientist with a strong background in skeletal muscle physiology, confirmed that it caused dose-dependent muscle relaxation without significant side effects or cardiopulmonary depression. Ellis systematically narrowed down the site of action of dantrolene to involve intracellular calcium-release. When he read about porcine stress syndrome and recognized that dantrolene was a potential treatment for malignant hyperthermia, he forwarded the drug to several researchers of malignant hyperthermia and, thus, initiated its eventual use for the treatment of the disorder (Pollock et al 2017). Since then it has been established that dantrolene reduces calcium release or leak from RYR1-dependent intracellular stores; it also suppresses increased extracellular calcium entry (Eltit et al 2013). Genetic studies have demonstrated that malignant hyperthermia is a heterogeneous disorder (Robinson et al 2000). Thus, anesthetic-induced myopathies could be a more appropriate name for this syndrome.

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