Malignant hyperthermia (MH) is a serious and possibly fatal syndrome of skeletal muscle hypermetabolism and calcium dysregulation that occurs when genetically susceptible individuals are exposed to certain anesthetic “triggering” agents- the potent halogenated inhaled volatile anesthetics and the nondepolarizing neuromuscular blocker succinylcholine.

MH susceptibility is conferred by the inherited or spontaneous (de novo) acquisition of a variant in genetic loci that encode for proteins that are integral for normal functioning of the skeletal muscle excitation-contraction (EC) complex. They include RYR1 , which encodes for the ryanodine receptor, CACNA1S , which encodes for the alpha-1 subunit of the dihydropyridine receptor, and STAC3 , which has an unknown function in the complex. A current listing of these MH causative variants is located on the European MH Group (EMHG) website.

There are currently two methods to determine MH susceptibility: molecular genetic testing for known MH-causative variants, and an open muscle contracture biopsy. Molecular genetic testing uses an individual’s DNA specimen, such as blood or buccal smear. It is noninvasive, and the sample can be sent from anywhere in the world. A positive result (finding the presence of a diagnostic variant) confirms MH susceptibility. A negative result, however, cannot rule out MH susceptibility because of known discordances between contracture testing and molecular genetic results; many families exist in whom a pathogenic variant has not been detected but have been proven MH susceptible either by a convincing clinical event or a positive contracture biopsy. Thus, MH can only be excluded by negative contracture biopsy testing.

A contracture biopsy test requires an open incision (usually from the quadriceps muscle, using either regional anesthesia or trigger-free general anesthesia) for immediate testing to determine the muscle’s contractile properties when exposed to halothane and caffeine ( Fig. 21.1 ). Its most important advantage is its high sensitivity (at least 99%); a negative result rules out MH susceptibility. Its main disadvantage is its surgical invasiveness, and limited availability at only several centers throughout the world. In North America the test is called the caffeine-halothane contracture test (CHCT) and in European centers it is called the in-vitro contracture test (IVCT). The protocols differ slightly, but both have a sensitivity close to 100% and a reasonably high specificity (yielding some possible false positive tests). Because of the size of the muscle required for analysis, children less than about 40 kg weight are usually excluded from testing, but this is biopsy-center dependent.

Halothane contracture test. The muscle is stimulated electrically throughout the test and the electrically evoked twitches (thin vertical lines) indicate muscle viability. The thick blue line indicates the baseline tension of the muscle. The muscle is initially stretched to its physiologic length (increase in baseline tension) and maintained at this length (decline in baseline tension). Thereafter, any increase in baseline tension is defined as a contracture. (A) In a normal individual as exposure of the muscle to halothane is increased from 0.5 to 2.0%, the baseline tension tends to decrease further. (B) On the other hand, in a susceptible patient a concentration-dependent contracture develops in the presence of halothane.

(From: Gupta PK, Hopkins PM. Diagnosis and management of malignant hyperthermia. BJA Educ . 2017:17(7):249–254.)

A person should be tested for susceptibility to MH if they or someone in their family has experienced a clinically suspicious episode of MH during exposure to an anesthetic triggering agent. However, it is very difficult to assess the accuracy of an intraoperative MH diagnosis in the absence of a bedside diagnostic test. When these clinical events are examined carefully, very few are unambiguously attributable to MH. A less common reason for MH susceptibility testing is when a person has experienced exaggerated and unexpected muscle breakdown (i.e., rhabdomyolysis) in response to nonextreme heat exposure or exercise.

The EMHG has published a suggested diagnostic pathway for MH susceptibility testing ( Fig. 21.2 ). Individuals who have experienced a clinically convincing MH event should initially obtain noninvasive molecular genetic testing. This testing, however, is only useful when the analysis demonstrates a known diagnostic MH variant, which confirms MH susceptibility. If a family member has experienced the suspicious MH event, then they should ideally be the first member of the family to undergo testing. In the absence of finding an MH-diagnostic variant, a contracture test is required to exclude or confirm MH susceptibility.

EMHG suggested diagnostic pathway for MH susceptibility testing.

(From: Hopkins PM, Rüffert H, Snoeck MM, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth , 2015;115(4):531-539.)

Patients with a positive contracture biopsy without prior molecular genetic investigations should subsequently undergo molecular genetic analysis. If this investigation reveals a pathogenic variant for MH, then other members of the family can be tested for that variant at less expense.

The most frequent reason for investigating an individual’s MH susceptibility is the suspicion of MH susceptibility in a blood relative, either by a convincing clinical event or diagnostic testing. How closely related should this “proband” be to warrant testing or avoidance of MH triggering agents? Although a classic mendelian inheritance of MH is an oversimplification, the autosomal dominant mode of inheritance is helpful to estimate the risk for MH susceptibility. Each offspring of an MH susceptible parent has a 50% risk to be MH susceptible. With every generation, the risk for MH susceptibility decreases by 50%. Therefore, the next generation (grandchildren) each have a risk for 25% and so on. Using a conservatively high prevalence of MH variants of approximately 1 in 1500 in the general population, it would take approximately 10 generations to decrease the calculated familial risk to be similar to that of the general population. As this example illustrates, any familial history within 10 generations (essentially everyone) should be cause for suspicion of MH susceptibility and should prompt the use of a nontriggering general anesthetic and referral for susceptibility testing. If ever possible, the family member with the highest risk for MH susceptibility should be tested for MH to rule out, or confirm, the risk for MH in subsequent generations.

Clinical Presentations

MH most often presents as a constellation of physiologic signs indicative of uncontrolled hypermetabolism during the administration of general anesthetic triggering agents ( Table 21.1 from Smith’s chapter). This includes unexplainable hypercarbia that is resistant to increases in minute ventilation, sinus tachycardia , and metabolic acidosis . Spontaneously breathing patients will develop tachypnea to counteract the respiratory and metabolic acidosis. However, the onset of MH may manifest in a variety of clinical presentations. For example, in some patients the first signs of MH are abnormally prolonged skeletal muscle contractures , either generalized throughout the body or confined only to the masseter muscle soon after the administration of succinylcholine. In other patients, the first sign of MH is an arrhythmia caused by hyperkalemia from acute rhabdomyolysis . These arrhythmias are variable and are thought to depend on the absolute level and rate of rise of serum potassium and the degree of acidosis and sympathetic stimulation. They range from seemingly benign premature ventricular contractions (PVCs) or changes in the electrocardiogram (e.g., peaked T waves, broadened and decreased amplitude of the P wave, widened QRS) to sudden heart block, ventricular tachycardia, ventricular fibrillation, or asystole. Hyperthermia may occur any time in the clinical course of MH, from the initial onset to the later stages. It may be indolent, rising slowly without attracting much attention, or accelerated, rising more than one degree Celsius every few minutes in its initial stages. Lack of temperature monitoring and failure to detect hyperthermia has been associated with increased morbidity and death caused by MH. Therefore, core temperature monitoring (e.g. distal esophagus, nasopharynx, tympanic membrane, pulmonary artery, bladder) should be used in all general anesthetics expected to last longer than 30 minutes, or less when perturbations in body temperature are expected because of unique patient or surgical characteristics.

Table 21.1

Clinical Characteristics of Acute MH

Hypercarbia

• Unexpected and unexplainable increase in P ET CO 2 that is resistant to increasing minute ventilation • Usually one of the first signs of acute MH • Tachypnea or breathing over the ventilator in a spontaneously breathing patient • Results in respiratory acidosis • One of the first signs of MH to abate with successful treatment with dantrolene • According to the Clinical Grading Score (CGS), a diagnosis of acute MH is consistent with: • P ET CO 2 > 55 mm Hg with appropriately controlled ventilation • Arterial P A CO 2 > 60 mm Hg with appropriately controlled ventilation • P ET CO 2 > 60 mm Hg with spontaneous ventilation • Arterial P A CO 2 > 65 mm Hg with spontaneous ventilation • Before ascribing to MH, rule out causes of hypoventilation

Sinus Tachycardia

• Usually develops early in the acute MH event and is often one of the presenting signs • Probably represents a response to the increase in skeletal muscle metabolism, acidosis, sympathetic stimulation, or all combined • Is not specific for MH but used in combination with additional supporting evidence

Metabolic Acidosis

• Venous or arterial blood sample acceptable • An arterial base excess more negative than −8 mEq/L or a pH < 7.25 have shown be consistent with acute MH

Muscle Rigidity

• Presenting sign, along with hypercarbia and tachycardia, in some cases of acute MH • Unusually prolonged and severe (“jaws of steel”) masseter muscle rigidity (MMR) after administration of succinylcholine has been associated with the onset of MH • Generalized rigidity as sustained muscle contractures may also occur early in some patients with MH; however, may be difficult to differentiate the often severe myoclonus that occurs with administration of sevoflurane or propofol • Skeletal muscle contractures in the presence of neuromuscular blockade should be considered pathognomonic for MH • Serum creatine kinase (CK) will begin to rise soon after the MH event and may not peak for several days, despite appropriate treatment • Urine may appear tea-colored from presence of myoglobin

Hyperkalemia

• May occur any time during an MH event • May cause life-threatening or fatal cardiac arrhythmias such as ventricular tachycardia or fibrillation, or cardiac arrest

Hyperthermia

• May occur early or later in the course of an acute MH event • May rise as high as 1ºC every few minutes • Severe hyperthermia (> 41ºC) associated with development of disseminated intravascular coagulation (DIC) • Is not indicative of MH when isolated in the postoperative period without other signs of MH

Rhabdomyolysis

• MH consistent with an elevated CK >20,000 U/L after anesthetic that included succinylcholine • Elevated CK >10,000 U/L after anesthetic without succinylcholine

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