Malignant Hyperthermia—Deaths in General Anesthesia

The name malignant hyperthermia (MH) is derived from the clinical observations of Denborough and Lovell, who analyzed the unexplained deaths of previously asymptomatic patients undergoing general anesthesia in 1960. These patients exhibited symptoms of muscle rigidity and rapidly rising, irrepressible core body temperature; hence the term MH. Within 2 years, Denborough and colleagues realized that young age and blood relationship is a risk factor for the development of the syndrome. An autosomal dominant mode of inheritance was later identified in 1990.

In due course, more sophisticated anesthesiological equipment allowed the analysis of signs and symptoms of MH crises in more detail ( Table 45.1 ), the main features of which are rigidity of skeletal muscle, severe acidosis, and inadequate increase in body temperature ( Figure 45.1 ). The majority of reported MH crises indicate that the phenomenon is pharmacologically provoked; crises are triggered by the volatile anesthetic halothane and the depolarizing muscle-relaxant succinylcholine. This predominance is most likely due to the fact that these drugs were common for many years—and still are in economically poorer countries—and that they were not only used frequently, but also regularly in combination. With the exception of xenon and nitrous oxide, MH crises have been observed with all volatile anesthetics (i.e. halothane, sevoflurane, enflurane, isoflurane, and desflurane). The preservative 4-chloro-m-cresol (4-CmC) was found to trigger MH and was consequently removed from succinylcholine preparations and other muscle relaxants in the 1980s. 4-CmC is still used as preservative (e.g. for insulin formulations); however, the enclosed dosages are two orders of magnitude below clinical relevance in terms of MH-triggering effects. Hence, modern 4-CmC containing pharmacological formulations can be used safely in MH-disposed individuals.

Pathophysiology of malignant hyperthermia (MH). Cartoon of the key structures of excitation-contraction coupling in the transverse tubule (T-tubule) of skeletal muscle. The dihydropyridine receptor (DHPR) is linked to the ryanodine receptor (RyR1), which is the calcium release channel situated in the membrane of the sarcoplasmic reticulum (SR). The cardinal symptoms of MH are explained by excessive calcium release, and stimulated glycolysis and respiratory chain.

Reprinted with permission from Lehmann-Horn et al. (2011).

Muscular Hypermetabolism by Rampant Ca ²⁺

In predisposed individuals, application of MH triggers leads to excessive release of Ca ²⁺ in skeletal muscle cells. Here, Ca ²⁺ is accumulated in intracellular Ca ²⁺ stores within the sarcoplasmic reticulum (SR). Ca ²⁺ release is regulated by a complex of four dihydropyridine-receptors (DHPR) and the homotetrameric ryanodine receptor type 1 (RyR1), arranged in clusters along the triadic junction between the transverse tubular system and the SR. The voltage sensitive DHPR activates RyR1 predominantly by direct (mechanical) protein-protein interaction and secondarily by promotion of Ca ²⁺ -induced Ca ²⁺ release (CICR). Volatile anesthetics are direct and potent agonists on RyR1, which is the largest known ion channel (>2MDa, roughly 5000 amino acids) allowing high ion flux and increase in cytoplasmic Ca ²⁺ concentration by several orders of magnitude within milliseconds.

Ca ²⁺ unmasks actin and leads to force generation by myosin-ATPase. Rampant Ca ²⁺ release in MH muscle leads to generalized muscle rigidity, consumption of energy carriers, and stimulation of glycolysis and respiratory enzymes. Accumulation of acidic metabolites, ATP exhaustion, and Ca ²⁺ overload finally result in loss of cellular integrity and rhabdomyolysis ( Figure 45.1 ). Clinically, a severe hypermetabolism can be observed including tachypnea, tachycardia, hypoxemia, and rapid increase in end-tidal CO ₂ concentrations. Anesthesiologists refer to hot soda lime, which is the CO ₂ -absorbing component in the breathing circuit of the anesthesia machine. Due to the rigidity of respiratory muscles, blood gas analysis yields a combined metabolic and respiratory acidosis (i.e. mixed acidosis). Laboratory investigations further show increasing K ⁺ and creatine phosphokinase levels originating from rhabdomyolysis. The course of an MH crisis may be complicated by renal failure and myoglobinuria, which can appear as “cola-colored” urine, and/or disseminated intravascular coagulation. Cardiac arrhythmia is a phenomenon in MH mainly due to an increase in serum K ⁺ .

Membrane depolarization by succinylcholine can boost and rarely induce an MH reaction by stimulation of DHPR and nonspecific Ca ²⁺ influx. Nondepolarizing muscle relaxants can be used safely in MH-predisposed individuals. Moreover, precurarization (i.e. pretreatment with nondepolarizing muscle relaxants) may attenuate or even prevent clinical MH reactions.

There is no specific symptom pathognomonic for MH because clinical features and time course of MH crises vary markedly. In 1994, Larach and colleagues developed a mathematical scoring model to estimate the likelihood of a clinical MH event. Five main processes are assessed: muscle rigidity, muscle breakdown (i.e. rise of the muscle enzyme creatine phosphokinase above 10,000 units/L), acidosis, inadequate increase in body temperature, and the beneficial effect of the specific antidote dantrolene, which also contains mannitol to prevent renal failure.

Treatment of an MH crisis is based on interruption of the positive feedback loop of self-sustaining myoplasmic hypermetabolism. Dantrolene significantly reduces myoplasmic Ca ²⁺ overload by various mechanisms, and should be administered immediately after stopping the trigger anesthetics. A clinical MH event can be suspected upon observation of beneficial effects of dantrolene (i.e. reversal of hypermetabolism).

Regarding hypermetabolism and hyperthermia, most interestingly, RyR1 has been identified in B-lymphocytes, where it plays a role in the regulation of specific immune response. In B cells RyR1-liberated Ca ²⁺ promotes the release of interleukin 1β (IL-1β), which is an endogenous pyrogen. B-lymphocytes from MH patients show an elevated cellular metabolism and increased IL-1β release after pharmacological challenge with MH-triggering drugs. Action of endogenous pyrogens may explain recrudescence of MH hypermetabolism and even delayed onset, which has been described several hours after anesthesia.

Anesthesia-Related Muscle Spasms

Localized muscle stiffness can present as jaw stiffness (trismus), which may be a threatening condition during induction of general anesthesia because ventilation and endotracheal intubation can be hindered. Anesthesia-related muscle spasm is a nonspecific sign for neuromuscular dysregulation and occurs predominantly in pediatric patients. Independent of underlying disease, masseter spasm is observed in roughly 0.3% of children after administration of the depolarizing muscle relaxant succinylcholine. Compared to other muscles, the masseter has an atypical composition that may explain, in part, the increased sensitivity to succinylcholine. Specific features of the masseter muscles include a highly variable and heterogeneous distribution of myosin isoenzymes, the expression of neonatal and alpha-cardiac myosin heavy chain, and the existence of small motor units. In other words, jaw muscles contain a comparatively high number of motor endplates, where succinylcholine is an agonist on nicotinic acetylcholine receptors (nAChR). nAChR are nonspecific cation channels that depolarize the muscle membrane by influx of Na ⁺ and, notably, Ca ²⁺ . Membrane depolarization initiates excitation-contraction coupling (i.e. Ca ²⁺ -release from SR). There are hints that in patients with neuromuscular disorders, most notably MH, the incidence of clinically relevant succinylcholine-induced masseter spasm may be increased.

Anesthesia-related localized and generalized muscle spasm is a phenomenon also seen in other conditions, and may complicate artificial ventilation. In disorders of neuromuscular transmission (e.g. denervation, immobilized patients, paralyzed patients, and myasthenia gravis), reference is made to the pathological upregulation of nAChR and expression of abundant extrajunctional nAChR. Enhanced excitability of muscle membranes is also found in inherited channelopathies, such as chloride channel myotonia (myotonia congenita, Thomsen and Becker types) and sodium channel myotonia (paramyotonia). Clinically, the symptoms can mimic an MH event.

Awake Episodes

Outside general anesthesia, individuals carrying the trait for MH are usually asymptomatic. Some patients complain about exercise-dependent myalgias, predominantly in gross muscle such as the thigh. Other observations include heat intolerance and inadequate temperature increase after physical exercise. Case reports describe clinical crises after heavy physical exercise and in febrile conditions. Even if there are not enough data for statistical evaluation of incidence, children are obviously more prone to awake MH episodes. Case reports often refer to children, adolescents, or young adults. Crises have been described in hot surroundings, such as a car interior, or during infections with fever.

Awake MH episodes are also found in animal models for MH. Most extensively studied is porcine MH, where stress-induced rhabdomyolysis reduces meat quality. The syndrome was named “porcine stress syndrome” and a homozygote mutation in RyR1 was identified. The mode of inheritance is recessive in porcine stress syndrome and dominant in the horse and mouse MH model. In all animal models, nonanesthetic MH crises occur frequently and can be triggered reproducibly by heat or physical exertion. In affected quarter horses, rhabdomyolysis can occur without evident hyperthermia.

MH and Childhood

The incidence of clinical MH crises as well as awake episodes is more frequent in children ( Figure 45.2 ). Roughly half of the crises occur in children younger than 12. Several reasons may account for this observation. Children have fewer developed compensatory mechanisms for increased body temperature. Heat tolerance and dissipation is reduced. Generally, children have a higher metabolic rate in skeletal muscle than adults; CPK levels show an age-dependent decline. Fiber type composition is different in children and adults with a shift to fiber type II with increasing age. In other words, children exhibit a relatively high portion of oxidative type I fibers (slow twitching). In the in vitro contracture test (IVCT), type I fibers are more sensitive to pharmacological triggers. Indeed, other factors of development such as influence of growth hormones and temperature regulation in the central nervous system may contribute to the enhanced vulnerability of skeletal muscle in childhood.

Age dependence and male predominance. The graph shows age and gender distribution of 200 clinical MH crises evaluated in a European multicenter study. All events were later diagnosed to be proven malignant hyperthermia events by in vitro contracture testing on surgically dissected muscle biopsies. Patients were 70% male; 50% of crises occurred in patients younger than 12 years old. 1% of the crises were triggered by succinylcholine, 18% by volatile anesthetics, and 81% by a combination of both.

Figure modified and adapted from: Klingler et al. (2014).

Epidemiological observations in children show that MH-predisposition is associated with anomalies of the musculoskeletal system and connective tissue. Specific diagnoses overrepresented in the MH-predisposed population are various forms of myopathies, strabismus, and scoliosis.

Functional Diagnostics— In Vitro Contracture Test

The in vitro contracture test (IVCT) is a robust method to diagnose predisposition to MH. The classification yields MH susceptibility (MHS) or an MH negative (MHN) result. IVCT requires a surgical muscle biopsy at a specialized MH unit. A minimum of four muscle bundles of roughly 20 mm length and 300 mg weight are dissected from human vastus lateralis muscle. To avoid pharmacological interferences, regional or spinal anesthesia is preferred over local anesthesia. The IVCT is a functional test on fresh muscle tissue, so muscle bundles need to be investigated freshly within a maximum of 5 hours; dispatch of specimens to a distant laboratory is impossible. Muscle bundles are suspended and pre-stretched in an organ bath containing physiological Krebs-Ringer solution, pH and temperature are controlled, and the muscle tissue is continuously bubbled with 95% O ₂ and 5% CO ₂ . Force is measured with a highly sensitive force transducer. The generated contracture force is used as an indirect marker for myoplasmic Ca ²⁺ concentration. Halothane and caffeine, the pharmacological trigger substances, are added to the organ bath in respectively cumulative bolus doses ( Figure 45.3 ). Protocol variants differ depending on the recommendations of the respective North American and European Malignant Hyperthermia Groups. Nonetheless, there is a high concordance between the protocol variants. In Japan, skinned muscle fibers are investigated. In MHS muscle, pharmacologically induced CICR is significantly increased. Although caffeine in the millimolar range is a potent in vitro trigger for MH, this is not the case in vivo because concentrations differ greatly.

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