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Risk factors for malignant hyperthermia (MH) include a family history of severe hyperthermia or sudden hypermetabolic state during anesthesia with exposure to succinylcholine and/or potent inhalation anesthetics, and ryanodine receptor type one myopathy.
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Clinical presentation includes uncontrollable hypercarbia and rapidly increasing temperature due to excessive metabolism. Tachycardia, muscle rigidity, acidemia, and rhabdomyolysis are frequent. The clinical diagnosis of malignant hyperthermia may be confirmed by genetic testing or muscle contracture testing.
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Treatment consists of administration of repeated doses of 2.5 mg/kg of dantrolene intravenously until metabolism and muscle tone are normal. The patient should be cooled aggressively if temperature is higher than 39°C. Treat hyperkalemia, myoglobinuria, disseminated intravascular coagulation, and cerebral edema as needed. After initial treatment, 1 mg/kg of dantrolene should be given every 4 to 6 hours for at least 24 hours, because 20% of patients experience an exacerbation or recrudescence of MH.
Malignant hyperthermia (MH) was first described in the 1960s, and the case fatality remained greater than 70% through the 1970s. Since then, advances in intraoperative monitoring, decreased use of succinylcholine in pediatric anesthesiology, and the discovery of dantrolene as an effective treatment have reduced morbidity and mortality substantially. However, the apparent genetic susceptibility to MH is 1:2000, and deaths continue to occur when MH is not suspected and treated soon enough in the operating room. Further, many of these deaths occur in otherwise healthy patients presenting for low- or intermediate-risk surgeries. There remains a great opportunity for saving lives with improved understanding, timely diagnosis, and effective treatment of MH.
The physician in the pediatric intensive care unit (PICU) may first encounter a patient with MH in transfer from the operating room or from an outpatient facility where general anesthesia was given and treatment for acute MH was begun. Alternatively, the intensivist may be the first to entertain the diagnosis of MH in a patient admitted to the ICU for medical care or postoperative management. In either case, the ability to deliver timely and comprehensive care is critical to the patient surviving this potentially fatal syndrome.
Pathophysiology
MH is a hypermetabolic reaction of genetically abnormal skeletal muscle, typically triggered in humans by the exposure to volatile anesthetics and/or the depolarizing muscle relaxant succinylcholine. If not promptly recognized and aggressively treated, clinical effects of fulminant MH may rapidly progress from muscle injury to multiorgan system failure and death. The underlying defect is a sudden, sustained increase in the concentration of calcium ion in the sarcoplasm. Resultant increased skeletal muscle metabolism increases carbon dioxide (CO 2 ) production severalfold. Even with markedly increased minute ventilation, it may be difficult to achieve normocarbia. The associated lactic acid production overwhelms the body’s buffering capacity. Increased oxygen (O 2 ) demand and the concomitant sympathetic response stress the cardiovascular system. MH can progress rapidly to severe mixed acidosis, hyperkalemia, elevated temperature as in heatstroke, and rhabdomyolysis. Renal failure, disseminated intravascular coagulation (DIC), cerebral edema, pulmonary edema, dysrhythmias, and cardiovascular collapse are potential consequences of fulminant MH. Before dantrolene, the mortality rate of MH was 70%. Symptomatic therapy—including mechanical ventilation, active cooling, administration of bicarbonate, expansion of intravascular volume, and treatment of dysrhythmias—can prolong life during an episode of fulminant MH. However, by far, the most rapid and effective therapy is intravenous dantrolene.
In the majority of MH-susceptible (MHS) mammals, skeletal muscle calcium dysregulation results from a defect in the ryanodine receptor type one channel (RYR1) calcium release channel, producing increased sensitivity to agonists , and decreased sensitivity to inhibitors. Furthermore, excitation-coupled calcium entry (ECCE) is greater than normal in myotubes expressing MHS RYR1. Dantrolene increases the affinity of the ryanodine receptor for the endogenous inhibitor magnesium and inhibits ECCE in both MHS and normal muscle. Store-operated calcium entry (SOCE) is another process, occurring after depletion of SR calcium, that moves extracellular calcium into the myoplasm. SOCE is coupled to RYR1 and decreased by dantrolene.
Genetics
MH susceptibility is a syndrome with autosomal-dominant inheritance, incomplete penetrance, and variable expressivity. The first-degree relatives of an MHS individual are treated as MHS until they have normal results of a caffeine-halothane contracture test (CHCT). Incomplete penetrance means that a person with a mutation recognized to be causative of MH may not experience MH during the first or subsequent exposures to MH trigger agents. Multifactorial inheritance may be relevant. , Variable expressivity means that clinical symptoms of MH vary from minor to fulminant depending on factors such as anesthetic agent, genetics, and temperature. Severe MH episodes are more often observed in males and in muscular individuals.
The primary genetic locus of MH (MHS 1) is the ryanodine receptor gene (RYR1) on chromosome 19q13.1. Variants associated with MH susceptibility are found throughout RYR1 and are thought to account for 50% to 70% of families affected by MH. Two other genes, CACNA1S on chromosome 1q32 and STAC3 on chromosome 12, are now recognized to contain MH mutations. CACNA1S encodes the main subunit of the dihydropyridine receptor that interacts with the RYR1 channel and accounts for approximately 1% of MHS families. The STAC3 protein, involved in excitation-contraction coupling, was first found to be abnormal in a group of myopathic Lumbee Indian families with MH susceptibility.
In families with a known MH-causative genetic mutation, genetic analysis is a useful initial step in the diagnosis of MH susceptibility. , The roles of deoxyribonucleic acid (DNA)-based tests and muscle contracture tests are discussed later.
While the genetic risk of developing MH was historically considered an “all-or-none” phenomenon, there is emerging evidence that some RYR1 variants have more profound functional consequences. This may account for some of the variability in clinical presentation of MH. For example, one RYR1 mutation has been shown to affect vascular smooth muscle, leading to a prolonged bleeding phenotype.
Clinical recognition of malignant hyperthermia
The clinical presentation and initial signs of an MH episode are varied and nonspecific ( Box 130.1 ). However, anesthesiologists and critical care physicians must promptly diagnose and treat MH, as the likelihood of complications increases 2.9 times for every 2°C increase in maximum core temperature and 1.6 times for every 30 minutes of time between the appearance of the first clinical sign of MH and the beginning of dantrolene administration.
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History of recent exposure to trigger agent, including volatile anesthetic agents or succinylcholine
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Family or personal history of MH susceptibility
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Total body rigidity
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Masseter spasm
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Inappropriately elevated (38.8°C) or rapidly increasing temperature (>1.5°C over 5 min)
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Inappropriate tachypnea
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Profuse sweating
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Mottled, cyanotic skin
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Dark urine, urine dipstick testing shows a positive result from blood without red cells in the sediment and no hemolysis
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Unexplained, excessive bleeding
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Unexplained ventricular tachycardia or fibrillation
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Inappropriate hypercarbia (venous Pa co 2 >65 mm Hg, arterial Pa co 2 >55 mm Hg) if the patient is receiving positive-pressure ventilation or is spontaneously breathing with greater than normal minute ventilation
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Arterial base excess more negative than −8 mEq/L
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Arterial pH <7.25
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Potassium concentration >6 mEq/L
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Creatine kinase >10,000 IU/L
MH, Malignant hyperthermia; Pa co 2 , partial pressure of arterial carbon dioxide.
In a study of 129 MH reactions in Canadians, the most frequent clinical signs of MH were hyperthermia greater than 38.8°C (in 67%), sinus tachycardia (62%), and hypercarbia (52%). Other MH signs noted in this group include masseter rigidity, total body rigidity, arrhythmia, skin mottling, and cyanosis. This report is consistent with data from the North American MH Registry. , A patient’s muscles may be rigid enough to pull the legs above the horizontal. Laboratory findings frequently include mixed respiratory and metabolic acidosis, hyperkalemia, myoglobinuria, and increased serum creatine kinase (CK). However, rhabdomyolysis does not occur during every MH episode.
Differential diagnosis
Given the nonspecific nature of many of the common signs of MH, a number of other medical, metabolic, and endocrinologic pathologies should be considered in the differential diagnosis. These include sepsis, drug abuse and withdrawal, thyroid storm, and untreated pheochromocytoma ( Box 130.2 ). In the intensive care unit (ICU), a septic patient with kidney disease or chronic lung disease may exhibit fever, tachycardia, mixed respiratory and metabolic acidosis, and hyperkalemia. If sepsis, cardiovascular failure, central nervous system injury, heat stroke, or other medical or surgical conditions could have produced the abnormal vital signs, then these more common diagnoses must be pursued and treated. However, in the setting of recent exposure to volatile anesthetic agents or succinylcholine—especially in a patient with a family history of problems after general anesthesia or muscular diseases associated with MH—the presumptive diagnosis of MH must be made.
Neuroleptic malignant syndrome
Exertional hyperthermia and heat stroke
Serotonin syndrome
Sepsis associated with renal and respiratory failure
Central nervous system injury
Postoperative fever
Thyrotoxicosis
Rhabdomyolysis
Pheochromocytoma
Porphyria
Allergic reaction secondary to medications
Blood transfusion reactions
Administration of hypertonic dye, such as diatrizoate intrathecally
Drug abuse (cocaine, amphetamines, Ecstasy)
Drug withdrawal
Iatrogenic overheating
Delirium tremens
In the PICU, the most likely cause of fever is a bacterial infection, but elevated temperature can also be the result of trauma, viral infection, lymphoma, leukemia, drug withdrawal and allergy, and other causes. Inadequate fluid replacement predisposes to increased core temperature in children. Excessive environmental heat with inadequate opportunity for evaporative heat loss can result in temperature elevation. Postoperative fever is also common and usually resolves spontaneously. In some cases, increased core temperature can be associated with tachycardia, increased expired CO 2 , and metabolic acidosis, which are consistent with the expected increase in metabolic demand produced by fever. This can be so extreme as to mimic MH, but if O 2 consumption has not increased severalfold, MH is unlikely.
When hyperthermia occurs in a child with history of exposure to succinylcholine or volatile anesthetic agents, MH must be considered in the differential diagnosis. However, in a retrospective cohort study conducted to analyze the causes of hyperthermia in the PICU over a 9-year period, Schleelein et al. noted that the incidence of clinically diagnosed MH was low (0.4%).
Likewise, the vast majority of episodes of rhabdomyolysis are not attributable to MH. The most frequent causes are trauma, overexertion, immobilization, alcoholism, vascular insufficiency, and orthopedic surgery. Grand mal seizures, delirium tremens, psychotic agitation, and amphetamine overdose also can lead to rhabdomyolysis in individuals with otherwise normal muscle. Some drugs, such as hydroxymethylglutaryl-CoA reductase inhibitors (statins) and colchicine, are directly myotoxic. Rhabdomyolysis may also occur in patients with mitochondrial and metabolic myopathies, such as carnitine palmitoyltransferase deficiency and myophosphorylase deficiency or McArdle disease.
Course of malignant hyperthermia
The vast majority of human cases of MH follow exposure to a potent inhalational anesthetic agent (sevoflurane, isoflurane, desflurane, or halothane) or the depolarizing neuromuscular blocker succinylcholine. The combination of succinylcholine and potent inhalation anesthetic agents produces more episodes of MH than either agent alone. , On very rare occasions, MH may occur during an anesthetic in which no trigger agents were administered or without exposure to any anesthetic. An athletic adolescent who had an RYR1 mutation associated with MH died after strenuous exercise. While rare in humans, this has been observed repeatedly in MHS animals.
Signs of MH usually present within 30 minutes after administration of the triggering agent but have also been reported more than 1 hour after admission to the postanesthetic care unit. MH can also develop insidiously during a long anesthetic. , When the nonspecific early signs of MH are noted during induction of anesthesia, the potent inhalation anesthetics should be discontinued. Early termination of inhalation anesthetic agents may allow spontaneous resolution of the syndrome, which is termed abortive MH . Differentiating an abortive episode of MH from an anesthetic complicated by other factors can be difficult, so such patients are considered to be MHS until proven otherwise. Core temperature monitoring during anesthesia may improve identification of early MH and decrease the risk of progression to fatal MH events.
There are cases in which a patient was treated for MH with dantrolene, appeared to recover, and then hours later had another episode of increased metabolic rate and muscular rigidity. Recrudescence of MH was seen in 20% of cases reported to the MH Registry after initial treatment appeared to be successful. Muscular body type, hyperthermia during the MH episode, and a longer time between induction of inhalation anesthesia and the first sign of MH were associated with a greater risk of recrudescence. There is no definite or guaranteed time course for these events. Close observation of the patient rescued from an MH event for 24 hours will allow for the early recognition of recrudescence, which can progress into fulminant MH and warrants aggressive retreatment with dantrolene and supportive therapy.
Potential systemic complications
Significant complications were noted in 35% of 181 MH events reported to the North American MH Registry. These included changes in level of consciousness or coma in 9.4%, cardiac dysfunction in 9.4%, pulmonary edema in 8.4%, renal dysfunction in 7.3%, DIC in 7.2%, and hepatic dysfunction in 5.6%. The development of DIC was associated with a 50-fold increased likelihood of cardiac arrest and an 89-fold likelihood of death. Other reported complications included compartment syndrome, stroke after cardiac arrest, bilateral brachial plexopathy, generalized muscle weakness, significant muscle loss, and prolonged intubation.
Changes in level of consciousness continue to be seen in over 10% of MH Registry reports, with cerebral edema and coma occurring less frequently. These neurologic consequences likely result from thermotoxicity and inadequate O 2 supply to the central nervous system during MH events. Therefore, supportive care during and after an episode of fulminant MH should include measures to document cerebral function and maximize cerebral perfusion.
Respiratory failure may occur early in an episode of fulminant MH. Desaturation can occur secondary to increased O 2 demand; the workload of the respiratory system may be further increased by the occurrence of capillary leak and pulmonary edema. Acidemia and electrolyte abnormalities may impair cardiac contractility and promote cardiac dysrhythmias, while increased levels of circulating catecholamines may lead to foci of myocardial fibrosis.
Rhabdomyolysis will occur when the energy supply of the muscle is exhausted. It is characterized by muscle necrosis and the release of intracellular constituents, including CK, myoglobin, and potassium. Clinical manifestations include myalgias, swollen extremities, red-to-brown urine due to myoglobinuria, elevated muscle enzymes, and electrolyte imbalances (hyperkalemia, hyperphosphatemia, hypocalcemia). Acute renal failure, compartment syndrome, and life-threatening hyperkalemia may develop.
Management of an episode of malignant hyperthermia
Initial steps: Discontinue trigger agents and administer dantrolene
When an episode of MH is suspected, additional help should be summoned immediately. Multiple life-threatening complications may soon develop—efficient and expert care will be required to prevent significant morbidity and mortality.
As soon as possible, triggering inhalation anesthetic administration must be stopped. High fresh gas flows of 10 L/min or more, or charcoal filters placed into the breathing circuit, are needed to eliminate residual anesthetic gas from the circuit. If the patient remains in the operating room, general anesthesia should be maintained with intravenous agents and further surgery should be aborted whenever a safe point is reached.
The most effective treatment of MH is timely administration of dantrolene. MH-associated morbidity increases significantly for every 30-minute delay in intravenous dantrolene administration. In most hospitals and surgical centers, dantrolene will be stocked on a dedicated MH cart in perioperative areas in addition to the pharmacy supply. This hydantoin with muscle relaxant properties has greatly changed the treatment of and risk of death from MH. Before the introduction of dantrolene, Brit and Kalow reported a 36% MH survival rate with symptomatic treatment only. Dantrolene decreases both ECCE into muscle cells and SOCE coupled to RYR1, ultimately decreasing the hypermetabolic state of skeletal muscle and resultant complications. , It does not act on the neuromuscular junction or on the passive or active electrical properties of the surface membranes of muscle fibers.
Dantrolene in the formulations Dantrium and Revonto is supplied in 70-mL vials, containing 20 mg dantrolene sodium and 3 g mannitol. It must be diluted with 60 mL of sterile, preservative-free, distilled water to produce a clear yellow solution. Dantrolene is also available as Ryanodex, 250 mg of dantrolene with 125 mg mannitol, to which 5 mL of water is added to produce an opaque orange fluid for injection. The initial dose of intravenous dantrolene for treatment of MH is 2.5 to 3 mg/kg. Repeated dosing may be required to return metabolism and muscle tone to normal. If clinical improvement is not seen with cumulative doses greater than 10 mg/kg, alternative diagnoses should be considered. Dantrolene may irritate veins and, if it extravasates, it will not be effective in treating MH. Therefore, large-bore venous access should be used, with central access being preferable. As soon as dantrolene is ordered to treat fulminant MH, replacements should be obtained by the pharmacy.
In children, the intravenous infusion of dantrolene, 2.4 mg/kg IV over 10 to 12 minutes, produces stable blood levels of about 3.5 μg/mL for 4 hours, after which a slow decline in plasma concentration occurs ( Fig. 130.1 ). It appears that the half-life of dantrolene in the plasma of children is somewhat shorter than in adults: 7 to 10 hours compared with 12 hours, respectively. This is consistent with the recommendation to repeat dantrolene (1 mg/kg) every 4 to 6 hours for at least 24 hours as prophylaxis against recurrence of MH in a child. The goals of treatment with dantrolene are normalization of heart rate, respiratory rate, and muscle tone, as well as correction of hypercarbia, hyperthermia, electrolyte disturbances, and metabolic acidosis. Urinary output should increase and mental status should improve. Continuous infusion of dantrolene has not been shown to be superior to intermittent dosing and is not certain to prevent recurrence.
