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Malignant hyperthermia: Clinical diagnosis and management of acute crisis
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Malignant hyperthermia: Clinical diagnosis and management of acute crisis
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Literature review current through: Oct 2017. | This topic last updated: Sep 01, 2017.

INTRODUCTION — Malignant hyperthermia (MH) manifests clinically as a hypermetabolic crisis when an MH-susceptible (MHS) individual is exposed to a volatile anesthetic (eg, halothane, isoflurane, enflurane, sevoflurane, desflurane) or succinylcholine [1-5].

This topic will discuss the incidence, pathophysiology, clinical manifestations, and acute management of MH. Susceptibility to MH and administration of anesthesia to MHS patients are discussed elsewhere. (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

INCIDENCE — The clinical incidence of malignant hyperthermia (MH) for a given population depends upon the prevalence of MH susceptibility and use of triggering anesthetics. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Prevalence'.)

The incidence of episodes of MH in the general population is estimated as 1:100,000 administered anesthetics [6]. This is probably an underestimate because unrecognized, mild, or atypical reactions occur due to variable penetrance of the inherited trait. Approximately half of patients who develop acute MH have one or two uneventful exposures to triggering agents [7,8].

Epidemiology — MH occurs in all ethnic groups in all parts of the world. Reactions occur more frequently in males than females (2:1) [6,7,9]. Children under 19 years account for 45 to 52 percent of reported events [7,9].

PATHOPHYSIOLOGY — Malignant hyperthermia-susceptible (MHS) patients have genetic skeletal muscle receptor abnormalities, allowing excessive calcium accumulation in the presence of certain anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis [4,5,10]. During an episode of MH, the clinical manifestations are due to cellular hypermetabolism, leading to sustained muscular contraction and breakdown (rhabdomyolysis), anaerobic metabolism, acidosis, and their sequelae.

Normal muscle physiology — Depolarization spreads throughout the muscle cell via the transverse tubule system, which activates dihydropyridine (DHP) receptors located within the t-tubule membrane (figure 1). These receptors are coupled to ryanodine receptors (RYR1), which are calcium channels embedded in the wall of the sarcoplasmic reticulum. Calcium release through the DHP receptor triggers the RYR1 receptors to release calcium from the sarcoplasmic reticulum into the intracellular space [11,12]. Calcium combines with troponin to cross-link actin and myosin, resulting in muscle cell contraction. Reuptake of calcium by the sarco(endo)plasmic reticulum calcium ATPase (SERCA) leads to muscle cell relaxation.

Malignant hyperthermia — The majority of MHS patients have mutations encoding for abnormal RYR1 or DHP receptors; exposure to triggering agents in these patients may lead to unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular space, leading to an acute MH crisis (figure 1) [11-20]. The accumulation of myoplasmic calcium causes sustained muscle contraction.

Accelerated levels of aerobic metabolism sustain the muscle for a time, but produce carbon dioxide and cellular acidosis, and deplete oxygen and adenosine triphosphate [21-23]. This causes the early signs of MH: hypercarbia and mixed respiratory/metabolic acidosis. A change to anaerobic metabolism worsens acidosis with the production of lactate. Once energy stores are depleted, rhabdomyolysis occurs and results in hyperkalemia and myoglobinuria. Hyperkalemia from rhabdomyolysis may occur early in muscular patients.

Over time, sustained contraction generates more heat than the body is able to dissipate. Marked hyperthermia occurs minutes to hours following the initial onset of symptoms. In some cases, core body temperature may rise 1ºC every few minutes. Severe hyperthermia (up to 45ºC [113ºF]) leads to a marked increase in carbon dioxide production, and increased oxygen consumption can cause widespread vital organ dysfunction. Severe hyperthermia is associated with the development of disseminated intravascular coagulation, a poor prognostic indicator and often terminal event [24]. (See 'Mortality' below.)

The mechanism whereby certain anesthetic agents trigger these events in MHS patients is unclear. Prolonged RYR1 channel opening has been demonstrated in an experimental model [25]. Volatile anesthetics potentiate sarcoplasmic calcium release in patients with MHS. Halothane, for example, increases the fluidity of the lipid membrane, activating SERCA, limiting reuptake of calcium from the cytosol [26]. Succinylcholine is an analog of acetylcholine and stimulates the motor endplate to initiate muscle depolarization, which can become sustained in MHS patients.

The only known therapy for MH, dantrolene, binds to the RYR1 receptor to inhibit the release of calcium from the sarcoplasmic reticulum; this reverses the negative cascade of effects [27-29].

TRIGGERING AGENTS — The vast majority of cases of malignant hyperthermia (MH) have occurred while the patient was receiving a volatile anesthetic agent (eg, halothane, enflurane, isoflurane, sevoflurane, desflurane) with or without administration of succinylcholine [7].

MH has been reported following administration of succinylcholine in the absence of an inhalational agent (eg, to facilitate endotracheal intubation). The majority of such cases come from a series of 129 patients who were biopsy-proven MH-susceptible (MHS); 20 of whom manifested their signs of MH with succinylcholine alone (without coadministration of a volatile agent) [30].

Acute MH has also been reported in MHS patients exposed to heat stress or vigorous exercise. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Exertional rhabdomyolysis'.) In addition, there are several reports of children that developed spontaneous fatal MH under normal living conditions. Postmortem, these children demonstrated abnormal ryanodine receptor mutations that likely conferred MHS [31,32].

MHS patients may not consistently develop the acute syndrome with every anesthetic exposure. While an acute MH crisis may develop at first exposure to a triggering agent, the average patient has had previous exposures prior to having a documented reaction [9].

CLINICAL PRESENTATION — The clinical manifestations of malignant hyperthermia (MH) vary, but early presentation typically includes hypercarbia, sinus tachycardia, or masseter or generalized muscle rigidity [7,33]. The most common initial sign of an MH crisis is an unexpected rise in end-tidal carbon dioxide (ETCO2), which is difficult to decrease as minute ventilation is increased. Generalized muscle rigidity in the presence of neuromuscular blockade is virtually pathognomonic for MH when other signs are present.

Most patients do not develop all the signs of MH; however, those that occur typically present in a similar order (table 1).

The clinical signs present perioperatively in several possible patterns:

Immediately following anesthetic induction, manifested by masseter muscle rigidity (MMR) (in the presence of succinylcholine and/or volatile agents).

Intraoperatively during any phase of the anesthetic, manifested by gradually worsening hypercarbia, tachycardia, metabolic acidosis, and sometimes generalized rigidity.

After the cessation of the anesthetic agent, but usually within minutes [34-38].

Postoperatively, with isolated rhabdomyolysis in otherwise asymptomatic patients. These patients do not have classic clinical signs of MH, and it is unclear whether these episodes represent true MH crises [39-43].

Following successful treatment, recrudescence occurs in up to 25 percent of patients and is more likely in patients with increased muscle mass [44].

There is a widespread misconception that acute MH begins with hyperthermia as the presenting sign. Hyperthermia is generally a later sign of MH and is typically absent when the diagnosis is initially suspected; in a large series of 255 patients, rapidly-increasing or inappropriately-elevated temperature was one of the first signs in only 8.2 percent of MH crises, and was the sole initial sign in only 3.9 percent [7].

CLINICAL FEATURES

Early signs — The early signs of malignant hyperthermia (MH) are (table 2):

Hypercarbia

Sinus tachycardia

Masseter muscle rigidity (MMR)

Generalized muscle rigidity

Hypercarbia — The most reliable initial clinical sign heralding the development of acute MH is hypercarbia resistant to increasing the patient's minute ventilation. Patients developing MH while under anesthesia with spontaneous ventilation develop tachypnea as a response to end-tidal carbon dioxide (ETCO2) >60 mmHg and carbon dioxide tension (PaCO2) >65 mmHg; those with controlled ventilation have a rising level of CO2 at fixed or increasing ventilator settings.

Due to the increased level of exhaled CO2, not only does the CO2 absorbent rapidly change color, but the exothermic reaction causes the ventilator absorbent canister to become warm to the touch. (See 'Evaluate and manage hypercarbia' below.)

Masseter muscle rigidity — MMR is the inability to open a patient's mouth after the administration of a triggering agent. Historically, MMR has been thought to be an early sign of MH, and many of the patients tested because of MMR history were positive by contracture test [45], but those sent for testing were most likely patients with the most severe MMR. A certain level of increased tension is normal following succinylcholine administration, and, although MMR is common following triggering agents, very few develop MH [46,47]. Only severe MMR is thought to indicate the development of MH [33]; mild MMR following succinylcholine is typical and of no particular concern, as long as it terminates within approximately one minute and is not associated with generalized rigidity.

Generalized muscle rigidity — Generalized muscle rigidity (ie, sustained contracture) in the presence of neuromuscular blockade is considered pathognomonic for MH, provided other confirmatory signs of hypermetabolism are also present. In a large series of 255 patients, 40.8 percent developed generalized muscular rigidity, almost always as one of the first few signs [7].

Later signs — Later signs of MH are (table 2):

Hyperthermia

Electrocardiogram changes related to hyperkalemia (see "Clinical manifestations of hyperkalemia in adults", section on 'Cardiac manifestations')

Ventricular ectopy/bigeminy

Ventricular tachycardia/fibrillation

Myoglobinuria (see "Clinical manifestations and diagnosis of rhabdomyolysis", section on 'Urine findings and myoglobinuria')

Excessive bleeding

Hyperthermia — Hyperthermia is often a later sign of MH and may be absent when the diagnosis is initially suspected, even though it is a common clinical sign of MH. An analysis of reports of MH events to the North American MH Registry (NAMHR) for 1987 to 2006 found that elevated or rapidly increasing temperature was one of the first signs noted in only 8.2 percent, and the only initial sign in 3.9 percent, but was among the first three signs of an MH event in over 60 percent of patients with a mean temperature of 39.1ºC [7]. A temperature elevation or rapidly increasing temperature occurred in over 50 percent of events (table 2). Higher maximum temperatures correlated with a higher likelihood of all complications of MH events. Further, the study found that skin temperature monitoring did not track well with core temperature monitoring when both methods of measurement were used.

An updated analysis of NAMHR reports from 2007 to 2012 found that the risk of death with an MH event was twice as likely when no temperature monitoring was used, compared with core temperature monitoring [48]. Accurate temperature monitoring may allow earlier diagnosis of MH and earlier treatment. (See 'Mortality' below.)

We agree with the recommendation of the Malignant Hyperthermia Association of the United States that core temperature should be monitored for general anesthetics lasting more than 30 minutes [49].

The idea that acute MH generally begins in the postoperative period with isolated hyperthermia is a widespread misconception.

Myoglobinuria — Brownish-, cola-, or tea-colored urine indicates the presence of myoglobinuria, which peaks about 14 hours after an acute MH episode.

A number of reports have described seemingly normal patients with postoperative rhabdomyolysis and myoglobinuria without any of the other classic signs of MH. MH contracture testing in these patients may be positive; however, it is unclear whether this is due to true MH susceptibility or to a subclinical muscle disease resulting in false-positive test results [39-42]. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'MH susceptibility testing' and "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Muscle disorders with intraoperative rhabdomyolysis'.)

Laboratory findings — Typical laboratory findings during acute MH are found in the table (table 3).

Mixed metabolic and respiratory acidosis — In a series of 196 cases of MH crisis with arterial blood gas (ABG) measurements available, 99 percent of patients developed respiratory acidosis and 26 percent of these MH cases developed a metabolic acidosis (all but one also had respiratory acidosis) [7].

Hyperkalemia — Elevated potassium levels from muscle breakdown can occur rapidly, especially in muscular patients.

Elevated creatine kinase and myoglobinuria — Plasma creatine kinase (CK) and urine myoglobin levels peak approximately 14 hours after an acute MH episode. Peak CK levels depend upon the muscle mass of the patient and severity of muscle breakdown; in muscular patients, levels may exceed 100,000 units/L.

Pediatric presentation — Pediatric patients with acute MH present somewhat differently at different ages. In a retrospective analysis of patients under age 18 years using data from the North American Malignant Hyperthermia Registry, the most commonly observed physical findings in all children were sinus tachycardia (73.1 percent), hypercarbia (68.6 percent), and rapid temperature increase (48.5 percent) (table 4) [50]. The youngest children (age 0 to 24 months) were half as likely to have muscle rigidity, but had skin mottling more often than older children; they also had higher peak lactic acid, and lower peak CK levels. Children age 25 months to 12 years had lower maximum ETCO2 and blood gas PaCO2 compared with the youngest and oldest age groups, but were over three times more likely to have masseter spasm. Children age 12 to 18 years had higher peak potassium levels, higher maximum temperatures, were more likely to sweat, and took longer to reach their maximum ETCO2 levels.

CLINICAL DIAGNOSIS — During an acute event, diagnosis of malignant hyperthermia (MH) is presumptive, based upon a presence of one or more of the typical clinical manifestations associated with MH (table 5). The diagnosis must be considered in all patients receiving triggering agents, as over 90 percent of patients developing acute MH episodes have negative family histories for MH, and over half have had uneventful general anesthetics in the past [7].

Treatment must be initiated emergently, as soon as the diagnosis of MH is considered reasonable; this is often before other diagnoses in the differential can be definitively ruled out.

Early clinical features reflect increased metabolic demand; the most important of these is the presence of a mixed metabolic and respiratory acidosis, presenting as an increased end-tidal carbon dioxide (ETCO2) level which does not normalize with increasing ventilation.

MH should be suspected when one or more of the clinical features arise without another persuasive clinical explanation; more features increase the strength of the presumptive diagnosis:

An increased ETCO2 level (>55 mmHg), which does not normalize with increasing ventilation

Generalized muscle rigidity, especially in the presence of neuromuscular blockade

Hyperkalemia-related arrhythmias and electrocardiographic changes

Tachycardia (not explained by clinical scenario)

Tachypnea (not explained by clinical scenario)

Myoglobinuria

Hyperthermia

Laboratory studies are not required for presumptive diagnosis; findings which support the diagnosis include:

Arterial blood gas with pH <7.25, base excess below -8 mEq/L

K >6 mEq/L

Creatine kinase (CK) >10,000 international units (without succinylcholine)

CK >20,000 international units (with succinylcholine)

Serum myoglobin >170 mcg/L

Urine myoglobin >60 mcg/L

Following an acute event, the determination of whether a suspected clinical event represents a true MH episode can be estimated using the MH clinical grading scale (calculator 1) [33]. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'MH clinical grading'.)

Definitive diagnosis can be achieved through susceptibility testing. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'MH susceptibility testing'.)

Differential diagnosis — A number of conditions may present perioperatively with clinical manifestations (eg, hypercapnia, tachycardia, muscle rigidity, rhabdomyolysis, hyperthermia, and arrhythmia) that are similar to those of acute MH. Although treatment for MH may have been initiated, it is imperative to continue to consider other causes so as not to miss an alternative diagnosis. (See 'Clinical presentation' above.)

Anesthesia/surgery-related issues

Insufficient anesthesia/analgesia – Patients with insufficient anesthesia/analgesia can have tachycardia, hypertension, and tachypnea (in a spontaneously-breathing patient), causing hypocarbia; muscular signs (generalized rigidity, masseter spasm, rhabdomyolysis, and hyperkalemia) and hypercarbia would not be present.

Insufficient ventilation/fresh gas flow – Patients with insufficient ventilation/fresh gas flow commonly have hypercarbia, respiratory acidosis, and, possibly, tachycardia and hypertension; metabolic acidosis and muscular signs (generalized rigidity, masseter spasm, rhabdomyolysis, and hyperkalemia) would not be present.

Anesthesia machine malfunction – A malfunctioning expiratory valve on the anesthesia machine will lead to rebreathing of exhaled CO2, with similar findings as for insufficient ventilation. A malfunctioning temperature probe may indicate hyperthermia that is not present.

Overheating – Fever alone, no matter how high, is not a useful indicator of acute MH. This may occur as a result of an infectious process or iatrogenic warming; the clinical situation should be taken into account. Postoperative fever is relatively common; in the absence of other signs and symptoms of MH, alternate diagnoses should be sought.

Increased CO2 absorption during laparoscopy – Hypercarbia resistant to increases in minute ventilation may be due to continuous CO2 absorption during laparoscopy. The presence of subcutaneous emphysema, or known insufflation of CO2 into tissues, makes this a likely explanation. Tachycardia and hypertension are often noted during laparoscopy; muscular signs (generalized rigidity, masseter spasm, rhabdomyolysis, and hyperkalemia) and metabolic acidosis would not be present.

Drug-related issues

Anaphylaxis – Reduced blood pressure may be seen in both anaphylaxis and MH. Anaphylaxis leads to bronchospasm, wheezing, and increased airway pressures, causing lower minute ventilation and thus increased PaCO2; MH-related hypercarbia persists despite higher minute ventilation (from tachypnea or increasing ventilator settings). Ninety percent of anaphylactic episodes include skin symptoms and signs. Muscular signs (generalized rigidity, masseter spasm, rhabdomyolysis, and hyperkalemia) would not be present with anaphylaxis. (See "Anaphylaxis: Acute diagnosis", section on 'Definition and diagnosis'.)

Transfusion reaction – Signs common to both transfusion reaction and MH may include fever, brown urine, hypotension, and signs of hyperkalemia. Concomitant transfusion of blood products should raise this possibility. (See "Immunologic transfusion reactions".)

Drugs of abuse – A number of drugs of abuse may cause signs that overlap with MH:

Cocaine may cause tachycardia, cardiac arrhythmias, hypertension, and rhabdomyolysis. (See "Cocaine: Acute intoxication".)

MDMA (ecstasy) may cause tachycardia, cardiac arrhythmias, hypertension, hyperthermia, and rhabdomyolysis. It may also lead to serotonin syndrome. (See "MDMA (ecstasy) intoxication" and "Serotonin syndrome (serotonin toxicity)".)

Methamphetamine may lead to tachycardia, hypertension, sudden cardiovascular collapse, and tachypnea. (See "Methamphetamine: Acute intoxication".)

Alcohol withdrawal – Delirium tremens generally begins 48 to 96 hours after the last drink, and may include tachycardia, hypertension, and fever. (See "Management of moderate and severe alcohol withdrawal syndromes".)

Neuroleptic malignant syndrome – The slow onset of neuroleptic malignant syndrome (NMS) (heralded by mental status changes evolving over one to three days) generally distinguishes it from MH. Both syndromes may include fever, rigidity, and autonomic instability, but NMS does not generally occur during administration of general anesthesia. (See "Neuroleptic malignant syndrome".)

Serotonin syndrome – This can result from excess ingestion or inadvertent interactions of the many drugs that increase serotonergic activity. It has many signs in common with MH (tachycardia, volatile blood pressure, hyperthermia, and muscle rigidity), as well as elevated CK and metabolic acidosis; but serotonin syndrome may also have signs not seen in MH (tremor, clonus, hyperreflexia, akathisia, and dilated pupils). (See "Serotonin syndrome (serotonin toxicity)".)

Extrapyramidal side effects of antipsychotic medications – These can include muscle spasms, but rapid onset and characteristic localization (usually neck, tongue, or jaw) distinguish them from MH. (See "Pharmacotherapy for schizophrenia: Side effect management", section on 'Extrapyramidal symptoms'.)

Pyrogenic contaminants – Pyrogenic contaminants to intravenous solutions can cause fever.

Coexisting medical conditions

Infection/septicemia – Sepsis may be accompanied by fever, metabolic acidosis, and elevations in CK; this makes it difficult to distinguish from MH. Generalized rigidity would not be seen in sepsis. Other perioperative causes of fever are much more common than acute MH. Patients undergoing surgery involving endothelial surfaces (gastrointestinal tract, urogenital tract, etc) are particularly prone to develop fever, which can be due to transient bacteremia or the effects of anesthetics and/or surgery on the hypothalamic thermoregulatory system [51,52].

Pheochromocytoma – Undiagnosed pheochromocytoma may present during surgery with episodic severe hypertension and tachycardia [53]. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Thyroid storm – Thyroid storm may occur in patients with untreated hyperthyroidism, precipitated by surgery or trauma. Symptoms which overlap with MH include tachycardia, cardiac arrhythmia, and hyperthermia to 104 to 106°F. Hypotension and cardiovascular collapse may develop. Muscular signs (generalized rigidity, masseter spasm, rhabdomyolysis, and hyperkalemia) would not be present with thyroid storm. Mental status changes and gastrointestinal symptoms of thyroid storm are not apparent under general anesthesia. (See "Thyroid storm".)

Cerebral pathology – Fever may result from hypoxic encephalopathy, intracranial bleed, traumatic brain injury, or meningitis.

Neuromuscular disorders – Patients with various muscular disorders, including Duchenne and Becker muscular dystrophy, may develop rhabdomyolysis or hyperkalemia when exposed to volatile anesthetics or succinylcholine; this is not fulminant MH (although these drugs are contraindicated in patients with these conditions). Other disorders (myotonias, osteogenesis imperfecta) may have increased muscular symptomatology or fever during anesthesia without other signs of MH. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Muscle diseases needing non-triggering anesthetics'.)

Rhabdomyolysis – Rhabdomyolysis may occur from other causes and must be distinguished from MH by the clinical situation. (See "Causes of rhabdomyolysis".)

APPROACH TO SUSPECTED MH CRISIS — Acute malignant hyperthermia (MH) is strongly suspected when the anesthesiologist cannot bring down a rising end-tidal carbon dioxide (ETCO2) level despite compensatory increases in minute ventilation. The diagnosis is further supported by muscle rigidity (generalized or prolonged masseter muscle rigidity [MMR]) or an otherwise unexplained metabolic acidosis. When these clinical signs occur without a persuasive alternative diagnosis, treatment of presumed MH must be initiated (table 6). Additional anesthesia personnel should be summoned to assist in preparing the dantrolene and initiating the MH protocol. As recommended by the Malignant Hyperthermia Association of the United States (MHAUS), an appropriately stocked MH treatment cart should be immediately available at all times (table 7).

Evaluate and manage hypercarbia — An unexpected rise in the ETCO2 level is often the earliest sign of MH; therefore, early exclusion of technical factors or sources of increased CO2 production or decreased CO2 elimination that could account for hypercarbia help to focus the differential diagnosis. (See 'Differential diagnosis' above.)

Increase minute ventilation – Hypercarbia that returns to normal levels when ventilation is increased is not likely to be due to MH. During sedation or general anesthesia, hypercarbia is usually due to hypoventilation (a decrease in CO2 elimination); it is identified as a rise in ETCO2 and treated by assisting spontaneous ventilation or increasing tidal volume or rate settings on the ventilator.

Eliminate obstruction of ventilation – Technical problems that impair ventilation or the elimination of CO2 will increase the level of ETCO2. A reasonable method to correct this is to look sequentially:

Examine the patient (look for bronchial obstruction or pneumothorax, mainstem intubation)

Inspect the breathing circuit (look for leaks, disconnects, malfunctioning expiratory valve)

Inspect the anesthesia machine/ventilator (look for exhausted CO2 absorbent, low fresh gas flow, tidal volume not being delivered)

A high ETCO2 that decreases with increased ventilation without becoming normal may also be due to a faulty CO2 monitor; this can be checked by having the clinician exhale into the CO2-monitoring tubing.

Seek sources of increased CO2 – During laparoscopic surgery, ETCO2 may rise due to absorption of insufflated CO2. Temporarily releasing the pneumoperitoneum should restore CO2 levels to normal within a reasonable timeframe; however, CO2 that has been insufflated into the tissues (eg, subcutaneous emphysema) may be slow to clear.

The use of a vascular clamp (eg, aortic cross clamp) or tourniquet for prolonged periods of time leads to retention of metabolic products (ie, CO2 and lactate), which are then released into the circulation when the clamp or tourniquet is released; the resulting metabolic acidosis is usually transient and not likely to be confused with the mixed acidosis of acute MH.

Survey for supporting signs of MH — Once the diagnosis of MH has been considered, the patient (who has received volatile anesthetics or succinylcholine) should be surveyed for other signs MH (see 'Clinical features' above):

Increasing ETCO2

Generalized rigidity

Premature ventricular contractions (or other signs of hyperkalemia)

Tachycardia (not explained by the clinical situation)

Unstable arterial pressure (high or low)

Masseter spasm

Unexplained metabolic acidosis

If one or more of these signs is present without an alternate working diagnosis, the patient should be presumed to have MH, and therapy initiated.

Initiate MH protocol — Additional personnel should be mobilized, as care of a patient with MH is very labor-intensive (table 6). The MH treatment cart should be brought into the immediate area (table 7). Assistance in diagnosing and managing an MH crisis is available from the MHAUS Hotline at 1-800-644-9737 in the United States (00+1+209-417-3722 outside the United States). (See 'MHAUS hotline and support' below.)

Optimize oxygenation and ventilation – Increase inspired oxygen to 100 percent. Increase ventilation rate and/or tidal volume to maximize ventilation and reduce the ETCO2. If the patient is not intubated, an endotracheal tube should be placed, using only non-depolarizing muscle relaxants, if paralysis is required.

Discontinue triggering agents – Immediately discontinue volatile anesthetic agents and inform the operating surgeon of the diagnosis. The surgical procedure should be terminated as quickly as possible; a surgical procedure that cannot be aborted should be completed under intravenous anesthesia with non-triggering agents (most often propofol). A charcoal filter should be attached to the inspiratory and expiratory limbs of the breathing circuit (picture 1). It is not necessary to change the anesthesia machine. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Management of anesthesia in malignant hyperthermia-susceptible patients'.)

Administer dantrolene – Dantrolene is the only known antidote for MH. It should be administered as a loading bolus of 2.5 mg/kg intravenously (IV), with subsequent bolus doses of 1 mg/kg IV until the signs of acute MH have abated. It should be administered rapidly through a large-bore IV line, if possible. The ETCO2 will generally return to normal as the dantrolene takes effect; in most cases, dantrolene reverses the acute hypermetabolic process within minutes. The need to use higher doses is uncommon, and the clinician should question the diagnosis if a rapid response is not seen; however, some patients, especially muscular males, may require initial dantrolene doses approaching 10 mg/kg IV.

In the United States, there are two types of dantrolene preparations. The older form is supplied as a lyophilized powder in a 20 mg vial, containing 3 g of mannitol and sodium hydroxide to maintain pH of 9 to 10. Each 20 mg vial requires mixing with 60 mL of sterile water; warming will enhance its solubility [54]. It is important to summon additional personnel to assist with drug preparation and administration; the initial bolus of dantrolene in a 70 kg patient will require the mixing and administration of nine vials, at a time when multiple other interventions are required.

A new dantrolene formulation (Ryanodex), which is dissolves rapidly, became available for clinical use in 2014. It is supplied in 250 mg vials, reconstituted with only 5 mL of sterile water, and warming is not needed. Because it is hyperconcentrated, blood concentrations will be achieved faster in patients with acute MH, with less of a sterile water volume load than the older form. There are no clinical reports of emergency use of this formulation, but preclinical animal studies and phase 1 human volunteer studies demonstrate a favorable clinical and side effect profile that does not differ from existing dantrolene formulations.

All facilities where general anesthesia is administered should have an adequate stock of dantrolene on site to treat an MH event. Each facility should have a treatment protocol and a dedicated MH treatment cart containing dantrolene (2.5 mg/kg for an averaged sized patient available at all times), other necessary medications, and equipment needed to immediately treat an acute episode (table 7). (See "Susceptibility to malignant hyperthermia: Evaluation and management" and "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Malignant hyperthermia resources'.)

Monitor and treat hyperkalemia – Hyperkalemia is treated (ie, calcium, bicarbonate, and insulin-glucose) based upon the presence of abnormal electrocardiogram waveforms (eg, peaked T waves) to prevent the development of life-threatening arrhythmias or cardiac arrest. Individuals with greater muscle mass appear to be at an increased risk for hyperkalemia from rhabdomyolysis, based on the cases reported to the author and others on the MHAUS hotline. (See "Treatment and prevention of hyperkalemia in adults" and "Management of hyperkalemia in children".)

Use of calcium channel blockers during an acute MH crisis is contraindicated because of the possibility that it can worsen hyperkalemia and hypotension.

Check labs – Measure electrolytes, blood gasses for acid/base status, CK, serum myoglobin, coagulation parameters, and fibrin split products (table 3). Arterial or venous blood gases should be collected initially and as needed until pH and potassium levels trend toward normal values.

Initiate supportive care

Monitor and treat acidosis; consider bicarbonate. (See "Approach to the adult with metabolic acidosis", section on 'Overview of therapy'.)

Treat cardiac arrhythmias as per advanced cardiac life support. (see "Advanced cardiac life support (ACLS) in adults"). Dysrhythmias usually respond to the treatment of acidosis and hyperkalemia.

Monitor core temperature continuously (eg, esophageal, tympanic, rectal probe). Skin liquid crystal temperature indicators do not accurately trend with core temperature [7]. Patients with core temperature >39ºC should be cooled (infuse cold saline intravenously; lavage open body cavities; apply ice to surface; other techniques as needed) and continued until the patient's temperature drops below 38.5ºC (101.3ºF). (See "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Cooling measures'.)

Insert a bladder catheter to monitor urine color and volume. A urine dipstick positive for heme (without red blood cells) indicates myoglobinuria. Urine output should be kept above 1 mL/kg/hour until the urine color returns to normal and the CK begins to decrease (see "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'). CK values will usually peak around 14 hours after the initiation of MH and should be measured twice daily until decreasing levels are observed.

Monitor muscle compartments for acute compartment syndrome; rhabdomyolysis can result in compartment syndrome, especially in patients who have developed disseminated intravascular coagulation (DIC). Muscle compartment release (ie, four compartment fasciotomy) may be required. (See "Acute compartment syndrome of the extremities".)

Institute measures to prevent myoglobinuria-induced renal failure (ie, hydration, diuretics, bicarbonate). (See "Prevention and treatment of heme pigment-induced acute kidney injury", section on 'Prevention'.)

Monitor for DIC. The maximal temperature of patients who develop DIC tends to be significantly greater than those who do not (40.3ºC versus 39.0ºC) [7]. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults".)

Refractory MH — Extracorporeal membrane oxygenation (ECMO) may be considered as a last resort for patients with persistent cardiac arrest unresponsive to the treatments in the MH protocol. Successful use of ECMO has been reported in one such case [55]. (See "Extracorporeal membrane oxygenation (ECMO) in adults", section on 'Indications'.)

MHAUS hotline and support — 24-hour support is available from consultants at MHAUS at 1-800-MH-HYPER (1-800-644-9737 in the United States [00+1+209-417-3722 outside the United States]).

The MHAUS acute management algorithm can be found on the MHAUS website, at www.mhaus.org.

Additional information about MHAUS is presented separately. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Malignant hyperthermia resources'.)

ONGOING CARE — Following completion of the surgical procedure, the patient should be transferred to an intensive care unit for ventilatory support (as needed) and hemodynamic monitoring for at least 24 hours. Dantrolene can be stopped, or the interval between doses increased to every 8 or 12 hours if all of the following criteria are met:

Metabolic stability for 24 hours

Core temp is less than 38°C

Creatine kinase (CK) is decreasing

No evidence of myoglobinuria

Muscle is no longer rigid

Recrudescence occurs in up to 25 percent of patients after initial treatment, at a mean of 13 hours (standard deviation, 13 hours) after the initial reaction [44]. Maintenance doses of dantrolene (1 mg/kg intravenous [IV] every four to six hours) should continue for 24 to 48 hours after the last observed sign of acute malignant hyperthermia (MH) [44,56]. If recurrent signs appear in spite of ongoing treatment, additional dantrolene boluses may be required.

Dantrolene has no effect on cardiac or smooth muscle. Its most common local adverse reaction is venous irritation or thrombosis at the site of administration due to its high pH; side effects include nausea, malaise, lightheadedness, and mild to moderate muscle weakness [57]. Respiratory muscle weakness may occur when larger doses are used, especially in patients who are debilitated.

MORTALITY — Estimates of mortality from malignant hyperthermia (MH) have come from data derived from the National Inpatient Sample [58], and from reports submitted to the North American Malignant Hyperthermia Registry (NAMHR) [48,59]. Mortality from MH has declined significantly with the routine use of end tidal CO2 monitoring and availability of dantrolene and is reported to be between 1 and 17 percent [57,58].

However, the exact mortality rate is unknown because of the paucity of accurate data on the number of actual MH cases and the number of deaths reported to the Malignant Hyperthermia Association of the United States (MHAUS). On average, MHAUS receives notice of approximately 100 cases of MH per year, and reports of one or two MH related deaths every one to two years. Thus a rough estimate of mortality is 0.5 percent.

Of note, an analysis of MH reports submitted to MHAUS between 1987 and 2006 found that the risk of dying with an MH episode correlated with the use and type of temperature monitoring [48]. Patients whose temperature was not monitored were at least twice as likely to die as those who had core temperature monitoring. Skin temperature monitoring was not as effective as core temperature monitoring. In theory, continuous core temperature monitoring allowed more rapid diagnosis of an MH event, more rapid treatment, and reductions in peak temperature and duration of hyperthermia. All deaths occurred in patients with a peak temperature of 38.9ºC or higher.

Other factors that increase risk for cardiac arrest and death with MH include advanced age, comorbidities, heavy muscular build (eg, young males), and the development of disseminated intravascular coagulation (DIC) [58].

COUNSELING AFTER ACUTE MH — Following recovery from an acute malignant hyperthermia (MH) event, we counsel patients that, until definitive testing for MH susceptibility (MHS) is complete, they should:

Not have anesthesia with triggering agents

Avoid exercise in excessive heat or humidity, as this may trigger an event

Inform family members of the possible MH episode, as MHS is a genetic condition and family members may also need to be evaluated

MHS patients are encouraged to learn as much as possible about the nature of their condition and should be directed to the appropriate educational resources. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Counseling' and "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Malignant hyperthermia resources'.)

SUMMARY AND RECOMMENDATIONS

Malignant hyperthermia (MH) is an autosomal dominant disorder that may present with a hypermetabolic crisis when susceptible individuals are exposed to volatile anesthetics or succinylcholine. Unrecognized, mild, or atypical reactions likely occur due to variable penetrance of the autosomal dominant inherited trait. (See 'Introduction' above and 'Triggering agents' above.)

MH-susceptible (MHS) individuals have skeletal muscle receptor abnormalities, most often in ryanodine receptors (RYR1), which allow excessive intracellular calcium to accumulate in response to triggering agents. This triggers intracellular events leading to skeletal muscle hypermetabolism. (See 'Pathophysiology' above.)

Although the initial clinical signs of MH typically occur within one hour of anesthesia induction, the onset of MH can occur any time during the administration of triggering agents. The onset of MH in the postoperative period is extremely rare and does not generally manifest solely as temperature elevation. (See 'Clinical presentation' above.)

We suggest continuous core temperature monitoring during anesthetics lasting more than 30 minutes. (See 'Hyperthermia' above.)

Clinical diagnosis

The diagnosis of acute MH is based upon clinical signs (eg, hypercapnia, tachycardia, muscle rigidity, rhabdomyolysis, hyperthermia, and arrhythmia); the most reliable sign is hypercapnia that is resistant to increasing the patient's minute ventilation, with a mixed metabolic and respiratory acidosis. Other prominent early clinical signs include sinus tachycardia and muscle rigidity. Hyperthermia is a later sign of MH, and can be absent when the diagnosis is initially suspected. (See 'Clinical features' above.)

Technical factors that would account for hypercapnia should be excluded; this includes decreased carbon dioxide elimination (eg, inadequate ventilation, rebreathing exhaled CO2) or increased production (eg, absorption of laparoscopic CO2). Other medical causes of these clinical signs are numerous and more common than MH. However, unless the clinician is persuaded that an alternative diagnosis is responsible, consideration of the differential diagnoses should not interfere with a presumptive diagnosis of MH and initiation of the acute MH management protocol. (See 'Clinical diagnosis' above.)

Acute management

As soon as the presumptive diagnosis of MH is made, call for assistance and the MH treatment cart (table 7) and initiate the following (see 'Initiate MH protocol' above):

Discontinue volatile anesthetic agents; if available, add charcoal filters to anesthesia breathing circuit (picture 1).

Hyperventilate with 100 percent oxygen.

If surgery cannot be terminated immediately, begin non-triggering anesthetic (eg, propofol). (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Safe anesthetic agents'.)

We recommend immediate administration of dantrolene (Grade 1A). The initial dose is 2.5 mg/kg intravenous (IV), to be given rapidly through a large-bore IV. The end-tidal carbon dioxide (ETCO2) typically normalizes within minutes; subsequent bolus doses of 1 mg/kg (up to 10 mg/kg) may be needed if signs of MH have not abated, most often in muscular males.

Assess for hyperkalemia and treat if present. (See "Clinical manifestations of hyperkalemia in adults" and "Treatment and prevention of hyperkalemia in adults".)

Monitor blood gases, core temperature, creatine kinase (CK), urine output, urine color, electrolytes, coagulation parameters, and fibrin split products, and treat abnormalities as needed.

Treat cardiac dysrhythmias, which are usually responsive to treatment of acidosis and hyperkalemia. Advanced cardiac life support protocols should be used as indicated. (See "Advanced cardiac life support (ACLS) in adults".)

Patients should have supportive care in an intensive care unit for at least 24 hours and be closely monitored for recurrence. Continue dantrolene for 24 to 48 hours. (See 'Ongoing care' above.)

Following an acute event, the likelihood that a suspected clinical event represents a true MH episode can be estimated using the MH clinical grading scale. Definitive diagnosis requires susceptibility testing. While awaiting evaluation, the patient should be counseled to receive only non-triggering anesthetics, to limit exposure to excessive heat and humidity, and to inform family members of the diagnosis. (See 'Clinical diagnosis' above and 'Counseling after acute MH' above.)

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REFERENCES

  1. DENBOROUGH MA, FORSTER JF, LOVELL RR, et al. Anaesthetic deaths in a family. Br J Anaesth 1962; 34:395.
  2. Denborough M. Malignant hyperthermia. Lancet 1998; 352:1131.
  3. Rosenberg H, Fletcher JE. International Malignant Hyperthermia Workshop and Symposium, Hiroshima, Japan, July 16-19, 1994. 82, 803-805. 1995.
  4. MacLennan DH, Phillips MS. Malignant hyperthermia. Science 1992; 256:789.
  5. Wappler F. Malignant hyperthermia. Eur J Anaesthesiol 2001; 18:632.
  6. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth Analg 2009; 109:1162.
  7. Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 2010; 110:498.
  8. Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anaesthesiol Scand 1997; 41:480.
  9. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis 2007; 2:21.
  10. Lee-Chiong TL Jr, Stitt JT. Disorders of temperature regulation. Compr Ther 1995; 21:697.
  11. O'Sullivan GH, McIntosh JM, Heffron JJ. Abnormal uptake and release of Ca2+ ions from human malignant hyperthermia-susceptible sarcoplasmic reticulum. Biochem Pharmacol 2001; 61:1479.
  12. Berchtold MW, Brinkmeier H, Müntener M. Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol Rev 2000; 80:1215.
  13. Ohnishi ST, Taylor S, Gronert GA. Calcium-induced Ca2+ release from sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia. The effects of halothane and dantrolene. FEBS Lett 1983; 161:103.
  14. Struk A, Lehmann-Horn F, Melzer W. Voltage-dependent calcium release in human malignant hyperthermia muscle fibers. Biophys J 1998; 75:2402.
  15. Vilven J, Coronado R. Opening of dihydropyridine calcium channels in skeletal muscle membranes by inositol trisphosphate. Nature 1988; 336:587.
  16. Wappler F, Scholz J, Köchling A, et al. Inositol 1,4,5-trisphosphate in blood and skeletal muscle in human malignant hyperthermia. Br J Anaesth 1997; 78:541.
  17. Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet 2001; 59:178.
  18. Quane KA, Healy JM, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993; 5:51.
  19. Censier K, Urwyler A, Zorzato F, Treves S. Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors. J Clin Invest 1998; 101:1233.
  20. Sambuughin N, Holley H, Muldoon S, et al. Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population. Anesthesiology 2005; 102:515.
  21. Gronert GA, Theye RA. Halothane-induced porcine malignant hyperthermia: metabolic and hemodynamic changes. Anesthesiology 1976; 44:36.
  22. Mickelson JR, Louis CF. Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Physiol Rev 1996; 76:537.
  23. Louis CF, Zualkernan K, Roghair T, Mickelson JR. The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum. Anesthesiology 1992; 77:114.
  24. Nelson TE. Porcine malignant hyperthermia: critical temperatures for in vivo and in vitro responses. Anesthesiology 1990; 73:449.
  25. Dirksen RT, Avila G. Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1. Biophys J 2004; 87:3193.
  26. Schuster F, Müller R, Hartung E, et al. Inhibition of sarcoplasmic Ca2+-ATPase increases caffeine- and halothane-induced contractures in muscle bundles of malignant hyperthermia susceptible and healthy individuals. BMC Anesthesiol 2005; 5:8.
  27. Paul-Pletzer K, Yamamoto T, Bhat MB, et al. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002; 277:34918.
  28. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 1975; 47:62.
  29. Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyperthermia. Anesthesiology 1982; 56:254.
  30. Riazi S, Larach MG, Hu C, et al. Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands. Anesth Analg 2014; 118:381.
  31. Lavezzi WA, Capacchione JF, Muldoon SM, et al. Case report: Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old. Anesth Analg 2013; 116:420.
  32. Groom L, Muldoon SM, Tang ZZ, et al. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology 2011; 115:938.
  33. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771.
  34. Litman RS, Flood CD, Kaplan RF, et al. Postoperative malignant hyperthermia: an analysis of cases from the North American Malignant Hyperthermia Registry. Anesthesiology 2008; 109:825.
  35. Beldavs J, Small V, Cooper DA, Britt BA. Postoperative malignant hyperthermia: a case report. Can Anaesth Soc J 1971; 18:202.
  36. Newson AJ. Malignant hyperthermia: three case reports. N Z Med J 1972; 75:138.
  37. Britt BA. Combined anesthetic- and stress-induced malignant hyperthermia in two offspring of malignant hyperthermic-susceptible parents. Anesth Analg 1988; 67:393.
  38. Kalow W, Britt BA, Terreau ME, Haist C. Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 1970; 2:895.
  39. Evans TJ, Parent CM, McGunigal MP. Atypical presentation of malignant hyperthermia. Anesthesiology 2002; 97:507.
  40. Harwood TN, Nelson TE. Massive postoperative rhabdomyolysis after uneventful surgery: a case report of subclinical malignant hyperthermia. Anesthesiology 1998; 88:265.
  41. McKenney KA, Holman SJ. Delayed postoperative rhabdomyolysis in a patient subsequently diagnosed as malignant hyperthermia susceptible. Anesthesiology 2002; 96:764.
  42. Birmingham PK, Stevenson GW, Uejima T, Hall SC. Isolated postoperative myoglobinuria in a pediatric outpatient. A case report of malignant hyperthermia. Anesth Analg 1989; 69:846.
  43. Fierobe L, Nivoche Y, Mantz J, et al. Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia. Anesthesiology 1998; 88:263.
  44. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007; 106:901.
  45. O'Flynn RP, Shutack JG, Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis. Anesthesiology 1994; 80:1228.
  46. Van der Spek AF, Fang WB, Ashton-Miller JA, et al. The effects of succinylcholine on mouth opening. Anesthesiology 1987; 67:459.
  47. Carroll JB. Increased incidence of masseter spasm in children with strabismus anesthetized with halothane and succinylcholine. Anesthesiology 1987; 67:559.
  48. Larach MG, Brandom BW, Allen GC, et al. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesth Analg 2014; 119:1359.
  49. http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/temperature-monitoring (Accessed on May 21, 2015).
  50. Nelson P, Litman RS. Malignant hyperthermia in children: an analysis of the North American malignant hyperthermia registry. Anesth Analg 2014; 118:369.
  51. Frank SM, Kluger MJ, Kunkel SL. Elevated thermostatic setpoint in postoperative patients. Anesthesiology 2000; 93:1426.
  52. Halsall PJ, Ellis FR. Does postoperative pyrexia indicate malignant hyperthermia susceptibility? Br J Anaesth 1992; 68:209.
  53. Ramani NS, Stoppacher R, Morani AC, Catanese C. Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia. Am J Forensic Med Pathol 2017; 38:262.
  54. Mitchell LW, Leighton BL. Warmed diluent speeds dantrolene reconstitution. Can J Anaesth 2003; 50:127.
  55. Huh H, Jung JS, Park SJ, et al. Successful early application of extracorporeal membrane oxygenation to support cardiopulmonary resuscitation for a patient suffering from severe malignant hyperthermia and cardiac arrest: a case report. Korean J Anesthesiol 2017; 70:345.
  56. Podranski T, Bouillon T, Schumacher PM, et al. Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work? Anesth Analg 2005; 101:1695.
  57. Brandom BW, Larach MG, Chen MS, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg 2011; 112:1115.
  58. Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology 2009; 110:89.
  59. Larach MG, Brandom BW, Allen GC, et al. Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesthesiology 2008; 108:603.
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