Malignant Hyperthermia

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40 Malignant Hyperthermia

MALIGNANT HYPERTHERMIA (MH) is a pharmacogenetic disease of skeletal muscle that may precipitate a potentially fatal sequence of metabolic responses in the presence of triggering anesthetics. The primary triggers for MH—inhalational anesthetics and succinylcholine—induce an uncontrollable release of intramyoplasmic calcium (Ca²⁺) that results in sustained muscle contractures, which produce a hypermetabolic response. The hypermetabolic response manifests with hypercarbia, hyperpnea, tachycardia, and if not treated early, a mixed metabolic and respiratory acidosis. It is usually accompanied by some form of muscle rigidity: isolated muscle rigidity (e.g., masseter muscle tetany in the temporomandibular joint) or total body muscle rigidity (e.g., sustained contraction of major peripheral muscle groups).

MH was first described by Denborough and Lovell in 1960, who reported a 21-year-old man with compound fractures of his right tibia, who, with great trepidation, underwent general anesthesia with halothane.¹ After 10 minutes of anesthesia, he became hemodynamically unstable with hypotension, tachycardia, and mottled skin that was hot to the touch. The soda lime canister was found to be hot and was changed because it appeared to be exhausted. The anesthetic was discontinued, the patient was packed in ice, and he recovered without sequelae. Postprocedural examination did not reveal any known medical abnormalities. A careful family history disclosed that 10 blood relatives had previously died after ether anesthesia, suggesting an autosomal dominant pattern of inheritance for the disorder. This patient required a subsequent operation and was administered a spinal anesthetic without incident, demonstrating the effectiveness of nontriggering anesthetics.² Subsequent reports from around the world established this disorder as a familial entity that was potentially fatal.^3,⁴ The term malignant hyperpyrexia (later changed to malignant hyperthermia) was coined in 1967 at the first international meeting on this disorder.

The incidence of MH based on occurrences of MH reactions has been reported to be 1 case per 50,000 to 100,000 adults and 1 case per 3000 to 15,000 children.^5,⁶ Subsequent surveys of suspected MH reactions revealed even greater incidences; the incidence of suspected MH was 1 case per 16,000 anesthetics in adults in Denmark, an incidence that increased to 1 case per 4200 adults when an inhaled anesthetic and succinylcholine were combined.⁷ However, a survey of anesthesia in a pediatric hospital in the United States during the halothane era revealed an MH incidence of 1 case per 20,000 to 40,000 children, almost one half of that reported previously.⁸ The incidence of fulminant MH (i.e., rapid increase in temperature accompanied by life-threatening metabolic changes, arrhythmias, and increased serum creatine kinase level) was 1 case per 250,000 general anesthetics in Denmark.⁷ A similar incidence of 1 case of fulminant MH per 200,000 general anesthetics was reported from the United Kingdom.⁹ The Danish survey found an incidence of 1 case of masseter muscle spasm per 12,000 anesthetics among children who received succinylcholine, whether in combination with inhalational or intravenous anesthetics.⁷ Clinically, the demographic data suggested that the incidence or suspicion of MH was greater among children than adults and that the incidence was even greater among children in whom succinylcholine was used.

The frequency of MH reactions is greatest in childhood, with a peak age of 3 years, although recent data suggest that only about 18% of MH reactions occur in childhood.^10,¹¹ Reactions have also been reported in neonates and infants, although they have been infrequent.¹² Many have perceived a decrease in the incidence of MH reactions in the past 2 decades, although some have challenged this perception.¹¹ Two reasons for the perception that the incidence of MH reactions have decreased are that many families with a genetic predisposition to MH have been identified and bring it to the attention of their surgical and anesthetic care providers preoperatively, and that the routine use of succinylcholine has decreased dramatically as a result of concerns regarding rare complications, such as hyperkalemic cardiac arrest. The latter has resulted in a black box warning admonishing against the routine use of succinylcholine in children, particularly male children younger than 8 years of age who may have unrecognized muscular dystrophy or other myopathy.^13,¹⁴

It remains certain that all inhalational anesthetics and succinylcholine are potent triggers of MH reactions in susceptible patients,¹⁵^–¹⁹ with the possible exception of xenon based on evidence from MH-sensitive pigs²⁰ and caffeine-halothane contracture tests (CHCTs) from MH-susceptible and normal humans.²¹ No other drugs used for intravenous or regional anesthesia trigger MH reactions. A comprehensive list of triggering and nontriggering drugs is available from the Malignant Hyperthermia Association of the United States (MHAUS) (http://www.mhaus.org/ [accessed July 2012]).

The mortality rate for MH has decreased dramatically from more than 80% in the 1960s to 1.5% to 5% in recent years (Fig. 40-1).^11,²²^–²⁴ For children, the MH mortality rate (0.7%) is 15-fold less than the rate (14%) for adults.¹¹ The overall decrease in mortality may be attributable to several factors: better identification of MH-susceptible individuals; the routine use of capnography and pulse oximetry, facilitating early identification of the signs and symptoms of an acute MH reaction^25,²⁶; a better understanding of the pathogenesis of MH; and the widespread availability of dantrolene.¹⁰

FIGURE 40-1 The trend in fatality rate in malignant hyperthermia is shown over time. The blue bars represent data from 361 patients, and the magenta bars represent data from 142 patients. Notice the marked decrease in mortality with dantrolene treatment.

(Modified from Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth Analg 1993;77:297-304.)

Clinical Presentation

The most common presentation of MH is a hypermetabolic response to the inhalational anesthetics, with or without succinylcholine (Table 40-1). Among the earliest clinical signs is a marked increase in the end-tidal CO₂ that resists control by either mechanical ventilation or an increase in minute ventilation when the patient is breathing spontaneously.^23,²⁷ Other nonspecific early signs include tachycardia and hemodynamic instability with a trend toward hypertension. Severe masseter muscle spasm (i.e., masseter tetany) refers to the inability to insert a laryngoscope blade into the mouth, the so-called “jaws of steel,” even with no twitches evident on a blockade monitor after administration of succinylcholine, and it strongly indicates MH susceptibility (Fig. 40-2). In vitro live muscle biopsy testing revealed a 28% to 50% incidence of MH susceptibility among children with jaws of steel (Table 40-2).²⁸^–³⁰ Generalized muscle rigidity develops as a result of the excessive accumulation of myoplasmic Ca²⁺ concentrations in MH-susceptible skeletal muscle, causing sustained muscle contractures.²⁷ This occurs even in the presence of neuromuscular blockade with nondepolarizing neuromuscular blocking drugs (NMBDs).

TABLE 40-1 Clinical and Laboratory Findings Associated with Malignant Hyperthermia

Clinical Findings	Laboratory Findings
Tachycardia, tachypnea and hypertension	Increased Paco₂
Hypercarbia (etco₂)	Acidosis (mixed respiratory and metabolic)
Greatly increased minute ventilation	Relative hypoxia, increased alveolar to arterial partial pressure gradient for oxygen
Generalized muscle rigidity (unresponsive to nondepolarizing muscle relaxants)	Hyperkalemia
Skin mottling	Elevated plasma lactate concentration
Hyperthermia (late sign)	Abnormal coagulation studies (late sign)
Cardiac arrhythmias (hyperkalemia-induced: PVC, VT, VF)	Myoglobinuria, myoglobinemia
Cola-colored urine (late sign)	Increased CPK level (usually a late sign)
Disseminated intravascular coagulation (late)

CPK, Creatinine phosphokinase; etco₂, end-tidal carbon dioxide; Paco₂, arterial partial pressure of carbon dioxide; PVC, premature ventricular contraction; VF, ventricular fibrillation; VT, ventricular tachycardia.

Data from Malignant Hyperthermia Association of the United States. Available at http://www.mhaus.org (accessed July 2012).

FIGURE 40-2 The spectrum of masseter muscle responses to succinylcholine varies from a slight jaw stiffness that does not interfere with endotracheal intubation to the extreme “jaws of steel,” which is masseter muscle tetany that does not allow the mouth to be opened. The latter response is likely highly associated with malignant hyperthermia (MH). Even with the inability to open the mouth, the child’s lungs should still be able to be ventilated by bag and mask because all other muscles are relaxed.

(From Kaplan RF. Malignant hyperthermia. Annual refresher course lectures. Washington, DC: American Society of Anesthesiologists; 1993.)

TABLE 40-2 Limited Excursion of the Mandible: Differential Diagnosis

Temporomandibular joint dysfunction: congenital, inflammatory/infectious, trauma, neoplasm, collagen vascular disease (rheumatoid arthritis)

Muscle disease: malignant hyperthermia, Duchenne or Becker muscular dystrophy, myotonia congenita

Integumentary disease: inflammatory or infectious disease, neoplasm, radiation effects, collagen vascular disease (scleroderma)

Neurologic injury

Ultra-rapid metabolizer of succinylcholine (Nietlich or Cynthiana [C5 enzyme] variant of pseudocholinesterase) (see Chapter 6)

Ineffective succinylcholine

Hyperthermia, often a late sign, results from the greatly increased aerobic and anaerobic metabolic activity of triggered skeletal muscle; the overlying skin soon becomes hot to the touch. In many instances, the large muscle groups such as calf or thigh muscles feel tight or knotted. This is accompanied by exaggerated carbon dioxide (CO₂) production, which usually is the first sign of an evolving MH reaction, and the accumulation of lactate fueled by markedly increased glycogenolysis and glycolysis (i.e., mixed respiratory and metabolic acidosis).^31,³² If an acute MH reaction is diagnosed and treated early in its evolution, before the body becomes unable to maintain this exaggerated aerobic metabolism, arterial blood gases may show an almost pure respiratory acidosis, which can make the diagnosis of MH difficult (Table 40-3). A mixed venous or peripheral venous blood gas analysis can be helpful in establishing the presence of hypermetabolism because it is more likely to demonstrate an increased CO₂ level, significant oxygen desaturation consistent with increased oxygen consumption ( less than 40 mm Hg, despite administering supplemental oxygen for which the expected is greater than 60 mm Hg), and a possible increased lactate concentration.

TABLE 40-3 Arterial Blood Gas Data from a Child in Early Malignant Hyperthermia

In fulminant cases, untreated MH may increase the temperature as rapidly as 1° C every 10 minutes.²⁷ In one case, the temperature reached 43.8° C (110.8° F) within 18 minutes.³³ In addition to the profound hypercarbia and tachycardia, severe hypoxia, skin mottling, exuberant metabolic acidosis, rhabdomyolysis, coagulopathy, and hyperkalemia may follow. Unstable hemodynamics and ventricular arrhythmias inevitably follow. Intractable ventricular arrhythmias, pulmonary edema, disseminated intravascular coagulation, cerebral hypoxia or edema, and renal failure due to myoglobin deposition in the renal tubules are often associated with fatal outcomes.

In the early years of treating acute MH reactions, before dantrolene was identified as the specific antidote, symptomatic treatment was the mainstay of therapy. This included treatment of the acidosis and hyperkalemia with bicarbonate, and insulin with glucose, respectively; active cooling with iced saline gastric lavage; infusion of cold intravenous saline; and infusions of procainamide (a drug that was later shown to be ineffective). These interventions helped to reduce the mortality rate to about 50%, but with the availability of dantrolene, the mortality rate has decreased dramatically.

The presenting signs of MH vary (see Table 40-1). The syndrome may be fulminant or indolent, not all features of a classic MH reaction may be immediately evident, and it may occur intraoperatively or postoperatively, although the frequency of MH reactions occurring postoperatively is only 2%.^27,³⁴ The latest that an MH reaction has reportedly occurred postoperatively is 11 hours, although a recent review of reports of postoperative MH in the North American Malignant Hyperthermia Registry has not found any case occurring beyond 40 minutes after the end of the anesthetic.^34,³⁵ The likelihood that an MH-susceptible patient will develop MH in the presence of inhalational anesthetics is exasperatingly unpredictable. In one study, 50% of susceptible individuals reported two or more uneventful general anesthesias before an MH reaction was triggered.^23,³⁶ Only 6.5% of probands in a retrospective review reported a family or personal history of MH.³⁶ A negative personal or family history is insufficient to conclude that a child is not susceptible to MH. Other disease states may be confused with MH (Table 40-4) and must be distinguished from it to provide correct therapy.

TABLE 40-4 Differential Diagnosis of Malignant Hyperthermia

Diagnosis	Distinguishing Traits
Hyperthyroidism	Patients often present with similar symptoms and physical findings; blood gas abnormalities gradually evolve; creatine phosphokinase value does not increase substantively.
Sepsis	Usually, blood gases are normal early, and metabolic acidosis occurs late; creatine phosphokinase remains normal.
Pheochromocytoma	Similar to MH, except for marked blood pressure swings
Metastatic carcinoid	Flushing, diarrhea, hypotension
Cocaine intoxication	Fever, rigidity, rhabdomyolysis similar to NMS
Heat stroke	Similar to MH, except that the patient is outside the operating room
Masseter muscle rigidity (MMR)	May progress to MH; total body spasm more likely than isolated MMR
Neuroleptic malignant syndrome (NMS)	Similar to MH but evolves over weeks; usually associated with the use of antipsychotics
Serotonergic toxicity	Similar to MH and NMS; associated with the administration of mood-elevating drugs (e.g., selective serotonin reuptake inhibitors)
Nonmalignant hyperthermia syndrome	Reported only once; severe hyperthermia seemingly associated with fentanyl

Given the variability of the clinical presentation of MH and the dearth of pathognomonic signs for this syndrome, establishing the diagnosis can be difficult. In response to the need for an objective measure to verify a clinical episode of MH, a retrospective, multivariable clinical grading scale was developed.³⁷ This grading scale was devised to clarify the cutoff value for a positive muscle CHCT result. It was not intended to be a clinical guide in the operating room. Despite recommendations not to use this scale to guide treatment and to be more conservative in its application, Tables 40-5 and 40-6 are provided to help clinicians identify true MH reactions. Although this clinical grading scale is somewhat cumbersome and has not been prospectively validated in clinical settings for use by nonexperts, it is a useful guide for the clinician.

TABLE 40-5 Clinical Indicators for Determining the Malignant Hyperthermia Raw Score

Process	Indicator	Points
Rigidity	Generalized muscular rigidity	15
Rigidity	Masseter spasm	15
Muscle breakdown	Creatine kinase >20,000 IU after succinylcholine	15
	Creatine kinase >10,000 IU with no succinylcholine	15
	Cola-colored urine in perioperative period	10
	Myoglobin in urine >60 µg/L	5
	Myoglobin in serum >170 µg/L	5
	Blood, plasma, or serum K⁺ >6 mEq/L, no renal illness	3
Respiratory acidosis	Petco₂ >55 mm Hg with controlled ventilation	15
	Arterial Paco₂ >60 mm Hg with controlled ventilation	15
	Petco₂ >60 mm Hg with spontaneous ventilation	15
	Arterial Paco₂ >65 mm Hg with spontaneous ventilation	15
	Inappropriate hypercarbia, anesthesiologist’s call	15
	Inappropriate tachypnea	10
Temperature increase	Inappropriately rapid increase	15
Temperature increase	Inappropriately increased temperature >38.8° C (101.8° F)	10
Cardiac involvement	Inappropriate sinus tachycardia	3
Cardiac involvement	Ventricular tachycardia or fibrillation	3
Family history	Positive family history for first-degree relative	15
Family history	Positive family history for more distant relative	5
Others	Arterial base excess more negative than −8 mEq/L	10
	Arterial pH <7.25	10
	Rapid reversal of maligant hyperthermia (MH) signs after intravenous administration of dantrolene	5
	Positive MH family history with another indicator from the patient’s anesthesia experience other than increased creatine kinase level	10
	Elevated creatine kinase level and a family history of MH	10

From Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771-9.

TABLE 40-6 Malignant Hyperthermia Clinical Grading Scale

Raw Score Range	Rank	Likelihood
0	1	Almost never
3-9	2	Unlikely
10-19	3	Somewhat less than likely
20-34	4	Somewhat greater than likely
35-49	5	Very likely
≥50	6	Almost certain

Modified from Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771-9.

Patient Evaluation and Preparation

Optimal treatment begins with prevention and preparation. Obtaining an accurate family history of suspicious or unusual reactions to general anesthesia in blood relatives, unexpected admissions to intensive care after surgery, or unexplained sudden death during anesthesia should signal the surgeon and anesthesiologist to consider MH or another problem related to anesthesia. These questions assume the patient is part of a classic nuclear family, but with increasing levels of adoption, artificial insemination, surrogate motherhood, and egg donations, standard probing may not elicit clear family histories. The anesthesiologist must be sensitive but decisive in determining the true genetic relationship between the guardians and the child. Despite attempts to obtain an accurate history, misinterpretation of the questions may occur. In one case, an adopted child died of succinylcholine-induced hyperkalemic cardiac arrest, even though the parents denied that anyone in the family had anesthesia problems or muscle disease during the preoperative assessment. Only immediately after the event did the parent reveal that the child had been adopted and that the child’s birth uncle had muscular dystrophy.

If the anesthesiologist is informed that the child has a blood relative who had an MH reaction or who has a myopathy with high concordance with MH, the most prudent course of action is to plan using a nontriggering anesthetic for total intravenous or regional anesthesia, or both. In the rare circumstance in which such prudence cannot be followed, extreme vigilance and preparation to treat MH are of the utmost importance.

Ambulatory surgery has rapidly expanded to include most pediatric surgery. Consequently, the safety of discharging children with a personal or family history of MH after an uneventful, trigger-free anesthesia on the day of surgery has raised concerns. Two retrospective studies concluded that the risk of a child developing an MH reaction after an uneventful, trigger-free anesthesia was exceedingly small.³⁸ Postoperative monitoring for an MH reaction while in the hospital was gradually reduced from 6 hours to 2 hours before discharge.^39,⁴⁰ For MH-susceptible children, parents should be provided with a written description of the signs and symptoms of an MH reaction and a phone number for the on-call anesthesiologist for further advice. Families should contact an anesthesiologist rather than return to the emergency department, because the emergency physician may be unfamiliar with MH, particularly in children. Additional advice for the parents should include the use of an oral antipyretic drug (e.g., acetaminophen) to treat a mild fever. If the fever abates after a dose or two of acetaminophen, the fever was not caused by MH. If the fever persists despite acetaminophen and sponge baths, and is accompanied by tachycardia and tachypnea, the parents should notify the on-call anesthesiologist and return the child to the hospital.

When a child with a known susceptibility to MH is scheduled for general anesthesia, the anesthesia machine (i.e., anesthetic workstation [AWS]) must be prepared to preclude the delivery of triggering agents. First, succinylcholine should be removed from the local vicinity to avoid inadvertent administration. Second, all vaporizers should be physically disengaged from the AWS, which is preferable because they can leak trace concentrations of inhalational anesthetics even in the off state, or if they cannot be removed from the AWS, tape should be placed across them in the off position to avoid accidentally turning them on.⁴¹ Third, to accelerate the washout of anesthetics, the CO₂ absorbent should be replaced, a new anesthetic breathing circuit installed, and the ventilator bellows flushed and left operating.⁴¹^–⁴³ Fourth, to eliminate inhalational anesthetics from the AWS, many clinicians follow a standardized protocol of flushing the workstation with 10 L/min of oxygen for 10 to 20 minutes, depending on the manufacturer and age of the machine.⁴⁴ However, the assumption that one protocol fits all to reduce the anesthetic concentration to less than 10 ppm, which is assumed to be the threshold below which an MH reaction cannot be triggered,⁴⁵ may not hold true for every AWS, particularly the newer ones, which are more complex in construction and more likely to contain internal working parts made of plastic, which act as sumps for inhalational anesthetics. To address the various types of AWS, the duration of flushing with large fresh gas flows (Table 40-7) and the need to exchange contaminated internal components with clean versions must be determined for each AWS. For some types of AWS, more than 60 minutes may be required to reach anesthetic concentrations less than 10 ppm.^44,^46,⁴⁷ To achieve an anesthetic concentration of 10 ppm or less in the Drager Primus, Fabius, and Zeus machines in a timely manner, the ventilator diaphragm and integrated breathing system should be replaced with autoclaved components and then flushed for 20 minutes at a fresh gas flow of 10 L/min.^46,⁴⁷ Table 40-7 lists the published times required to reach an anesthetic concentration of less than 10 ppm without replacing any AWS components.^44,^47,⁴⁸ These data support the notion that the previously held protocols to wash out inhalational anesthetics from older AWSs do not hold true for the newer AWSs. The need for a single protocol or intervention that consistently achieves an anesthetic concentration of less than 10 ppm in all AWSs is of even greater importance because none of the available anesthetic agent analyzers is capable of measuring anesthetic concentrations in the 10 ppm range to confirm adequate removal of inhalational anesthetics.

TABLE 40-7 Time to Wash Out Inhalational Anesthetics to Less than 10 ppm from Anesthetic Workstations

After the AWS has been flushed with 10 L/min of an air and oxygen mixture, most anesthesiologists reduce the fresh gas flow during anesthesia. However, evidence has shown that the concentration of inhalational anesthetic surges (≥50 ppm) when the fresh gas flow is reduced, and the magnitude of the rebound directly depends on the fresh gas flow rate.^48,⁴⁹ Those who reduce the fresh gas flow after purging the AWS may be exposing their patients to concentrations of inhalational anesthetics that may trigger an MH reaction, although no MH reactions have been reported in patients in whom a reduced fresh gas flow was used in an AWS that had been purged using a large (>10 lpm) fresh gas flow. To avoid confusion, a single, consistent, effective, and reliable intervention is required to prevent MH reactions in patients exposed to trace gases from a previously contaminated AWS.

A commercially available charcoal filter (Vapor-Clean, Dynasthetics, LLC, Salt Lake City) fitted to the expiratory and inspiratory limbs of the AWS reduces the concentration of inhalational anesthetics to less than 5 ppm within several minutes.⁵⁰ These filters are sold in pairs. The manufacturer recommends that a filter should be inserted into both limbs of the anesthesia breathing circuit just distal to the valves, which is reasonable during an acute MH reaction. However, when only the machine is contaminated with inhalational anesthetic (e.g., after flushing the AWS for elective MH cases), we apply a single filter in the inspiratory limb and keep the second of the pair to replace the first after 60 to 90 minutes, since it may become expended by that time.⁵⁰

Monitoring

Capnography and pulse oximetry, key monitors for early signs of an MH reaction, are required for all children who receive general anesthesia, irrespective of the duration of the procedure. Measurement of the body temperature is recommended for all children who undergo general anesthesia when fluctuations may be anticipated, according to the American Society of Anesthesiologists 2011 standards for basic anesthesia monitoring (www.asahq.org/For-Members/Standards-Guidelines-and-Statements.aspx). Monitoring the axillary temperature site (opposite the extremity with the intravenous line) is recommended rather than a core site for early detection of an MH reaction because the axillary region is surrounded by large muscle bulk in the pectoral shoulder girdle. Although most consider an increasing temperature a late sign of an MH reaction, a retrospective review suggested that an increasing body temperature may occur early in an evolving MH reaction.^36,⁵¹ Evidence also suggests that crystalline skin temperature tapes may not reliably track temperature changes during MH reactions.³⁶

Diagnosis

Because the underlying disorder in MH is a hypermetabolic reaction (i.e., increased CO₂ production and oxygen consumption), massive volumes of CO₂ are released into the circulation, which rapidly increase the partial pressure of CO₂ (Pco₂) and respiratory rate in the unparalyzed child. The cardiovascular response is an increased cardiac output, heart rate, and in some cases, blood pressure (E-Fig. 40-1). The first clinical signs and symptoms of this hypermetabolic reaction in a spontaneously breathing patient are hypercapnia, tachypnea, and tachycardia (see Table 40-1).³⁶ A steady and relentless increase in the end-tidal CO₂ pressure (Petco₂) is the earliest sign of a reaction and is usually evident whether respirations are spontaneous or controlled. In some instances, the increase in Petco₂ and heart rate occur contemporaneously, alerting the clinician to consider an evolving MH reaction (Fig. 40-3

FIGURE 40-3 Response of physiologic parameters to dantrolene during an apparent intraoperative episode of malignant hyperthermia. Notice the rapid fall in arterial and end-tidal carbon dioxide pressures after dantrolene (2.5 mg/kg) administration (arrow).

(Courtesy Steven C. Hall, MD.)

E-FIGURE 40-1 Malignant hyperthermia reaction in a 5-year-old child undergoing ptosis surgery. After an inhalational induction with halothane and establishment of IV access, anesthesia was maintained with an inhalational induction and spontaneous respiration. After 30 minutes of halothane, heart rate and temperature increased from 140 to 190 beats/minute and 36° to 37.5° C, respectively. Arterial blood gases showed a combined metabolic and respiratory acidosis. After 55 minutes of halothane, anesthesia was discontinued, and 100% oxygen and dantrolene 2.5 mg/kg IV were administered. Vital signs returned to normal within 25 minutes. By 75 minutes after induction of anesthesia, the severity of the acidosis was resolving.

). Sudden unexpected cardiac arrest is a very rare presentation of MH and suggests a disease process other than MH, such as acute rhabdomyolysis and hyperkalemia after succinylcholine in a (male) child with an undiagnosed myopathy.

The presenting signs of an MH reaction are nonspecific and may suggest several possible disease states or equipment problems. The earliest sign of an MH reaction, an increase in end-tidal pCO₂, may result from one or more of three factors from the CO₂ mass balance equation:

The circulating Pco₂ depends on the production of CO₂ (), the elimination of CO₂ (i.e., alveolar ventilation ([]), and the inspired concentration of CO₂ (Fico₂). The differential diagnosis of an increased Pco₂ can be analyzed by considering the causes for each of these three factors. Causes of an increased include fever, MH, thyroid storm, and sepsis. Causes of a decreased include a deep level of anesthesia, endobronchial intubation, bronchospasm, and a kinked tracheal tube or airway breathing circuit. Causes of increased Fico₂ include an incompetent expiratory valve, exogenous source of CO₂, low fresh gas flows with a partial or nonrebreathing circuit, and expired CO₂ absorbent. The initial evaluation should include a rapid assessment of the integrity of the breathing circuit, the presence of bilateral breath sounds and absence of wheezing, and examination of the CO₂ absorbent.

During airway obstruction and hypermetabolic states such as thyrotoxicosis and sepsis, an increased Petco₂ can be readily corrected with mild to moderate hyperventilation. During MH reactions, however, it is very difficult to restore the Petco₂ to the normal range, even with vigorous mechanical hyperventilation.²⁶ The CO₂ production is sometimes so great that the in-circuit CO₂ absorbent rapidly becomes exhausted in an exothermic reaction, and the absorbent container becomes hot to touch.

A child’s response to surgery during light anesthesia often includes tachycardia and may sometimes include bronchoconstriction. However, a dramatic and unexpected increase in heart rate from 120 to 180 beats/min in a healthy, 7-year-old child (or an increase from 70 to 120 beats/min in an adult) strongly suggests a pathologic process, and a differential diagnosis beyond light anesthesia should be seriously considered. Before intervening, it is important to quickly scan all of the monitors to determine whether the aggregate indices point to a specific diagnosis. If tachycardia is associated with an increase in body temperature, a differential diagnosis of fever and tachycardia under anesthesia should be considered. Fever related to sepsis or viral infection usually has a slow onset, whereas fever from an MH reaction typically has a rapid onset. The differential diagnoses include iatrogenic external overheating and an MH reaction (see Table 40-4). A rapid increase in the inspired concentration of desflurane and isoflurane, but not sevoflurane, may cause a sympathetic-based tachycardia that in isolation should not suggest a diagnosis of MH because the Petco₂ remains unchanged.^52,⁵³ Of the inhalational anesthetics, halothane appears to be the most likely to trigger an MH reaction and the best discriminator for the CHCT. Enflurane provides the smallest trigger, sevoflurane and isoflurane are intermediate, and preliminary data suggest that xenon does not trigger MH reactions.^21,^45,⁵⁴^–⁵⁶ If none of these factors appears to be causative and a deeper level of anesthesia (achieved with propofol with or without an opioid) fails to abate the signs, simultaneous venous and arterial blood gases should be analyzed to determine whether the patient has or is developing a hypermetabolic state.

A moderate but gradual increase in body temperature may occur in children excessively draped, those with forced-air warming devices, those with bilateral limb tourniquets, and those covered with plastic occlusive wrap. However, the sudden onset of a high fever must be more thoroughly investigated because it may result from several potentially fatal causes (see Table 40-4).⁵⁷^–⁶⁰

Management, Susceptibility Screening, and Counseling

Treatment

If the anesthesiologist suspects that a child is experiencing an MH episode, the inhalational anesthetic should be immediately discontinued, 100% oxygen administered at a large fresh gas flow rate (≥10 L/min), and the surgeon informed; if surgery cannot be aborted, it must be completed expeditiously. Charcoal filters should be inserted into both limbs of the breathing circuit until a clean breathing circuit is available (E-Fig. 40-2). They prevent the child from being contaminated by residual anesthetic in the AWS and to prevent the AWS from being contaminated by anesthetic in the patient.⁵⁰ The MH cart and additional personnel to assist in dissolving the dantrolene should be brought to the operating room immediately (Table 40-8). Minute ventilation should be increased to control the Paco₂ and Petco₂.

TABLE 40-8 Contents of a Pediatric Malignant Hyperthermia Emergency Cart

E-FIGURE 40-2 Charcoal filters should be inserted into both the inspiratory and expiratory limbs of the anesthesia breathing circuit during an acute MH reaction to remove inhalational anesthetic from the anesthesia workstation and to prevent the patient from being exposed to additional inhalational anesthetic. They can also be used preoperatively to rapidly prepare an anesthesia workstation for use with an MH susceptible patient in the event a “clean machine” is not available, although only a filter on the inspiratory limb would be required in such a case. These filters are effective within a few minutes and reduce the anesthetic concentration to 2-3 ppm, well below the theoretical threshold to trigger an MH reaction.

The anesthesia should be converted to total intravenous anesthesia, and if charcoal filters are not available, hyperventilation should be continued using an external self-inflating or anesthesia-type bag with an exogenous source of oxygen that is uncontaminated by inhalational anesthetics. If the airway was not intubated, tracheal intubation should be performed and ventilation controlled mechanically to achieve a normal Petco₂.

Because native dantrolene is quite insoluble in water, several strategies have been developed to speed its solubility. The current formulation is packaged as a lyophilized yellow powder in 20-mg vials that contain 3 g of mannitol and enough base to maintain a pH of about 9.5 (E-Fig. 40-3). The lyophilized formulation, mannitol, and the alkaline pH all speed the dissolution of dantrolene in water. Sixty milliliters of sterile water should be added to each vial to dissolve the dantrolene, with a resultant dantrolene concentration of 0.33 mg/mL. Warming the sterile water speeds dissolution.⁶¹ Most of the dantrolene in a vial dissolves within 60 seconds of adding the water. When the vial is vigorously shaken, any residual crystals dissolve, and the solution turns clear orange. The solution should be withdrawn immediately and administered intravenously as rapidly as possible. Occasionally, 1 or 2 additional minutes may be required to dissolve the last few crystals of dantrolene. Given the extreme alkaline pH of the dantrolene solution, it should be rapidly infused into a large vein to reduce the risk of phlebitis. Extravasation of dantrolene or prolonged continuous infusions of dantrolene may cause thrombophlebitis or thrombosis of large and small veins.⁶²^–⁶⁴ Some have recommended continuous infusions of dantrolene in adults after the initial bolus, although the risk/benefit ratio of this practice is unproved in adults and untested in children.⁶⁵ A new formulation of nanocrystalline dantrolene that rapidly dissolves and is available in a much greater concentration than the current formulation is undergoing federal review.⁶⁶

E-FIGURE 40-3 Dantrolene for intravenous treatment of an acute MH reaction. This formulation is lyophilized for storage, stability, and reconstitution. Each bottle contains 20 mg of dantrolene. The dantrolene is reconstituted by injection of sterile water 60 mL per bottle, producing an orange-colored solution. Dissolution may be accelerated by shaking the bottle or by injecting warmed sterile water. An initial dose of 2.5 mg/kg IV dantrolene should be administered as quickly as possible. If the reaction does not abate, further dantrolene should be administered 1 mg/kg IV until the reaction stops.

The pharmacokinetics of intravenous dantrolene have been studied in MH-susceptible children 2 to 7 years of age.⁶⁷ A loading dose of 2.5 mg/kg produced predictable blood concentrations (≥3 µg/mL) for about 6 hours after the loading dose (Fig. 40-4).⁶⁷ Based on these pharmacokinetic data, if half of the loading dose of dantrolene were repeated at 6 hours after the loading dose, therapeutic blood concentrations of dantrolene would be maintained for a total of 15 hours and possibly prevent a recrudescence.⁶⁷

FIGURE 40-4 Pharmacokinetics of dantrolene in children.

(From Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intravenous dantrolene in children. Anesthesiology 1989;70:625-9.)

An initial bolus dose of 2.5 mg/kg can control most MH reactions if the dantrolene is administered as soon after the onset of the reaction as possible (see Fig. 40-3).⁶⁸ Delay in instituting dantrolene therapy increases the probability of failed therapy and death.³⁶ For a 70-kg patient, this corresponds to 8 vials of dantrolene. The response to dantrolene should be evident within minutes, with a marked reduction in Petco₂, heart rate, and respiratory rate (see Fig. 40-3). If there is no response within 3 to 5 minutes, the initial dose should be repeated until signs that the physiologic variables are abating. The clinical end points include resolution of the hypercapnia, tachypnea, and tachycardia; resolution of muscle rigidity; restoration of clear urine output; return of normal consciousness when sedation is discontinued; self-correction of blood gas abnormalities; and resolution of electrolyte disturbances. If these do not occur or are incomplete, additional doses of dantrolene should be administered until all signs and symptoms of the MH reaction have abated or the diagnosis reevaluated.⁶⁸ There is no upper limit to the amount of dantrolene that can or should be given acutely to stop an MH reaction. In rare instances of persistent MH or recrudescence, a cumulative dose of up to 40 mg/kg has been required.⁶⁹ Dantrolene is a fairly potent muscle relaxant, and a child with an unintubated airway (particularly one with respiratory disorders) may become weak and require controlled respirations.

Although dantrolene is effective in terminating acute MH reactions, this effect may wane as the blood concentration of dantrolene decreases. In this case, the MH reaction may recrudesce. The prevalence of recrudescence has been reported to be as great as 20% and associated with several predictive factors, including muscular body type and a greater time interval between induction of anesthesia and the development of the initial reaction.⁷⁰ However, the first episode of recrudescence may occur any time after the initial reaction was successfully treated, up to and as late as 36 hours.⁷¹ The possibility of recrudescence must always be considered during the first 2 to 3 days after an MH reaction has occurred. Because recrudescence cannot be predicted, all children who experience an MH reaction must be admitted to the pediatric intensive care unit or a monitored bed until the reaction resolves and the child’s metabolic indices return to and remain normal for 2 to 3 days. MHAUS recommends that 1 mg/kg of dantrolene be administered intravenously every 6 hours for 24 to 48 hours after an MH reaction to prevent recrudescence. This recommendation remains empirical because there are no data to support the effectiveness of dantrolene in preventing recrudescence, although these dosages are consistent with pharmacokinetic data in children.⁶⁷ We recommend continued vigilance, frequent physical examinations for muscle tightness, and repeated laboratory tests (e.g., blood gas analyses), and monitoring of vital signs, particularly heart rate and expired CO₂ tension for evidence of a recrudescence during the first 48 hours after an MH episode. If recrudescence does occur, additional intravenous dantrolene should be administered until the reaction again abates.

Acute administration of dantrolene causes skeletal muscle weakness that can lead to respiratory embarrassment. Not surprisingly, neostigmine is ineffective in reversing the effects of dantrolene because the latter acts intracellularly, not at the neuromuscular junction (see the section on molecular mechanisms of dantrolene). It may be advisable to maintain control of the airway (combined with intravenous sedation) until there is no further need for dantrolene. Preoperative, orally administered dantrolene, initially recommended in MH-susceptible children 2 decades ago, caused skeletal muscle weakness, dysarthria, sialorrhea, and diplopia and was ineffective in preventing MH.⁷² As a result, this practice has been discontinued.⁷² There have been no reports of acute dantrolene toxicity, although reported adverse effects after intravenous administration include muscle weakness (about 22%), phlebitis (9%), gastrointestinal upset (about 4%), and respiratory failure (3.8%).⁶³ Long-term use in the treatment of chronic skeletal muscle spasticity has been reported to cause liver dysfunction and fatal hepatitis in about 1% and 0.1% of patients, respectively.⁷³ Given the risks of an MH reaction, there seems little downside to treating a child with dantrolene before the diagnosis is certain, provided all the necessary blood work and laboratory tests have been collected, because early treatment reduces mortality and morbidity (see Fig. 40-1).³⁶ The probability of developing a complication from an MH reaction increases almost threefold for every 2° C increase in body temperature and 1.6-fold for every 30-minute delay in administering intravenous dantrolene during a reaction.³⁶ Cardiac arrest and death during an MH reaction correlate with a muscular physique and greater time intervals between induction of anesthesia and the maximal value of Petco₂.²⁴ Other possible diagnoses should continue to be considered while the treatment for the suspected MH reaction is organized (see Table 40-4). A positive response to dantrolene is not pathognomonic of an MH reaction, because other conditions may respond with resolution of their signs.

Moderate external cooling measures may be instituted to control a rapidly increasing temperature, although ice should never be applied directly to the skin because it may cause tissue injury and intense cutaneous vasoconstriction. The latter may decrease heat loss further by accelerating acidosis and pyrexia. It is important to avoid overshooting with cooling measures (i.e., stop aggressive cooling at a temperature of about 38.5° C), because hypothermia may ensue, particularly if dantrolene has been administered. A urinary catheter should always be inserted during an MH reaction to identify myoglobinuria and to facilitate bladder emptying because 0.375 g of mannitol/kg body weight is given as part of the initial (2.5 mg/kg) loading dose of dantrolene.

Initial laboratory assessments should be obtained before the initial bolus dose of dantrolene, and in addition to arterial and venous blood gases, determinations should include electrolyte, glucose, blood urea nitrogen, and creatinine levels; a complete blood cell count with platelets; prothrombin and partial thromboplastin times; creatine kinase concentrations; and serum and urine myoglobin levels. Because creatine kinase concentrations peak 12 to 24 hours after the onset of an MH reaction, it is prudent to obtain a baseline blood sample as soon as an MH reaction is suspected. The provider should be especially aware of the potential for hyperkalemia due to muscle breakdown and for acute renal failure as a late complication. An arterial catheter should be inserted to continuously monitor blood pressure and for serial determinations of arterial blood gas and serum levels of electrolytes and creatine kinase.

The potential for life-threatening acidosis—a pure respiratory acidosis early in the syndrome, followed later by a mixed metabolic/respiratory acidosis—always exists. Metabolic acidosis should be treated with sodium bicarbonate (1 to 2 mEq/kg IV initially), as would be done for any acutely acidotic child, and continue treatment guided by pH and base deficit, although if hypercapnia persists despite aggressive hyperventilation, administration of sodium bicarbonate should be reconsidered because the severity of the respiratory acidosis may increase. Because an acute MH episode is associated with catecholamine stress, hemodynamic instability, particularly due to dysrhythmias, may develop and should be treated according to advanced cardiac life support protocols. Calcium channel blockers should be avoided when treating MH reactions because they may cause cardiovascular collapse or acute hyperkalemia in the presence of dantrolene.⁷⁴^–⁷⁶ Acute hyperkalemia is common in patients with MH complicated by rhabdomyolysis and acidosis. Glucose and insulin should be immediately available and combined with the judicious use of exogenous calcium for treatment. There is no evidence that the use of calcium in this setting exacerbates an MH reaction.

After the acute crisis has been treated, late complications, particularly severe rhabdomyolysis, are possible. It is important to follow serial concentrations of creatine kinase; if they are greater than 10,000 IU or urinary myoglobin concentrations increase, the urine should be alkalinized, and forced diuresis (>2 mL/kg/hr) with mannitol should be induced to prevent myoglobin from precipitating in the renal tubules, causing acute myoglobinuric renal failure. The enormous fluid requirements and edema associated with rhabdomyolysis may produce a compartment syndrome, which requires immediate surgical treatment.

Other organ systems may be affected after an acute episode of MH. It is common for markers of liver function to increase 12 to 36 hours after the crisis; some liver enzymes, including lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase, can also originate from muscle. A concomitant increase in creatine kinase to more than 10,000 IU strongly suggests a severe and acute muscle disorder. Accompanying increases in γ-glutamyltransferase and bilirubin suggest liver involvement. Disseminated intravascular coagulation as part of multisystem organ failure is a common and ominous late complication.⁷⁷ Coagulation profiles should be followed frequently to guide treatment appropriate to the case.

When necessary, the MH treatment algorithm should be accessed, available on the MHAUS web site (http://www.mhaus.org/). We think that an updated MH treatment algorithm should be attached to every MH cart and anesthesia machine and that operating room personnel should hold practice drills for the treatment of an MH crisis (see “Emergency Therapy for Malignant Hyperthermia” on the inside back cover of this text and at ExpertConsult.com). If the patient experiences what is thought to be an MH reaction, the care provider should call the MH emergency response line (1-800-644-9737 or 001-1-315-464-7079 if calling from outside the United States) for consultation with experienced anesthesiologists who are available 24 hours every day. We strongly encourage completion of an adverse metabolic reaction to anesthesia (AMRA) report by members of the team who provided anesthesia and postoperative care to the child. These forms can be downloaded (www.mhreg.org), sent by the hotline consultant, or obtained from the MHAUS office through regular mail. The data contained in the completed AMRA forms allow the North American Malignant Hyperthermia Registry (NAMHR) and MHAUS to produce better data regarding the variability of MH crises and the effectiveness of treatment. Because anesthesiologists should take a leading role in managing these patients, the families should be strongly encouraged to register the proband before leaving the hospital for MedicAlert identification (www.medicalert.org) that provides critical health information, such as “malignant hyperthermia susceptible, avoid inhaled anesthetics and succinylcholine.”

Stress-Triggered Malignant Hyperthermia

In 1974, Wingard described an MH-susceptible family with a history of exercise- and emotion-induced fevers and sudden death not associated with anesthesia or surgery; he considered the possibility that MH was part of a spectrum of human stress syndromes.⁷⁸ Likewise, the porcine model of MH, also known as porcine stress syndrome, was first described as an awake, stress-induced syndrome brought about by tightly packing pigs in a train, car, or truck for shipment.⁷⁹ Dantrolene-responsive cases of awake and heat stroke–induced MH have been reported.^80,⁸¹ Heat stress–induced MH also seems to be characteristic of susceptible animal models.⁸²^–⁸⁴ A fatal case of exercise-induced MH in a 12-year-old boy who had previously survived a suspected episode of MH during general anesthesia to set a fractured humerus has been reported.⁸⁵ Eight months after surgery, while playing a game of football, the child became hyperthermic, collapsed, and died. Postmortem DNA testing revealed an MH-associated RYR1 mutation in the child and his surviving father.⁸⁵ More cases of stress-induced MH have been reported, substantiated by genetic testing and in vitro contracture testing (IVCT).^86,⁸⁷

Screening for MH susceptibility in heat stroke patients and those suffering postexercise cramps or rhabdomyolysis using the in vitro CHCT has led to the laboratory diagnosis of MH susceptibility in some patients.⁸⁸^–⁹² Although there is laboratory evidence of similarities in skeletal muscle metabolism in exertional heat stroke and MH,⁹³ and one of the mouse MH knock-in models exhibits environmental heat triggering,⁵¹ there is as yet little evidence that these are anything more than clinically similar presentations.⁹² For this reason, dantrolene has rarely been an effective treatment for heat stroke.⁹⁴ Nonetheless, it seems reasonable to suggest that subsets of MH susceptible patients may be more sensitive to heat stroke. Therefore it may be helpful to test children with exertional heat illness for MH susceptibility.⁹⁵

MH reactions have been reported infrequently in susceptible patients who received a nontriggering anesthetic.⁹⁶^–⁹⁸ Of 2214 patients who presented for muscle biopsy for MH susceptibility, 5 (0.46%) of 1082 who had MH-positive biopsy results developed MH reactions in the recovery room. None of the patients with negative biopsy results developed MH reactions. There is a small incidence of MH reactions among susceptible individuals that may occur despite a safe anesthetic regimen. Whether this is caused by stress or trace anesthetic concentrations that were inhaled is unclear. Massive rhabdomyolysis has been reported on rewarming from cardiopulmonary bypass despite the patient having received a nontriggering anesthetic.^96,⁹⁷ The mechanism of these responses may be stress, but evidence is lacking.

Postepisode Counseling

Ideally, after treating a child for MH, the anesthesiologist should arrange for referral of the child and first-degree relatives to an MH diagnostic biopsy center. It is only at such centers that the CHCT can be performed in adults. The CHCT is the only test that can produce a true negative diagnosis (i.e., not MH susceptible),⁹⁹ but the sensitivity and specificity of this test are less than 100%. False-negative test results may occur, albeit rarely.¹⁰⁰ When the anesthetic management of a small number of MH biopsy-negative patients was reviewed, more than one half were given inhalational anesthetics, although the biopsy results for the remainder may not have been known at the time of anesthesia because they were given trigger-free anesthetics.¹⁰¹

Because there are no control muscle biopsy data for prepubescent children, contracture testing is not performed in this age group. Instead, children are more often fitted with MedicAlert bracelets, and the parents are counseled regarding their own need for biopsies. The children may be reconsidered for muscle biopsy upon reaching puberty.

Many persons suspected of having MH have normal muscle responses on the CHCT. In the event that an adult who experienced an MH reaction has a normal CHCT result, he or she should be referred to a neurologist with an interest in muscle diseases to determine whether an occult myopathy is responsible for the clinical events. Alternatively, the diagnosis may be incorrect, and other diagnoses should be considered (see Table 40-4). Individuals suspected of being MH susceptible should undergo CHCT; the family should also be evaluated and counseled.

Patients with strongly positive CHCT results should undergo screening for the ryanodine receptor 1 gene (RYR1), because mutations in this gene have been found in about 60% of family members who had an MH episode. If an MH-associated mutation (discussed later) is found in RYR1, first-degree relatives have a 50% probability of having a similar defect. Diagnostic testing for RYR1 is performed on DNA obtained from a blood specimen, obviating the need to travel to an MH diagnostic biopsy center or undergo muscle biopsy for the genetic test. Genetic testing of relatives can be undertaken through the office of the primary care physician or by the anesthesiologist, a process that will simplify evaluation of the family. Failure to identify an MH-causative RYR1 mutation (E-Fig. 40-4) does not confirm a negative diagnosis (i.e., not MH susceptible) because more than one gene is associated with MH susceptibility, and not all are known.

E-FIGURE 40-4 Distribution of known mutations associated with malignant hyperthermia and central core disease in the RYR1 gene, which comprises 106 exons. Reported mutations are summarized in exon-specific text boxes. The current distribution of mutations spans more than the putative mutation hot-spot regions of the gene first described by McCarthy and colleagues.

(From Robinson R, Carpenter D, Shaw MA, et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 2006;27:977-89; McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 2000;15:410-7.)

Genetic testing and counseling can be arranged by the anesthesiologist or primary care physician by scheduling an appointment; one such center is located at the Center for Medical Genetics at the University of Pittsburgh. The genetic counselors have extensive experience in counseling patients on the utility of the ryanodine receptor gene test for evaluation of MH susceptibility. The center currently screens 12 exons of genomic RYR1 that commonly contain MH mutations (exons 6, 9, 11, 14, 17, 39, 40, 44, 45, 46, 101, 102). A private commercial laboratory that also offers RYR1 testing is Prevention Genetics (www.preventiongenetics.com), which screens for MH mutations. It has adopted a two-tiered approach: Tier 1 involves bidirectional sequencing of exons 2, 6, 8, 9, 11, 12, 14, 15, 17, 39, 40-41, 44-47, 95, and 100-104. These 22 exons contain most of the conclusively documented MH and central core disease causative mutations in the RYR1 gene (http://www.emhg.org/genetics/). If the first tier is uninformative, their second-tier screen covers the remaining 84 exons of the 106 making up the human RYR1 gene. The Prevention Genetics company corresponds only with physicians and does not provide patient or family counseling.

As DNA sequencing has become more automated and the cost has drastically declined, many private companies have arisen that purport to diagnose the entire panoply of human genetic diseases and resultant predispositions, including MH. We have no information about the reliability of their screening or the recommendations based on their findings. If no causative RYR1 mutations are found, nothing more can be determined from genetic testing about susceptibility, because more than one mutated gene is linked to MH.

Genetics

MH in humans follows an autosomal dominant inheritance pattern with incomplete penetrance and variable expressivity.^27,^102,¹⁰³ In the context of MH, incomplete penetrance means that there are fewer patients with MH susceptibility than would be predicted by simple autosomal dominant inheritance. Variable expressivity means that the presence of a genetic mutation defining susceptibility is documented, but it does not mean that a patient will have an MH reaction when first exposed to triggering agents. One patient in the NAMHR received 30 anesthetics before an MH reaction was triggered.³⁶ Another was discovered to be MH susceptible by IVCT during screening of a proband’s family and later was inadvertently anesthetized with succinylcholine and isoflurane, but they did not trigger a reaction.¹⁰⁴ However, it seems that once an MH reaction has been triggered, the reaction will always be triggered when the patient is exposed to the offending agents.

The molecular and cellular bases of these phenomena remain unknown. Naturally occurring susceptibility to MH seems to follow autosomal dominant inheritance patterns in dogs ¹⁰⁵ and horses¹⁰⁶ but follows a recessive inheritance pattern in pigs.¹⁰⁷ This suggests that other genetic and epigenetic factors may play a role in determining the degree and timing of MH susceptibility.

The first breakthrough in finding a gene that predisposed to MH was the serendipitous finding of a similar syndrome in pigs.^108,¹⁰⁹ When anesthetized with halothane and succinylcholine or with halothane alone, the pigs developed full-blown MH reactions (E-Fig. 40-5). The pig model has been a primary pathophysiologic, genetic, and pharmacologic model for the study of MH over the past 5 decades. A second, serendipitous event introduced a South African anesthesiologist, GG Harrison, to dantrolene, and he successfully tested it in his pig model of MH.^110,¹¹¹ This observation was quickly followed by the successful treatment of a patient with dantrolene.¹¹² An interview about Harrison’s discovery of dantrolene is available from the Wood Library-Museum of the American Society of Anesthesiologists (http://www.woodlibrarymuseum.org/library/media).

E-FIGURE 40-5 A, A mask induction with halothane in a Landrace pig that is susceptible to malignant hyperthermia (MH). B, The anesthetized pig before the MH reaction. C, The pig’s limbs become rigid during the MH reaction.

One of the most surprising findings was that six separate breeds of pigs at different locations worldwide shared this MH susceptibility to inhalational anesthetics and succinylcholine. All reactions were treated successfully with dantrolene, and all were determined to have an autosomal recessive inheritance pattern. It was established that MH was associated with an uncontrolled increase in intramyoplasmic Ca²⁺, presumably the result of an exaggerated release of Ca²⁺ from the sarcoplasmic reticulum (SR).^113,¹¹⁴ Much effort has been expended in understanding the physiologic basis of excitation–Ca²⁺-release coupling (ECRC) as part of the general mechanism of skeletal muscle excitation-contraction coupling.

By the mid-1980s, a large channel in the SR membrane, now known as the ryanodine receptor (RyR1), was identified by its ability to bind a plant toxin, ryanodine. It was discovered to have properties consistent with being a Ca²⁺ channel.¹¹⁵^–¹¹⁷ In 1988, this presumed primary Ca²⁺-release channel of the SR was found to have gap junction–like channel properties.¹¹⁸ It was hypothesized that the ryanodine receptor might be the site of mutations that caused MH. Within a year, the cDNA for the skeletal muscle ryanodine receptor was cloned.¹¹⁹ Two years after the initial cloning of RyR1 the identical single amino acid mutation (Arg615Cys) was discovered in this channel in all six breeds of MH susceptible pigs.¹²⁰ RYR1 was immediately acknowledged as a potential target gene in MH susceptibility studies.

Detailed genetic evaluations have linked MH susceptibility to chromosome 19q12-13.2, the location of the human RYR1 gene (19q13.1), in most MH-susceptible families. This is the locus for malignant hyperthermia susceptibility type 1, symbolized by RYR1 (formerly designated MHS1) (Table 40-9).^102,^121,¹²² More than 300 variants have been identified in RYR1,¹²³ only about 30 of which have been documented as causing MH (www.emhg.org provides a comprehensive list of known causative mutations in RYR1). Not all MH-susceptible families have disorders linked to this chromosome (see Table 40-9), indicating that this syndrome is genetically heterogeneous.

TABLE 40-9 Malignant Hyperthermia Loci

Designation	Chromosome Locus	Gene
Ryanodine receptor 1 (skeletal) (formerly malignant hyperthermia susceptibility 1 [MHS1])	19q13.1	RYR1
Malignant hyperthermia susceptibility 2	17q11.2-q24	MHS2
Malignant hyperthermia susceptibility 4	3q13.2	MHS4
Calcium channel, voltage-dependent, L type, alpha 1S subunit (formerly malignant hyperthermia susceptibility 5 [MHS5])	1q32	CACNA1S
Malignant hyperthermia susceptibility 6	5p	MHS6

The next gene identified, MHS2, was found on chromosome 17q11.2-q24 in North Americans. The previously designated MHS3 locus, a voltage-dependent calcium channel (CACNA2D1), is no longer thought to be linked to MH susceptibility.¹²³ Although the data identify single genes that seem to affect individuals with MH susceptibility, there is discordance between a genetic marker and the likelihood of being MH susceptible.¹²⁴^–¹²⁶ Linkage analyses of six loci for MH susceptibility and other candidate loci suggest that multiple interacting genes may modify the primary genetic defect and subsequent clinical susceptibility to developing MH.^127,¹²⁸

Complicating the potential of genetic testing for MH even further is the phenomenon of gene silencing. This phenomenon mimics a recessive mutation in heterozygous individuals by allowing expression of only the affected allele while silencing the other, normal, allele.¹²⁹ Because MH is an autosomal dominant susceptibility, it is conceivable that a mechanism underlying the variability in MH triggering seen in patients with identical, monoallelic RYR1 mutations results from skeletal muscle–specific silencing of the affected gene. It follows that inhalational anesthetics or succinylcholine, after multiple exposures, may release a gene from the silenced state, allowing triggering to occur. This may be an explanation for discordance between genetics, linkage analysis, and trait expressivity.

Although the inheritance of human MH is described as autosomal dominant, there are a few individuals who are allelically homozygous for an RYR1 mutation,^130,¹³¹ intraallelically heterozygous for two different RYR1 mutations, or compound heterozygotes containing one mutation in RYR1 and a second mutation at another locus for MH susceptibity.¹³² Surprisingly, no overt myopathies have been reported in these affected individuals.

Physiology

Normal Skeletal Muscle: Excitation-Contraction Coupling

The neurochemical signal that triggers excitation-contraction coupling begins with the release of acetylcholine from the motor nerve terminal at the skeletal muscle nicotinic synapse, resulting in depolarization of the surface membrane, the sarcolemma. Sarcolemmal membrane depolarization is transmitted into the interior of the muscle cell by specialized invaginations of the surface membrane known as transverse tubules (TTs), which occur at regular intervals along the muscle cell (Fig. 40-5). The TT membrane is studded with the skeletal muscle isoform of the voltage-dependent Ca²⁺ channel known as the dihydropyridine receptor (DHPR). In skeletal muscle, this channel does not transmit Ca²⁺ in response to sarcolemmal depolarization. Rather, it functions as a sarcolemmal voltage sensor.

FIGURE 40-5 Structure of calcium release units in adult skeletal muscle fibers. In adult skeletal muscle, junctions are mostly triads: two sarcoplasmic reticulum (SR) elements coupled to a central transverse tubule (T tubule). A, A triad from the toadfish swimbladder muscle in thin-section electron microscopy shows the cytoplasmic domains of the SR Ca²⁺ release channel (RyR1), or feet, and calsequestrin (Cals.), the SR Ca²⁺ storage protein. B, A tridimensional reconstruction of a skeletal muscle triad shows the ultrastructural localization of ryanodine receptors (RyRs), dihydropyridine receptors (DHPRs), calsequestrin, triadin, junctin, and Ca²⁺/Mg²⁺-ATPases. Notice the localization of DHPRs in the T-tubule membrane; DHPRs are intramembrane proteins that are not visible in thin-section electron microscopy but can be visualized by freeze-fracture replicas of T tubules (in C). C, DHPRs in skeletal muscle form tetrads, a group of four receptors (inset), that are linked to subunit of alternate RyRs (in B and E). D, In sections parallel to the junctional plane, RyR feet arrays are clearly visible in toadfish swimbladder muscle; the feet touch each other close to the corner of the molecule (inset). E, The model summarizes the findings of C and D: RyRs (green) form two (rarely three) rows, and DHPRs (orange) form tetrads that are associated with alternate RyRs. The T tubule is shown in blue in B, and sandwiched between two portions of the SR in A.

(A, Courtesy Clara Franzini-Armstrong; B, courtesy T. Wagenknecht; from Protasi F. Structural interaction between RYRs and DHPRs in calcium release units of cardiac and skeletal muscle cells. Front Biosci 2002;7:d650-8.)

In response to depolarization, intrachannel charge movement across the TT membrane results in a conformational change of the DHPR. The TT is surrounded by specialized portions of the cellular organelle (i.e., SR) that are responsible for maintaining the cellular Ca²⁺ store, and the SR contains a high-capacity Ca²⁺ storage protein called calsequestrin, which regulates the ability of the RyR1 channel to open.¹³³ The face of the SR junctional membrane apposing the TT contains a packed, regular array of RyR1 proteins in close apposition to the DHPR. Physically, the DHPR and RyR1 receptor proteins overlie each other in a unique arrangement of four DHPRs (tetrad) per one RyR1, with every other RyR1 lacking a tetrad (Fig. 40-6).¹³⁴ Physical interaction of the DHPR with RyR1 after depolarization causes the RyR1 channel to open, and SR-stored Ca²⁺ is released into the myoplasm. Orthograde and anterograde communication between the DHPR and RyR1 results in reciprocal regulation of both entities^135,¹³⁶

FIGURE 40-6 Schematic of the known pathophysiology of malignant hyperthermia (MH). Exposure of an individual who has a genetic susceptibility because of a ryanodine receptor (RyR1) or dihydropyridine (DHP) receptor mutation to an anesthetic triggering agent may result in MH. Normally, muscle cell depolarization (1) is sensed by the DHP receptor (2), which signals RyR1 opening by a direct physical connection (3). The conventional view of the genesis of MH is that RyR1 opening is easier and more sustained in the presence of volatile anesthetics (4), allowing a sustained rise in the Ca²⁺ concentration in the myoplasm (5) that surpasses the sarcoplasmic reticulum Ca²⁺ reuptake activity of the Ca²⁺/Mg²⁺-ATPase. This results in unrelenting muscle contraction and uncontrolled anaerobic and aerobic metabolism, which translate into the clinical manifestations of respiratory and metabolic acidosis, muscle rigidity, and hyperthermia. If the process continues unabated, adenosine triphosphate (ATP) depletion eventually causes widespread muscle fiber hypoxia with resultant cell death and rhabdomyolysis. Rhabdomyolysis manifests clinically as hyperkalemia and myoglobinuria and an increase in the serum creatine kinase level. Dantrolene sodium binds to RyR1, presumably causing it to favor the closed state and stemming the uninhibited flow of calcium into the myoplasm. The contributions of store-operated Ca²⁺ entry (SOCE) to myoplasmic Ca²⁺ fluxes and its inhibition by dantrolene suggest that MH may have a significant component from SOCE or excitation-coupled Ca²⁺ entry (ECCE), or both, and dantrolene may inhibit the RyR1-dependent activation of SOCE or ECCE. TRPC1, ORAI1, and STIM1 are proteins involved in calcium transport. SR, Sarcoplasmic reticulum.

(Modified from Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA 2005;293:2918-24.)

In the myoplasm, the troponin C subunit of the troponin complex is bound to tropomyosin, which in the resting state inhibits myosin interaction with actin and maintains a relaxed muscle. Ca²⁺ binding to troponin C causes a conformational change in troponin and allows the complex to move away from tropomyosin, which rotates along the actin filament in a way that permits myosin head interaction with this fibrous protein. Fiber shortening and muscle contraction then occur in a myosin-ATPase–driven ratcheting reaction. The muscle relaxes when the SR membrane–bound Ca²⁺-ATPase transports free myoplasmic Ca²⁺ back into the SR against its concentration gradient in an energy-dependent reaction, thereby driving myoplasmic Ca²⁺ concentrations down to resting levels. Troponin I, with its bound Ca²⁺ removed, moves back to block the myosin interaction with actin, thereby preventing muscle contraction and inducing its relaxation. Although a detailed description of the complexity of this process is beyond the scope of this chapter, reviews of excitation-contraction coupling are available.^137,¹³⁸

Pathophysiology of Malignant Hyperthermia

Advances in the pathophysiology of MH have been reviewed in great detail elsewhere.¹³⁹^–¹⁴² In brief, at the cellular level, MH is characterized by an inhalational anesthetic–induced, uncontrolled increase in intramyoplasmic Ca²⁺ levels,^143,¹⁴⁴ which precedes the metabolic and clinical signs of this syndrome¹⁴⁵ (see Fig. 40-6). Increased intramyoplasmic Ca²⁺ has been demonstrated by directly measuring intracellular Ca²⁺ in anesthetic-triggered pigs¹⁴³ and by substantiating the sensitivity of stored Ca²⁺ release by isolated SR from MH-susceptible pigs.^113,^114,^146,¹⁴⁷ There is also a significant loss in the ability of magnesium (Mg²⁺), the natural inhibitory divalent cation that competes with Ca²⁺ for binding sites on RyR1, to inhibit Ca²⁺ release in MH-susceptible skeletal muscle.¹⁴⁸^–¹⁵⁰ RyR1 isolated from MH-susceptible pigs demonstrate greater open probabilities, greater sensitivity to Ca²⁺ activation, less sensitivity to Ca²⁺ inactivation, and reduced inhibition by Mg²⁺. As a result, the affected RyR1 channels spend more time in the open state and less time in the closed state than normal channels.¹⁵¹^–¹⁵⁵ Although not formally confirmed, this mechanism presumably underlies the sensitivity of RyR1 channels to volatile anesthetics and to the increase in intramyoplasmic Ca²⁺ seen in MH-susceptible skeletal muscle.

Similar single-channel studies of the Ca²⁺ responsiveness of human MH-susceptible RyR1 channels have yielded more equivocal results,¹⁵⁶ presumably because of the genetic heterogeneity of the human MH-susceptible population. Even within a single individual, heterozygosity for an MH mutation permits a given RyR1 channel that is supposed to be made up of four identical subunits to contain any combination of zero to four MH susceptibility subunits in combination with wild-type, normal RyR1 subunits. When examining single channels from a population of channels isolated from a heterozygous, MH-susceptible patient, the clinician can expect a wider range of channel responses than in the homozygous, inbred, porcine population used for MH models.

Several laboratories have reported the creation of knock-in mice containing one of two known MH-related RyR1 mutations: Tyr522Ser and Arg163Cys.^83,⁸⁴ In contradistinction to the pig model, and like their MH-susceptible human counterparts, the knock-in MH mice are heterozygous. Their homozygous littermates die in utero on day 17. These heterozygous mice become rigid, hyperthermic, and hypermetabolic; die after exposure to inhalational anesthetics or heat stress; and respond therapeutically to dantrolene. They display exaggerated responses to the RyR1 agonists caffeine and 4-chloro-m-cresol and to potassium depolarization. As with MH-susceptible humans and pigs, their muscle is less sensitive to inhibitory Mg²⁺ and possesses higher resting Ca²⁺ concentrations than wild-type animals. These experimental animals display a physiologic MH phenotype remarkably similar, if not identical, to the human syndrome and should prove extraordinarily useful in working out the details of MH pathophysiology.

Development of MH seems to require some form of neural input to muscle, because epidural anesthesia in the porcine MH model completely inhibits expression of MH.¹⁵⁷ However, complete inhibition of neural input into skeletal muscle in this model by the use of competitive, nondepolarizing, nicotinic cholinergic receptor antagonists such as d-tubocurarine, pancuronium, and vecuronium before a halothane challenge does not inhibit development of MH.^158,¹⁵⁹ Together, these results suggest that a neurologically significant contribution to MH arises from the central nervous system by means of sympathetic outflow or the neuroendocrine axis, rather than direct skeletal muscle stimulation. This theory is consistent with the awake or stress-related episodes of MH described earlier.

Molecular Mechanisms and Physiologic Effects of Dantrolene

Dantrolene (Fig. 40-7) is a hydantoin derivative originally synthesized as part of an effort to examine the muscle relaxant properties of a series of substituted furan derivatives.¹⁶⁰ Thinking that they might have an NMBD, scientists investigated its mechanism of action but found that it was different from the known skeletal muscle relaxants. It affected the intrinsic properties of skeletal muscle without affecting the central nervous system, neuromuscular transmission, electrical properties of the sarcolemma or the T tubule, electromyogram, or train-of-four method for testing neuromuscular blockade. Its action was intracellular (Fig. 40-8).¹⁶¹ Indirect evidence pointed to dantrolene affecting the Ca²⁺ fluxes that were intrinsic to skeletal muscle contraction.¹⁶²^–¹⁶⁴ Direct observations^165,¹⁶⁶ demonstrated that dantrolene suppressed the rate and amount of Ca²⁺ released from the SR without completely abolishing it. Subsequently, it was demonstrated that dantrolene inhibited halothane-induced Ca²⁺ release from the isolated SR of MH-susceptible pigs,^146,^167,¹⁶⁸ while the drug had no effect on calcium reuptake into the SR.^169,¹⁷⁰

FIGURE 40-7 Dantrolene and its congeners. Dantrolene and azumolene are equipotent drugs, but azumolene is far more water soluble. Only dantrolene is approved by the U.S. Food and Drug Administration for treatment of malignant hyperthermia. Aminodantrolene is a poorly active congener, demonstrating how small changes in drug structure can result in large changes in activity.

(Modified from Parness J, Palnitkar SS. Identification of dantrolene binding sites in porcine skeletal muscle sarcoplasmic reticulum. J Biol Chem 1995;270:18465-72.)

FIGURE 40-8 Intraoperative electromyogram of a child given intravenous dantrolene (2.4 mg/kg). The twitch tension decreased about 75% after dantrolene but was not reversed by administration of neostigmine, demonstrating the lack of involvement of the neuromuscular junction in the action of dantrolene.

After SR Ca²⁺ release was identified as the likely target of dantrolene activity, several unsuccessful attempts were made at identifying a dantrolene binding partner in the SR, mainly because of the difficulties of doing detailed pharmacologic receptor analyses with a drug as hydrophobic as dantrolene.^171,¹⁷² In 1995, an assay for radioactively labeled dantrolene helped to elucidate specific binding sites in porcine skeletal muscle SR.¹⁷³ Dantrolene inhibits RyR1-dependent cellular Ca²⁺ fluxes in skeletal muscle, albeit incompletely, but it does not seem to affect RyR1 channel activity or its ability to transport Ca²⁺.¹⁷⁴ With what does dantrolene interact, and how does this interaction relate to reduced Ca²⁺ fluxes in skeletal muscle and MH?

A second physiologic process, called store-operated Ca²⁺ entry (SOCE), contributes to the increase in intracellular Ca²⁺ as a result of the RyR1 channel opening in skeletal muscle.¹⁷⁵^–¹⁷⁷ SOCE is a process by which the SR store of Ca²⁺ is replenished from the extracellular milieu after significant loss of Ca²⁺ from the SR.¹⁷⁸ Experiments with azumolene, a more water-soluble congener of dantrolene, have demonstrated inhibition of skeletal muscle RyR1-dependent SOCE, not SR Ca²⁺ release.¹⁷⁹ These results raise profound questions. Do the induced Ca²⁺ fluxes during excitation-contraction coupling, experimental manipulation, and MH that result in an increase in intracellular Ca²⁺ all result from RyR1-dependent Ca²⁺ release or RyR1-dependent Ca²⁺ entry, or both?

Evidence of a dantrolene-sensitive, excitation-coupled Ca²⁺ entry mechanism of skeletal muscle (ECCE) that is more easily activated in MH skeletal muscle has been described, as well.¹⁸⁰^–¹⁸³ ECCE is different from SOCE in that it does not require depletion of the SR Ca²⁺ store and is activated by high-frequency electrical stimulation of the skeletal muscle membrane. ECCE and SOCE present new physiologic targets of investigation in to the pathophysiology of MH that involve Ca²⁺ entry rather than Ca²⁺ release (see Fig. 40-6).

Elucidation of the pathophysiology of MH and the mechanism of action of dantrolene has radically transformed our understanding of muscle physiology and pathophysiology. As our understanding continues to evolve, the future for advances in therapy and testing capabilities hold great promise.

Laboratory Diagnosis

Contracture Testing

The standard for testing susceptibility to MH in the human population is an in vitro contracture test that assesses live human muscle fibers from the vastus lateralis in a physiologic bath. With one end of the muscle tissue attached to a strain gauge, the degree of tension developed at baseline and on electrical stimulation is measured as a function of the concentrations of halothane or caffeine. The test is based on the observation that fresh muscle isolated from MH-susceptible patients behaved abnormally when exposed to halothane or caffeine in vitro (Fig. 40-9).¹⁸⁴^–¹⁸⁷ Two variations of this test have been developed and adopted: the CHCT by the North American Malignant Hyperthermia Group (NAMHG) and the IVCT by the European Malignant Hyperthermia Group (EMHG). The NAMHG test measures the response in separate muscle fascicles to a bolus of 3% halothane or incremental increases in the caffeine concentration,^22,^188,¹⁸⁹ and it requires a positive response to one of the challenges for a diagnosis of MH susceptibility. Those not responding are considered normal. The EMHG test measures the response to graded increases in the halothane concentration up to 2% and incremental increases in the caffeine concentration in different fascicles. The diagnosis of MH susceptibility by the IVCT requires a positive response to both challenges, whereas a positive response to one of the challenging agents results in equivocal diagnostic categorization (i.e., malignant hyperthermia equivocal [MHE]).¹⁹⁰^–¹⁹²

FIGURE 40-9 Caffeine-halothane contracture test. A, Abnormal (positive) response to 3% halothane. Each small box represents 0.1 g of tension. The contracture response in this case is 1.6 g. A normal response to 3% halothane is a contracture up to 0.7 g. After exposure to halothane, 32 mmol/L of caffeine is added to the bath to determine maximal response. B, Abnormal (positive) response to caffeine. Caffeine exposure is increased to 0.5, 1.0, 2.0, 4.0, 8.0, and 32 mmol/L for 4 minutes. A contracture of greater than 0.3 g to 2 mmol/L of caffeine or less indicates susceptibility.

(Modified from Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia. Anesthesiology 2002;96:232-7.)

Even though the EMHG protocol may prevent excess false-positive and false-negative results compared to the NAMHG protocol, overall results are comparable.¹⁹³ The EMHG reports that the sensitivity and specificity of its protocol are 99% and 94%, respectively,¹⁹¹ whereas the NAMHG reports that its sensitivity and specificity are 97% and 78%, respectively.¹⁹⁴ Because the North American protocol is less specific and tends to overdiagnose MH susceptibility, it has a very small likelihood of failing to diagnose an MH-susceptible individual. The fact that there are some false-positive findings in the contracture testing demonstrates that other myopathic conditions that are not necessarily concordant with MH have muscle tissue that is also capable of giving an abnormal response to halothane and caffeine exposures. Discordance between the results of an IVCT and the presence of MH mutations in RYR1 can occur in MH families such that 3.1% to 19.4% of family members who do not carry an MH mutation respond positively to an IVCT challenge.^75,¹⁹¹ This presumably indicates that there are other factors (e.g., a second MH susceptibility mutation in RYR1, another MH sensitivity locus, a sensitivity to caffeine and halothane that does not reflect MH susceptibility) in these individuals that give a positive IVCT result, but it does not necessarily mean that they are MH susceptible.

Genetic Testing

Limited examination of the RYR1 gene is available for the purpose of diagnosing MH susceptibility at two Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories in North America as discussed earlier. Any physician can write a prescription for the ryanodine receptor gene test for MH susceptibility or fill out the requisition form and send blood for genetic testing. However, the probability of a positive outcome with genetic testing depends in part on the results of the in vitro CHCT because the clinical signs of MH are nonspecific. Current genetic testing indicates that about 60% of those who are positive with the CHCT also have positive genetic test results, whereas only 20% of those without a positive CHCT result yield positive genetic results.⁷⁵

Other Disorders and Malignant Hyperthermia

Myopathic Syndromes

An incriminatory association between various myopathies and malignant hyperthermia susceptibility, now known to be far more restricted than originally thought, was described in the 1970s and 1980s with much debate over the biochemical and pathophysiologic character of the clinical episodes that resulted from exposure to MH-triggering agents.^195,¹⁹⁶ Did the clinical episodes represent true MH, did the episodes relate to the instability of myopathic muscle membrane with attendant destruction of muscle cells and release of intracellular proteins, and was there sometimes an associated hyperthermic reaction with these exposures? Although both types of episodes may result in increased creatine kinase levels, hyperkalemia, myoglobinemia, and myoglobinuria, one results from exaggerated ramping of cellular energy and heat production, and the other results from cellular destruction that does not involve abnormal cellular metabolism as a primary cause. Of the congenital myopathies, central core disease, the related multi-minicore disease, and the myopathy of King-Denborough syndrome are the only myopathies known to have a definite relationship with true MH (see Chapter 22).¹⁹⁷

Malignant Hyperthermia Mimics

Malignant Hyperthermia–like Syndrome in Pediatric Diabetes Mellitus

Diabetes mellitus has two well-characterized, life-threatening childhood presentations: diabetic ketoacidosis (DKA) and hyperglycemic hyperosmotic nonketotic syndrome (HHNS).¹⁹⁸^–²⁰¹ DKA, which is associated with type 1 diabetes, usually manifests as nausea, vomiting, dehydration, and weakness, but shock and coma are uncommon (1% to 2%) in the absence of cerebral edema. Fever is rarely a symptom and usually spurs a search for an underlying infection. HHNS is usually associated with type 2 diabetes and classically manifests with symptoms of increasing polyuria, polydipsia, and lethargy that develop over a few days. The estimated mortality rate is between 12% and 46%, somewhat more dramatic than that seen for DKA (2% to 10%), presumably because most cases of HHNS occur in adults with many other medical problems. The greatest rates of mortality with HHNS occur in adults older than 75 years of age or those with osmolarity values greater than 350 mOsm/L. The incidence of HHNS among U.S. children has been increasing rapidly and appears to be associated with the increase in childhood obesity. Despite this increase, pediatric HHNS is rare, and the presence of fever, as in DKA, usually prompts the search for an underlying infection.

A novel malignant hyperthermia–like syndrome (MHLS) against the background of pediatric diabetes mellitus was described in six adolescent boys between 14 and 18 years of age; the cases were culled from three tertiary care facilities in the United States.²⁰² The features of the syndrome included HHNS with coma, fever, rhabdomyolysis, and severe cardiovascular instability. Among the six adolescents with MHLS, five were obese, five had acanthosis nigricans, four were African American, and four died. Two more cases were later described; one patient died 14 hours after admission due to too rapid a correction of serum osmolarity and resultant cerebral edema and cardiovascular collapse, and a second patient was treated with dantrolene and completely recovered despite developing compartment syndrome in her left upper extremity due to rhabdomyolysis.²⁰³ The survivor was tested for metabolic abnormalities, and a deficiency in short-chain acyl-coenzyme A (acyl-CoA) dehydrogenase was found.

Investigators recommend that anyone presenting with symptoms of HHNS and MHLS should be treated with dantrolene as soon as the syndrome is recognized and that fluid and insulin therapy be used for an appropriate rate of correction of serum osmolarity. A search of the literature reveals a similar case described 10 years earlier as fulminant MH associated with DKA in a patient who survived with the addition of dantrolene to his treatment regimen.²⁰⁴ Although it is difficult to ascertain the efficacy of dantrolene in abrogating the deleterious effects on skeletal muscle and in saving critically ill patients with MHLS during HHNS with such a small number of successfully treated patients, it seems prudent to initiate immediate treatment with dantrolene in these cases until the data can inform us about the true efficacy of this drug in MHLS.

Disorders of Fatty Acid Metabolism

Growing numbers of reports have documented cases of rhabdomyolysis in patients with disorders of fatty acid metabolism that in some ways mimic awake MH. These disorders arise from mutations in the enzymes responsible for the metabolism of various fatty acids and for ensuring adequate energy substrate for the mitochondria during periods of reduced glucose availability, such as during stress. Although these disorders have profound effects on energy metabolism, they should not be confused with mitochondrial myopathies, which result from completely different molecular defects and have mutations in the proteins of the mitochondrial respiratory chain (see Chapter 22). In neither case has a real association with MH been established, but there have been case reports of rhabdomyolysis and cardiac arrest in patients with carnitine palmitoyltransferase II deficiency.²⁰⁵^–²⁰⁷

Various forms of acyl-CoA dehydrogenase deficiencies (i.e., very-long-chain, long-chain, medium-chain, and short-chain forms) lead to different types of myopathy that can have severe clinical consequences, including hypoglycemia and rhabdomyolysis with attendant multiple-organ dysfunction, which in some deficiencies are brought about by stress, particularly heat and severe exercise.^208,²⁰⁹ These diseases can manifest early in childhood or late in adolescence or young adulthood, and they can be a particular problem for individuals in the military or those who participate in intense sports.²⁰⁹ Patients with the very-long-chain acyl-CoA dehydrogenase deficiency can present with acute hypercapnic respiratory failure.²¹⁰ Dantrolene has been used successfully to treat one case of recurrent rhabdomyolysis in a patient with very-long-chain acyl-CoA dehydrogenase deficiency,²¹¹ and it may be useful to treat acute intraoperative rhabdomyolysis in these patients, although there is a dearth of evidence in this regard.

Children may present for surgery without a diagnosis of an inborn error of fatty acid metabolism and develop intraoperative rhabdomyolysis, mimicking aspects of a fulminant MH reaction. This may be the first manifestation of the child’s fatty acid metabolism disorder. Preoperative increases in serum creatine kinase and uric acid levels, presumably due to subclinical rhabdomyolysis, suggest an inborn error of metabolism or myopathy,²¹² but these tests are not part of the usual preoperative panel of blood tests in normal pediatric anesthesia practice. Perioperative stress that may result from fasting, fear, disease states, and other causes can induce metabolic decompensation and hypoglycemia. As a consequence, an intravenous glucose-electrolyte solution is recommended for affected children.²¹³ Because of a few reports of rhabdomyolysis when these children are anesthetized with inhalational anesthetics, there has been some reluctance to use inhalational anesthetics in them.^213,²¹⁴ It is, however, likely that the number of patients with inborn errors of fatty acid metabolism who undergo surgery is far greater than the paucity of reports of adverse outcomes with inhalational anesthetics. Because these patients vary considerably in their responses to stress, it is not surprising that most do well with any well-managed anesthetic. The available evidence suggests that the perioperative risk is no greater with any particular anesthetic in these children.

If the clinician elects to avoid inhalational anesthetics, two alternatives remain: regional anesthesia and total intravenous anesthesia (TIVA). In children, peripheral limb surgery often allows for the use of intravenous sedation and regional anesthesia that may be suitable depending on the age of the child,¹⁹¹ but most children do not tolerate this technique. However, TIVA often is used in children, most commonly with propofol.²¹⁵

Propofol infusion syndrome, a rare, usually lethal complication of prolonged infusions of propofol, is diagnosed by cardiovascular collapse associated with lipemic plasma, enlarged fatty liver, severe metabolic acidosis, and rhabdomyolysis or myoglobinuria.²¹⁶^–²¹⁸ In this syndrome, a large increase in particular fatty acids (i.e., malonylcarnitine and C5-acylcarnitine) that points to impaired entry of long-chain fatty acids into mitochondria and to resultant failure of mitochondrial respiration at complex II has been identified.²¹⁹ Others suggest that propofol infusion syndrome may uncover medium-chain acyl-CoA dehydrogenase deficiencies, although this remains unproved.²¹⁶ The notion that propofol can impair fatty acid uptake and subsequent oxidation raises the possibility that the acute administration of propofol to a patient with a defect in fatty acid metabolism can precipitate a metabolic crisis, although this has never been reported. It has also been suggested that the lipid load from a propofol infusion in the absence of adequate carbohydrate intake can expose a carnitine deficiency as a model for propofol infusion syndrome.²²⁰ Moreover, propofol itself has been shown to inhibit mitochondrial respiration, possibly compounding the effects of fatty acid oxidation deficiencies.²¹⁶ In these children, the use of propofol may be associated with an unclear risk of inducing a metabolic crisis. If their metabolic abnormalities are subclinical, there is no easy, inexpensive preoperative screening tool to establish a diagnosis for a rare abnormality. Even if the child is diagnosed with one of the subsets of fatty acid oxidation deficiencies, it is impossible to predict preoperatively which children will be sensitive to propofol and, if they are, how sensitive they are.

Other TIVA regimens that may be considered include ketamine, dexmedetomidine, benzodiazepines, and opioids. In these instances, the preoperative discussion with the parents, children, and surgeons must address the perioperative risks, including the lack of evidence that any particular anesthetic is more likely to precipitate rhabdomyolysis and a MH-like reaction than another.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, potentially lethal reaction to neuroleptics (0.1% to 2.5% of patients), which is characterized clinically by the slow onset of fever, muscle rigidity, altered consciousness, and autonomic instability over a protracted period of time.²²¹ Laboratory findings include increased creatine kinase levels, leukocytosis, increased liver enzyme values, and reduced serum iron or potassium concentrations.²²¹ NMS is similar to MH, and the distinction between the two is often difficult to make, except by medication history; neuroleptics are associated with NMS, and inhalational anesthetics and succinylcholine are associated with MH.

NMS has developed in children taking neuroleptics that block all dopamine D₂ receptors (i.e., high-potency neuroleptics, such as haloperidol; atypical neuroleptics, such as thiothixene; low-potency D₂-receptor antagonists, such as metoclopramide; and tricyclic antidepressants) and in those with the withdrawal of antiparkinsonian medications. It is suggested that the syndrome results from a deficiency of central dopamine, but other pathophysiologic mechanisms have been proposed to explain the many clinical findings that cannot be explained by lack of dopamine.

Successful therapy for NMS requires early recognition, cessation of offending medications, and intensive medical and nursing care geared toward hydration and restoration of electrolyte balance.²²¹ Specific pharmacologic therapy with dopamine agonists such as bromocriptine or with dantrolene has been advocated, although use of dantrolene is controversial. Despite the fact that textbooks of psychiatry list dantrolene as the first-line pharmacologic treatment for NMS, there are no good data that it has a therapeutic effect in NMS, except for the occasional case report declaring that dantrolene is effective.²²¹^–²²³

Children with psychiatric diagnoses requiring treatment with neuroleptics make up a significant percentage of these pediatric patients. NMS in this pediatric population continues to be a problem, even with the newest of drugs. The perioperative period for the pediatric patient on neuroleptics is one fraught with potential diagnostic dilemmas. For example, one report described postoperative NMS in a child with severe cerebral palsy and seizure disorder who was not taking any neuroleptics and who was successfully treated three times with dantrolene.²²⁴ Was this NMS or a mild form of MH? The answer is unclear.