Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

PART FOUR – Associated Problems in Pediatric Anesthesia

Chapter 31 – Malignant Hyperthermia

Barbara W. Brandom



Muscle Physiology, 1016



Normal Muscle Physiology, 1016



Pathophysiology of Malignant Hyperthermia,1016



Mechanism of Action of Dantrolene, 1017



Clinical Presentation, 1017



Masseter Spasm, 1018



Management of Masseter Spasm,1019



Treatment of an Acute Episode of Malignant Hyperthermia, 1020



Postanesthetic Considerations,1021



Prophylactic Management, 1022



Indications for Muscle Biopsy and Genetic Evaluation of Type I Ryanodine Receptor,1022



Care of Patients With a History of Malignant Hyperthermia, 1023



Preoperative Care of Malignant Hyperthermia-Susceptible Patients, 1024



Perioperative Care of Patients With Suspected Malignant Hyperthermia Susceptibility,1024



Anesthetic Techniques, 1025



Anesthetic Management for Muscle Biopsy, 1025



Postoperative Care of the Malignant Hyperthermia-Susceptible Patient,1026



Disorders Associated With Malignant Hyperthermia, 1026



Contracture Test, 1027



Anesthesiologists—Responsibility to Other Physicians, 1028



Summary, 1028

Deaths during anesthesia associated with high fever and tachycardia were described repeatedly in the first half of the 20th century ( Moschcowitz, 1916 ; Burford, 1940 ). These deaths were sometimes ascribed to heatstroke and dehydration, factors that were likely to occur in a time when intravenous hydration and air conditioning were unknown. In 1915 and 1919, two deaths occurred during chloroform anesthesia in one family. In these cases, severe muscle spasm was observed before cardiac arrest. In 1987, a young child from this family died during anesthesia for dental surgery. Subsequent in vitro contracture testing demonstrated susceptibility to malignant hyperthermia (MH) in several relatives ( Harrison and Isaacs, 1992 ).

Denborough and others were the first to describe MH as a clinical entity ( Denborough and Lovell, 1960 ; Denborough et al., 1962 ). They reported the case of a young Australian patient with a broken bone who was afraid to undergo general anesthesia because many of his relatives had died during ether anesthesia. The patient received halothane (a new drug at the time) as his anesthetic agent. Although the patient became febrile, tachycardic, cyanotic, and hypotensive, he survived the event. Extensive laboratory investigations of this patient were unrevealing. Further investigation of his family's medical history, however, showed a pattern of anesthetic deaths consistent with an autosomal dominant trait. Since then, MH has been recognized as a pharmacogenetic disorder of calcium regulation in muscle cells.

Several genetic differences may result in similar syndromes of increased metabolism and muscle cell injury ( Gillard et al., 1991 ; Deufel et al., 1992 ; Levitt et al., 1992 ; Olckers et al., 1992 ). However, in the majority of families in whom linkage to MH has been studied, mutations have been found ( MacLennan et al., 1992 ) in the gene encoding the skeletal muscle calcium release channel, the ryanodine receptor (RYR1). The ryanodine receptor is located at 19q13.1.

An episode of MH is identified by documenting an increased metabolic rate after exposure to a triggering agent. Rhabdomyolysis may also be observed. Susceptibility to MH is rarely associated with clinically evident hypermetabolism in the absence of drugs used during anesthesia ( Gronert et al., 1980 ; Tobin et al., 2001 ). Halothane and succinylcholine, two drugs formerly used frequently in pediatric anesthesia, are two of the most potent triggers of MH. A review of 25 years of halothane anesthetics in one pediatric hospital ( Warner et al., 1984 ) found the incidence of acute MH episodes to range from 1:20,000 to 1:40,000 anesthetic procedures. Because choice of anesthetic and neuromuscular blocker are likely to influence the development of this potentially lethal syndrome, MH is a disease of particular concern to the pediatric anesthesiologist who chooses to administer inhalation anesthetics and succinylcholine. The purpose of this chapter is to review the clinical manifestations, management, and underlying pathophysiology of MH.

The broad clinical spectrum of MH contributes to difficulty defining its incidence. In the past, some clinicians based the diagnosis of MH on the occurrence of masseter spasm alone, whereas others required total body rigidity, signs of hypermetabolism, and a positive contracture test for a definitive diagnosis. The contracture test is difficult to apply to large populations because of technical and financial reasons. In vitro examination of muscle for contracture threshold in the presence of halothane alone and caffeine alone remains the most reliable method to assess the potential for MH to develop in a particular North American patient ( Larach, 1993 ). Although there is a difference between the details of contracture testing in North America and Europe ( European Malignant Hyperpyrexia Group, 1984 ; Ording et al., 1984, 1997 [130] [134]; Larach, 1989 ), the diagnostic results are very similar with either method ( Fletcher et al., 1999 ). Intensive evaluation of anesthetic records and contracture test results in large genealogies from limited populations may reduce the number of individuals who are treated as MH susceptible (MHS) ( Bachand et al., 1997 ). This type of careful review is needed to determine the prevalence of MH susceptibility, as opposed to the incidence of acute MH episodes.

A countrywide study was undertaken in Denmark ( Ording, 1985 ) to define the risk of MH and its relation to type of anesthetic. The Danish figures are based on 386,250 anesthetic experiences in 87 hospitals in patients of all ages during a 6½-year period starting with January 1978. They report that fulminant MH, defined as a rapid increase in temperature with potentially life-threatening metabolic changes, arrhythmias, and elevated creatine kinase (CK), occurred in 1:250,000 cases of general anesthesia. No fulminant MH occurred during regional or intravenous anesthesia. These findings are similar to reports in the United Kingdom, where fulminant MH occurs once in 200,000 anesthetic procedures ( Ellis and Halsall, 1980 ). The Danish study further reported that masseter spasm occurred in 1:12,000 cases in which succinylcholine was used, along with both potent inhaled and intravenous anesthetics. Overall, suspicion of MH was raised in 1:16,000 anesthetic procedures and in 1:4,200 anesthetic procedures in which potent inhalation agents were combined with succinylcholine. The mortality rate for fulminant MH reported in this study was 10% ( Ording, 1985 ). Britt and Kalow (1970) noted a mortality rate of 64% in the era before dantrolene.

In 1997, a code specific for MH was added to the International Classification of Diseases, Ninth Revision. The Healthcare Cost and Utilization Project reports about 400 cases per year using the ICD-9-CMcode specific for hyperthermia related to anesthesia. Only a few of these cases are called into the MH Hotline Consultation Service. Unfortunately, overlap between these two independent sources of suspected cases of MH is small; the incidence of acute MH episodes may be greater than 500 per year in the United States.



The propagation of an action potential down a motor nerve fiber produces depolarization of that fiber and release of acetylcholine at the neuromuscular junction. Acetylcholine combines with its receptors at the neuromuscular junction, initiating a wave of depolarization along the muscle cell membrane or sarcolemma. The propagated depolarization wave spreads internally via transverse tubules that abut the sarcoplasmic reticulum ( Fig. 31-1 ). The wall of the transverse tubule contains the dihydropyridine receptor, a voltage-dependent calcium channel that in turn triggers the calcium-sensitive ryanodine receptor (RYR), to release large amounts of calcium from the sarcoplasmic reticulum ( Melzer and Dietze, 2001 ).


FIGURE 31-1  This three-dimensional reconstruction of the sarcoplasmic reticulum (SR) illustrates the continuity of the transverse tubules (T) surrounding the myofibrils and the fenestrations of the collar of the sarcoplasmic reticulum overlying the center of the A band of the myofibril.  (From Engel AG, Banker BQ, editors: Myology basic and clinical. New York, 1986, McGraw-Hill Book Co. Modified from Peachey LD: J Cell Biol 25:209, 1965, by copyright permission of The Rockefeller University Press.)




The RYR forms the footplate between the transverse tubule and the sarcoplasmic reticulum. The RYR is the largest known receptor in the body, four times the size of the acetylcholine receptor (Wagenknecht et al., 1989 ). RYR reacts with several other proteins. Type 1 ryanodine receptors are found in all skeletal muscle, in smooth muscle, in neurons, and in B lymphocytes. Type 2 ryanodine receptors are found in cardiac muscle, brain, and some hemopoietic cells. Type 3 ryanodine receptors are found in skeletal and smooth muscle and, to a lesser extent, in brain. Abnormalities in the type I ryanodine receptor (RYR1) cause MH ( Franzini-Armstrong and Protasi, 1997 ).

The sarcoplasmic reticulum is an internal cellular structure that forms a major storage site for calcium ions. When the muscle cell is depolarized, the sarcoplasmic reticulum releases calcium ions, which combine with troponin affixed to actin filaments. When troponin is bound to calcium ions, cross-bridges can form between actin and myosin filaments, and lead to muscle contraction. When the wave of depolarization ceases, calcium ions dissociate from troponin and are removed by adenosine triphosphate (ATP), requiring calcium pumps sequestered in the sarcoplasmic reticulum and other organelles. In short, calcium release leads to muscle contraction, and when calcium reuptake occurs, muscle fibers relax. Coupling of the excitation of the muscle membrane and contraction of the muscle cell entails changes in intracellular calcium concentration. Calcium release also initiates the breakdown of ATP and metabolic processes that support the energy needed for muscle contraction (e.g., glycolysis).


MH in humans is a result of failure of the muscle cell to maintain intracellular calcium homeostasis during excitation-contraction coupling. This can be due to malfunction of the RYR1 ( Censier et al., 1998). In porcine MH, there is a specific single-point mutation in the RYR1 in all major susceptible breeds ( Fuji et al., 1991 ). However, this point mutation is seen in a minority of human MHS families. Initial studies showed that only a third of patients ( Sambuughin, 2001) who have had positive contracture tests and therefore carry the diagnosis of MHS have a mutation in RYR1. However, as a larger proportion of the RYR1 is studied, the percentage of MHS patients with RYR1 mutations has increased. MH causative mutations have been located in three regions of this large receptor. The heterogeneous nature of human MH may be due to one of a number of mutations in RYR1 or to abnormalities in other entities such as the dihydropyridine ( Gallant and Lentz, 1992 ) receptor, hormone-sensitive lipase, other aspects of fatty acid metabolism, increased sensitivity to catecholamines, or inositol triphosphate. All of these entities affect calcium release mechanisms.

The metabolic dysfunction of MH is caused by increased intracellular free ionized calcium ( Mickelson and Louis, 1996 ). The direct result of increased intracellular calcium is to increase the need for intracellular ATP to drive calcium pumps that transfer calcium into the sarcoplasmic reticulum, across the sarcolemma into the extracellular fluid, or into mitochondria. Increased demands for ATP lead to the clinically detectable manifestations of MH (e.g., an increase in metabolism). The elevation of intracellular calcium observed in MH muscle is decreased by dantrolene ( Lopez et al., 1985 ; Mickelson and Louis, 1996 ). There are other conditions, such as mitochondrial myopathies and some enzyme deficiencies, in which generation of ATP in muscle is compromised. In such situations, the patient may have increased metabolism, but it is not clear how useful dantrolene would be. Dantrolene can produce weakness and decrease metabolism in normal muscle and in MHS muscle ( Flewellen et al., 1983 ).

Motor nerve activity and neuromuscular transmission are normal in MHS patients ( Gronert, 1980 ). However, susceptible porcine muscle has a lower mechanical threshold than does normal muscle (Moulds and Denborough, 1974 ; Okumura et al., 1979 ), and less depolarization is required compared with normal muscle ( Gronert, 1980 ). Calcium release from the sarcoplasmic reticulum occurs at more negative potentials in the presence of RYR1 mutations seen with MH, and calcium-induced calcium release from the sarcoplasmic reticulum is abnormal in susceptible subjects. The abnormal RYR1 is resistant to the inhibitory effects of both calcium and magnesium ( Mickelson and Louis, 1996 ).

During an episode of MH, lactate release from muscle increases before mixed venous oxygen tension decreases ( Gronert and Theye, 1976a ). This sequence is consistent with intracellular ATP depletion (Gronert, 1986 ). Using magnetic resonance imaging (MRI) techniques, Olgin and others (1988) noted an increased ratio of inorganic phosphate to phosphocreatine in vivo in human muscle susceptible to MH. This ratio is an indicator of the energy state of the muscle (Chance et al., 1985a, 1985b [28] [29]). An increased ratio suggests either impaired synthesis of ATP or increased breakdown of ATP. During an episode of MH, the use of high-energy phosphates exceeds their production, resulting in an increased ratio of inorganic phosphorus to phosphocreatine. A more subtle abnormality exists in the “unchallenged” metabolism of MHS muscle ( Allsop et al., 1991 ; Olgin et al., 1991 ; Bendahan et al., 2002 ).


Since dantrolene was introduced in the 1970s, its use has remarkably improved the treatment and survival of patients with MH. Dantrolene inhibits the release of calcium from the sarcoplasmic reticulum (Fruen et al., 1997 ) by limiting the activation of the calcium-dependent ryanodine receptor. Dantrolene does not act at the neuromuscular junction and has no effect on the passive or active electrical properties of the surface and tubular membranes of skeletal muscle fibers. Patients administered dantrolene have normal electromyographic results and depressed force of muscle contraction. Some situations where weakness is induced by dantrolene could be clinically significant. The protective effects of dantrolene against MH require significant depression of the force of contraction ( Flewellen et al., 1983 ).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


The initial clinical signs of an impending episode of MH are nonspecific; they may include tachycardia, arrhythmias, and tachypnea ( Box 31-1 ). Rigidity of the extremities and the jaw may be present. When MH is fulminant, there is severe metabolic acidosis (base deficit often greater than -8 mEq/L), respiratory acidosis (PaCO2 > 60 mm Hg) ( Gronert, 1980 ), tachycardia with arrhythmias, a rapid increase in body temperature to 39.5°C or greater, hyperkalemia, myoglobinuria, and a marked increase in serum CK. However, because of modern comprehensive monitoring and increased awareness of MH, fulminant MH is rarely observed. The clinical diagnosis of MH is often considered before metabolism and temperature reach these extremes ( Karan et al., 1994 ). The patient's medical history and clinical course usually, but not always ( Allen and Rosenberg, 1990 ), help to differentiate fulminant MH from other metabolic or endocrine crises such as porphyria, thyroid storm, and untreated pheochromocytoma. Some other conditions that produce signs similar to MH are sepsis, drug reactions, intracranial trauma, and hypoxic encephalitis.

BOX 31-1 

Steps in Identifying and Treating Malignant Hyperthermia (MH)

Clinical Events During MH



Total body rigidity



Masseter spasm



Increased oxygen consumption



Inappropriate increase in temperature; rapidly rising temperature (>1.5°C over 5 min) or temperature >38.8°C



Rapid respiratory rate and/or respiratory acidosis, PETCO2>55 mm Hg with appropriately controlled ventilation



Inappropriate sinus tachycardia



Ventricular tachycardia or ventricular fibrillation



Profuse sweating



Mottled, cyanotic skin



Cola-colored urine



If any two or more of these events occur, determine venous blood PCO2, PO2, base excess, lactate, potassium ion, creatine phosphokinase, and myoglobin to rule out MH and consider discontinuing trigger agents.



If total body rigidity is present, send blood for laboratory evaluation, discontinue trigger agents, and begin treatment for acute MH episode.

Laboratory Evaluation: Positive Findings Consistent with MH



Venous PCO2 >65 mm Hg



Arterial PCO2 >60 mm Hg or 65 mm Hg with spontaneous ventilation



Arterial base excess more negative than -8 mEq/L



Arterial pH <7.25



Potassium ion >6 mEq/L



Creatine kinase >10,000 IU/L after anesthetic without succinylcholine



Myoglobin in serum >170 mcg/L



Myoglobin in urine >60 mcg/L

MH may also occur in an abortive ( Ording, 1985 ) or insidious form. There may be only mild symptoms or signs suggestive of MH (e.g., moderate increases in heart rate, blood pressure, and temperature along with a slight metabolic or respiratory acidosis). Masseter spasm may or may not occur ( Ellis et al., 1990 ). There may be a moderate increase in CK and serum myoglobin. Myoglobin appears in the plasma within minutes of muscle injury. However, CK will continue to increase for 8 to 20 hours after a transient injury ( Florence et al., 1985 ) even in normal patients. According to Ording (1985) , the incidence of abortive MH is as high as 1:4,200 anesthetic procedures when succinylcholine is used in combination with potent inhalation anesthetics. There is disagreement about when and whether to terminate anesthetic administration in cases of “abortive MH.”

“Abortive MH” may also be confused with sudden fulminant rhabdomyolysis, which has occurred in pediatric patients after the administration of succinylcholine. In this condition, the sudden severe increase in plasma potassium can be fatal, but metabolic abnormalities are secondary to cardiac failure, not skeletal muscle pathophysiology, as in MH ( Delphin et al., 1987 ; Rosenberg and Gronert, 1992 ;Tang et al., 1992 ; Larach et al., 1997, 2001 [97] [98]).

In a group of 48 children, 17 of whom later proved to be MHS by muscle biopsy, two or more adverse signs or abnormal laboratory findings were present in all patients with positive in vitro contracture tests ( Larach et al., 1987 ). Yet similar adverse events occurred in 83% of the children who had negative muscle biopsy findings. Generalized muscle rigidity was the single factor significantly associated with positive biopsy findings for MH. However, generalized muscle rigidity was not an absolute predictor of MH susceptibility. Three of 24 patients who were referred for biopsy and who had negative contracture test results had experienced generalized muscle rigidity during induction of anesthesia. Signs consistent with abortive MH, such as tachycardia, premature ventricular contractions, elevated end-tidal carbon dioxide ( Lanier et al., 1990 ), and increase in tension of the masseter muscle (Van der Spek et al., 1987, 1988 [169] [170]), may be observed in the normal pediatric patient administered halothane or sevoflurane and succinylcholine. Larach and others (1987 ; Hackl et al., 1990 ) could not identify the MHS patient on the basis of these signs.

It has been recommended that to most effectively treat or prevent the crisis of MH, the anesthesiologist must presume an episode of MH is occurring before the patient's temperature increases. If events during the induction of anesthesia require explanation beyond light anesthesia or hypoventilation, further investigation to rule out the diagnosis of MH must be undertaken immediately, before surgery begins.

To confirm the diagnosis of MH, the anesthesiologist must document the presence of increased metabolic rate, rather than the decreased metabolic rate that usually follows induction of anesthesia. Evidence of an increase in oxygen consumption would be a simple confirmation that MH was occurring. Because oxygen consumption may be difficult to document, however, other diagnostic steps must be taken. Venous or arterial blood should be obtained for measurement of PCO2, lactate, potassium, myoglobin, and CK. Mixed venous blood, which is most likely to show significant alterations in PCO2 (Gronert and Theye, 1976a, 1976b [64] [65]), often is not readily available. During anesthesia there is increased arterial-to-venous shunting through the skin. Despite this fact, blood from a large peripheral vein, femoral or antecubital, may demonstrate increasing carbon dioxide tension and worsening base deficit before these changes are found in arterial blood. Increasing end-tidal carbon dioxide concentrations, particularly with increased minute ventilation, suggest that an episode of MH is occurring. Evidence of muscle injury, such as the presence of myoglobin in the serum and urine, and elevated CK and other enzymes in the blood, may not be observed if MH is treated very quickly. Once a hypermetabolic state is recognized, appropriate actions must be taken without delay, as described later.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Masseter spasm (also termed masseter muscle rigidity or trismus) is a marked increase in tension of the masseter that prevents opening of the mouth when succinylcholine has produced neuromuscular blockade. Masseter spasm may be an early sign of MH. However, succinylcholine can produce increased tension in normal muscle at the same time that it produces block of neuromuscular transmission (van der Spek, 1987, 1988 [169] [170]). Many anesthesiologists believe that only if the jaw cannot be forced open should this phenomenon be called masseter spasm. Hannallah and Kaplan (1994)distinguish between masseter rigidity and trismus. In masseter rigidity, the mouth cannot be fully opened even with firm pressure on the incisors, but intubation of the trachea is possible. In trismus, the mouth cannot be fully opened and intubation of the trachea is not possible. Using this definition of masseter rigidity, Hannallah and Kaplan noted muscle rigidity to occur in 0.2% of 500 children anesthetized with halothane and administered succinylcholine. None of these 500 patients experienced trismus ( Hannallah and Kaplan, 1994 ). It may be that the severalfold greater incidence of masseter spasm noted in the 1980s included some cases of incomplete jaw relaxation (i.e., the mouth opens fully with firm manual separation of the teeth), which was observed in 4.4% of these 500 pediatric patients. The 22 patients with incomplete jaw relaxation in this study continued to receive halothane anesthesia with no apparent complications. It seems likely that most of the cases in which the term “masseter spasm” was applied in the past were not trismus according to the definition of Hannallah and Kaplan.

Masseter spasm has been touted as a specific early warning sign of MH. Undoubtedly, deaths from MH have occurred during anesthetic procedures in which masseter spasm was observed. It may be that when masseter spasm is accompanied by rigidity of the entire body, MH is very likely to occur. However, transient increase in jaw stiffness, or resting tension of jaw muscles, is a normal response to succinylcholine (van der Spek et al., 1987, 1988 [169] [170]; Plumley et al., 1990 ). Increased tension of the masseter muscle after administration of succinylcholine is most easily appreciated by the clinician after induction of anesthesia with potent inhalation anesthetics. Increase in masseter muscle tension occurs in normal mammals after the administration of succinylcholine following prior administration of epinephrine ( Pryn and van der Spek, 1990 ). There is a greater increase in jaw tension after administration of succinylcholine during halothane anesthesia than in the presence of barbiturates. Jaw tension is also increased in animals that are febrile as opposed to those that are normothermic ( Storella et al., 1993 ). Temporomandibular joint abnormalities may confuse the diagnosis of masseter spasm by interfering with jaw opening.

Although masseter spasm usually occurs after anesthesia induction with halothane and the administration of succinylcholine, it may occur with other anesthetic agents ( Larach et al., 1987 ; Marohn and Nagia, 1992 ). Masseter spasm may be transient ( Rosenberg, 1987 ) or persistent. It occurs despite abolition of evoked muscle function in the extremities. Tachycardia or other nonspecific arrhythmias may accompany masseter spasm. MH may follow masseter spasm immediately; in the continued presence of anesthetic trigger agents, however, a period of 10 or more minutes often intervenes between masseter spasm and the clinical presentation of MH ( Rosenberg, 1987 ; O'Flynn et al., 1994) . In the O'Flynn and others study, clinical presentation of MH was defined as arterial PCO2 greater than or equal to 50 mm Hg, pH less than 7.25, and base deficit more negative than -8 mEq/L.

Anesthesia with halothane has been continued after isolated masseter spasm, with no increased metabolism or cardiovascular instability. Littleford and others (1991) reported on 57 such children, of whom 33% experienced transient arrhythmias intraoperatively. Most of these children also had some degree of hypercarbia and/or metabolic acidosis. CK levels measured 18 to 24 hours postoperatively were elevated in all but one of these children, and CK levels greater than 20,000 U/L were observed in many. However, there were 11 children who experienced generalized rigidity in combination with masseter muscle spasm (MMS). Anesthesia was aborted for four of these children and continued without inhalation agents in three. None of these children developed fulminant MH in the perioperative period. The remaining four patients who developed generalized rigidity received dantrolene.

Kaplan and Rushing (1992) documented a case of masseter spasm in which clinical abnormalities prompted administration of dantrolene, and postoperative creatine kinase was 40,000 IU. Nine years later this healthy adolescent underwent extensive evaluation for neuromuscular disorders, including in vitro testing for MH caffeine-halothane contracture test (CHCT). The patient and family remain well without signs, symptoms, or diagnosis of any myopathy. If this patient had been labeled MHS, it would have been a misdiagnosis.

Children exhibiting a normal response to succinylcholine (slight or no increase in jaw tension, transient arrhythmias, transient increase in exhaled carbon dioxide) are not at increased risk for the development of MH. How can the clinician know which child with increased resistance to mouth opening after succinylcholine administration is responding in a slightly exaggerated fashion to succinylcholine and which child may develop MH? This is often impossible to determine, especially within the few minutes during induction in which a decision must be made.

One could argue that true masseter spasm is a relatively infrequent event and that associated MH susceptibility ( Ording et al., 1984 ; Rosenberg and Fletcher, 1986 ; O'Flynn et al., 1994) has been overemphasized. In vitro contracture tests have documented an interaction between halothane and succinylcholine. In a study by Fletcher and Rosenberg (1985) , the combination of halothane and succinylcholine produced greater contractures in muscle from patients who had a history of masseter spasm compared with those who did not, regardless of whether the muscle had produced a degree of contracture diagnostic of MH susceptibility. Contracture also occurred in normal muscle when it was exposed to halothane before succinylcholine was administered. Masseter spasm certainly has physiologic significance, but its clinical significance remains uncertain. Perhaps the incidence of masseter spasm will decrease further when halothane is completely replaced by sevoflurane, desflurane, or other anesthetics.

After an episode of masseter spasm, myalgia and occasionally weakness may be present for several days or longer. Elevation of CK levels characteristically follows masseter spasm within 24 hours (Rosenberg, 1987 ). In normal patients undergoing ophthalmic surgery with halothane anesthesia who received succinylcholine intraoperatively, an increase in CK level was noted 24 hours after surgery. The highest postanesthetic CK level in these otherwise normal patients was 40 times normal ( Inness and Stromme, 1973 ). Myoglobin appears quickly in the plasma after halothane anesthesia and succinylcholine administration even in children who had no masseter spasm ( Plotz and Braun, 1982 ). If radioimmunoassay is used to measure serum myoglobin concentrations, increases in myoglobin can be measured within the first hour after succinylcholine administration in normal children anesthetized with isoflurane or halothane. Myoglobinemia was greater during halothane than during isoflurane anesthesia in these children ( Harrington and Ford, 1986 ). Inhalation anesthesia without succinylcholine was associated with fewer episodes of both fulminant (2 versus 8) and abortive (17 versus 110) MH than was succinylcholine with potent inhalation anesthetics in a Danish population ( Ording, 1985 ). Thus, avoiding succinylcholine administration to pediatric patients anesthetized with halothane, or other inhalation anesthetics, not only avoids the diagnostic uncertainties associated with masseter spasm but also produces fewer episodes of MH and other adverse events ( Delphin et al., 1987 ; Rosenberg and Gronert, 1992 ). Pediatric anesthesiologists may choose to administer succinylcholine only when definite indications for this drug have been identified.


There is no agreement among experienced clinicians concerning the preferred management of patients with incomplete relaxation of the masseter after the administration of succinylcholine ( Kaplan et al., 1993 ). If jaw stiffness was mild, so that the mouth could be opened with increased effort, there was no rigidity in the rest of the body, and cardiovascular function was stable, anesthesia may be continued with careful documentation of capnography and core temperature. Fluid deficits should be replaced completely so that urine output is greater than 3 mL/kg per hour. Urine should be obtained in the early postoperative period to check for the presence of myoglobin. Blood should be obtained for measurement of electrolytes and CK. It is not necessary to terminate anesthetic administration unless signs of increasing metabolic rate occur. If jaw stiffness is so great that the mouth cannot be opened, there are several reasons to terminate elective anesthetic administration, not the least of which may be the need to clear the upper airway. If the jaw is tight, signs of MH should be sought. Venous blood should be obtained for gas analysis and measurement of electrolytes, myoglobin, and CK. If surgery must continue, anesthesia can be changed to nontriggering drugs. Intra-arterial, central venous, and bladder catheters are useful if evidence of increased metabolism is found and dantrolene is administered. Muscle tension of the rest of the body should be noted. Total body rigidity accompanying masseter muscle rigidity does not absolutely guarantee that the patient has MH ( Larach et al., 1987 ). Anesthetic depth may have been misjudged. Alternatively, the patient may have occult myotonia.

Postoperative renal failure has occurred in patients who had myoglobinuria after administration of succinylcholine during anesthesia. In any situation in which injury to muscle may occur, it is important to document that myoglobinuria is not present. If any increased muscle stiffness was noted after administration of succinylcholine or the child complains of muscle pain postoperatively, urine should be obtained. If there is no blood in the urine as assessed by orthotolidin (Hematest), then there is no myoglobin present. If the response to blood is positive on the dipstick, urine should be examined for the presence of red blood cells, and free hemoglobin and myoglobin measured. If myoglobin is present, the patient should remain in the hospital. The patient should be observed for signs of MH, evaluated for the presence of occult muscle disease, and hydrated. Alkaline urine reduces the risk of renal tubular injury from myoglobin.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


When the diagnosis of MH is made or strongly suspected, the most important step to take is to administer dantrolene. The other steps in management are to discontinue the triggering anesthetic agents immediately, increase minute ventilation severalfold with 100% oxygen, and alert the surgeon that the procedure must be concluded promptly. Other anesthesiologists or paramedical personnel or both should be called in at once for assistance.

As noted earlier, dantrolene is a calcium channel antagonist, specific for the ryanodine receptor. Dantrolene must be diluted with sterile, preservative-free, distilled water, which should be stored in large quantities with the drug (see Table 31-1 ). It is important to store sterile water in clearly labeled containers of a different size from those used for routine intravenous solutions and to keep a mixing system nearby. Dantrolene will dissolve faster as temperature increases from 20° to 40°C ( Mitchell, 2003) . When the dantrolene preparation is dissolved, the initial intravenous dose should be 2.5 mg/kg, although much higher doses may be needed to control the episode. Repeated dosing of dantrolene should be guided by clinical and laboratory signs. A flow sheet including minute ventilation, end-tidal carbon dioxide concentration, heart rate and rhythm, arterial blood pressure, central venous pressure, core temperature, and urine output, along with arterial and venous blood gas tensions, serum electrolytes, and glucose and total fluid intake, provides a useful guide for continued therapeutic interventions. Dantrolene must be administered until respiratory and metabolic acidosis has resolved. The usual upper limit of 10 mg/kg may be exceeded as necessary. The most frequent side effects of dantrolene administration are muscle weakness and phlebitis.

TABLE 31-1   -- Drugs and dosages used to treat an acute episode of malignant hyperthermia


2.5 to 10.0 mg/kg or more (sterile water must be available to dilute dantrolene)

Sodium bicarbonate

2 mmol/kg PRN

Iced normal saline solution

PRN (10 to 12 L for 50-kg patient)


300 mg/kg (note there is 150 mg of mannitol per milligram of dantrolene in the vial)


0.5 to 1.0 mg/kg

Insulin (regular)

10 U regular insulin in 50 ml of 50% dextrose titrated to produce normokalemia


1 mg/kg


Dantrolene administration should be repeated until physical and chemical signs have returned to normal. When this degree of physiologic stability has been obtained, dantrolene [1 mg/kg or more] should be repeated approximately every 6 hours until creatine kinase has decreased consistently.


The anesthesia machine need not be switched to a standby unit that has been kept free of inhalation anesthetics. After 10 minutes of 10 L/min fresh gas flow, the isoflurane concentration at the gas outlet of the Datex-Ohmeda anesthesia workstation is less than 2 ppm ( Schonell et al., 2003 ). Gas flow of 12 L/min or more will remove residual volatile agent from an anesthesia machine within 6 to 12 minutes (McGraw and Keon, 1989 ). When practical, the carbon dioxide absorber and circuit tubing should be changed. If this is not done, 30 minutes is needed to reach 2 ppm isoflurane with an anesthesia workstation ( Schonell et al., 2003 ). If a vaporizer, which could continue to deliver anesthetic vapor despite being turned off, is present in the circuit, such as the Fluotec Mk.3 or Mini Boyle machine with cage-mounted vaporizer, it should be drained ( Ritchie et al., 1988 ).

Procedures to cool the body should be instituted quickly. The goal is to reduce muscle metabolism and avoid exposure to a critical core temperature of greater than 40°C ( Bouchama and Knochel, 2002 ). A core temperature of less than 36°C may not be beneficial. Drapes should be removed, heated humidifiers turned off, and water mattresses turned to cooling temperatures. Cold normal saline solution can be given intravenously to maintain normal central venous pressure. The stomach can be irrigated with iced saline solution through an orogastric tube. Open body cavities can also be lavaged with iced saline solution, and ice packs can be placed in the groin and axillae where large vessels come close to the skin surface. Wet cloths and a fan to facilitate surface evaporation can be useful. Even extracorporeal bypass with a heat exchanger was used successfully to cool patients with MH in the era before dantrolene was available. Now that dantrolene is readily available, extracorporeal bypass is not likely to be necessary to treat an episode of MH. An arterial catheter should be inserted to observe the patient's hemodynamic status and acid-base balance. A central venous catheter is useful for obtaining cardiac filling pressures and blood gas tensions, as well as for administering intravenous fluids. A pulmonary artery catheter will allow measurement of mixed venous blood gases and lactate and adjustment of cardiac filling pressures in the patient with pulmonary edema. Mixed venous blood is a more sensitive indicator than arterial blood of the patient's acid-base status. A blood sample should be taken to determine the blood gases and pH, potassium, glucose, CK, myoglobin, creatinine, and clotting profile as soon as feasible.

Arrhythmias usually stop when the episode is controlled with dantrolene. Lidocaine is recommended for treatment of arrhythmias in MH, because concern about amide-type local anesthetics such as lidocaine triggering or worsening an episode of MH has decreased.

Both metabolic acidosis and respiratory acidosis occur in MH. Increased metabolic rate leads to marked increases in carbon dioxide production, which can exceed the capability of breathing circuits to eliminate it. In addition, lactate production results when the body tries to maintain energy supplies through anaerobic metabolism. Treatment of the acidosis should include bicarbonate and hyperventilation. If a Mapleson system is used, very high flows are required for effective hyperventilation. High fresh gas flows also remove carbon dioxide adequately from a circle system.

Hyperkalemia results when cell membranes are disrupted. This is recognized on the electrocardiogram as increased T-wave amplitude in the early stages and later by widening QRS complexes, interventricular conduction delays and blocks, and finally no organized rhythm at all. Glucose and insulin (10 U regular insulin in 50 mL of 50% glucose titrated to effect) can be administered to lower serum potassium temporarily. β-Agonists can also be useful to move potassium intracellularly. Intravenous calcium is appropriate emergency treatment of the hyperkalemia associated with MH ( Gronert et al., 1986 ).

Large losses of intravascular volume should be anticipated. Evaporative loss of fluid may be great, and edema formation may occur in muscle and in other tissues during fulminant MH. Intravenous fluids should be given to maintain normal cardiac filling pressures, as evidenced by adequate perfusion pressure, urine output, and capillary refill. Although an osmotic diuresis may be induced to protect renal tubule function in the presence of myoglobinuria, it will promote acute intravascular volume loss. The management of the acute MH episode is summarized in Box 31-2 .

BOX 31-2 

Management of the Acute Malignant Hyperthermia (MH) Episode



Stop inhalation anesthetics immediately.



Cancel or conclude surgery as soon as possible.



Hyperventilate with high flow of 100% oxygen.



Administer dantrolene (2.5 mg/kg) IV over 5 min and repeat as needed. Give more dantrolene if signs of MH reappear.



Initiate cooling with hypothermia blanket; intravenous cold saline solution (15 mL/kg over 10 min), ice packs in the axillae and groin, and lavage of body cavities with cold saline solution if the core temperature is greater than 39°C. Stop cooling when the core temperature falls to 38°C.



Correct metabolic acidosis with 1 to 2 mEq/kg of sodium bicarbonate as an initial dose.



Administer calcium (10 mg/kg of calcium chloride) or insulin (0.2 mcg/kg) in 50% dextrose in water (1mL/kg) to treat the effects of hyperkalemia.



Administer Iidocaine (1 mg/kg) to treat ventricular arrhythmias.



Maintain urine output of 2 mL/kg per hour with furosemide (1 mg/kg) and additional mannitol if needed.



Insert arterial and central venous catheters.



Repeat venous blood gas and electrolyte analysis every 15 min until these and vital signs normalize.

Because calcium channel blockers might interfere with excitation-contraction coupling ( Lynch et al., 1986 ) and conserve energy reserves, it is reasonable to ask whether they might be useful in the treatment of MH or prophylaxis for MH susceptibility. Not all calcium channel-blocking drugs have the same effects in MHS subjects. Diltiazem inhibits halothane-induced contracture in MHS pig muscle (Illias et al., 1985 ), thus confirming a single similar observation in human muscle. Verapamil, however, is not a therapeutic agent in porcine MH ( Gallant et al., 1985 ). Furthermore, verapamil and dantrolene interact to produce severe hyperkalemia and myocardial depression ( Lynch et al., 1986 ; Rubin and Zablocki, 1987 ). Nifedipine administration has been associated with the development of MH in a child with underlying neuromuscular disease ( Cook and Henderson-Tilton, 1985 ). At this time it seems prudent to administer calcium channel-blocking drugs to patients with a history of MH or neuromuscular disease only with extreme caution. Calcium channel blockers are not recommended in the management of acute MH. If dantrolene must be administered to a patient who is also receiving calcium channel-blocking drugs, invasive hemodynamic monitoring and frequent measurement of serum potassium levels are recommended ( Lynch et al., 1986 ; Rubin and Zablocki, 1987 ).


A patient in whom MH has been successfully treated in the operating room requires intensive care to continue treatment and to monitor for late manifestations of the disease.

Continuation of treatment is necessary because recrudescence of MH can occur after an apparently successfully treated episode. This usually happens in the first few hours after the initial event. As much as 12 mg/kg of dantrolene has been required to treat recurrences over one 12-hour period ( Pollock et al., 1992 ). Continuous monitoring of vital signs and frequent measurement of venous lactate, blood gases, and electrolytes should detect metabolic changes. Dantrolene should be administered intravenously as necessary, not only until no evidence of metabolic acidosis remains but also until serum myoglobin levels decrease toward normal. The half-life of myoglobin in the blood is normally 1 to 3 hours. In contrast, CK peaks 24 to 36 hours after injury and usually decreases about 40% per day thereafter (Salluzzo, 1992 ). The CK may be measured repeatedly to demonstrate that it is decreasing and therefore that the process that produced rhabdomyolysis has abated.

After an acute episode, the patient with MH may die of a recrudescence, disseminated intravascular coagulopathy, or other nonspecific systemic injury. Disseminated intravascular coagulopathy is a frequent finding in fatal MH. The administration of dantrolene should be continued to stop the disruption of muscle, the presumed underlying cause of disseminated intravascular coagulopathy. Supportive care should be given as indicated, and coagulation function carefully monitored during and after an episode of MH.

Late manifestations of an episode of MH range from mild muscle pain to multiorgan system failure. Cerebral edema may occur. Fulminant cases of MH may have permanent neurologic sequelae (coma, paralysis) for no apparent reason. Even satisfactory care during anesthesia may not prevent these neurologic complications ( Gronert, 1980 ). Rehabilitation can take months after an episode of fulminant MH.

Pulmonary edema may occur owing to marked shifts in intravascular volume and to myocardial dysfunction. Its presence requires more careful assessment of the circulatory status to improve cardiac filling pressures and inotropic state. Areas of myocardium may have abnormal conduction, decreased contractility, or both. It is important to maintain adequate renal perfusion because massive myoglobinuria produced by fulminant MH can cause acute renal failure. Mannitol, which is part of the dantrolene formulation (150 mg of mannitol/mg of dantrolene), induces an alkaline osmotic diuresis and therefore helps to prevent precipitation of myoglobin in the renal tubules. Sufficient muscle damage to produce myoglobinuria and acute renal failure can occur in the absence of pigmenturia or dramatic elevation of CK ( Grossman et al., 1974 ). If myoglobin (or hemoglobin) is present, urine gives a positive reaction with orthotolidin (Hematest). In the presence of myoglobinuria, normal saline solution should be given to force a diuresis of at least 3 mL/kg per hour. If urine output is less than this, then mannitol (1 mL of 25% solution) and bicarbonate (1 mEq) in D5W (8 mL) should be given at twice the maintenance fluid rate. Rapidly increasing serum creatinine signals the onset of renal failure.

All cases of MH, anesthetic-related episodes of increased metabolism or rhabdomyolysis, isolated masseter spasm, and anesthetics administered to patients who have undergone a CHCT should be reported to the Malignant Hyperthermia Registry, so that the epidemiologic study of MH may have as broad a scope and as complete a collection of data as possible. Report forms may be obtained by telephone (412-692-5464).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier



Indications may vary depending on the particular goals being addressed. Individuals, both patients and physicians, concerned with improving the diagnostic tests for MH may urge all patients with any symptoms consistent with MH and those with a clear history of fulminant MH to undergo muscle biopsy. Others prefer to advise that this invasive test be performed only when the predictive value of the test may be helpful for patient management.

A new benefit of undergoing muscle biopsy and contracture testing is that patients with contracture tests indicating MH susceptibility are candidates for genetic study. Between 30% and 70% of such individuals have been found to have mutations in the ryanodine receptor gene that causes MH ( Sambuughin et al., 2001 ; Robinson et al., 2003 ; Sambuughin et al., 2005 ). The process of evaluating MH susceptibility in relatives can begin with genetic evaluation in search of the familial mutation ( Urwyler et al., 2001 ; Girard et al., 2004 ). A panel of RYR1 mutations has been selected to be the initial genetic test of MH susceptibility in North America ( Sei et al., 2004 ). Currently, genetic testing of MH susceptibility will be less sensitive ( Nelson et al., 2004 ) but less invasive and less costly than muscle biopsy and contracture testing. The genetics of MH susceptibility is not completely known. In large families, there has been discordance between contracture test results and genetic results ( Brown et al., 2000 ; Robinson et al., 2003 ). Continued evaluation of MH susceptibility by more than one type of test is needed to explain discordance. Genetic testing is of value for determining affected family members in a family in which an RYR1 mutation has been associated with MH in an affected individual. However, the value of genetic testing for RYR1 mutations as an initial screening for MH susceptibility has not been determined.

The sensitivity and specificity of the CHCT have been determined (Larach et al., 1992, 1993 [92] [94]; Ording et al., 1997 ; Allen et al., 1998 ). General statements about the predictive value of this test can be made. Sensitivity is the probability that a test result will indicate the disease is present, when in fact the individual tested has the disease in question. Specificity is the probability that a test result will indicate disease is not present, when in fact the individual tested does not have the disease in question. The clinician is interested in the predictive value of a test because the clinician does not know whether the patient has the disease of interest but can obtain the results of the diagnostic test.

The positive predictive value (PPV) of a test is the probability that an individual whose test result indicates that the disease is present does indeed have the disease of interest. The negative predictive value (NPV) of a test is the probability that an individual whose test result indicates that disease is absent does not have the disease in question. By definition, the predictive value depends on the probability that the individual has the disease in question before the test results are obtained, as well as the sensitivity and specificity of the test ( Rosner, 1990 ). This probability may be thought of as the prior probability of the individual having the disease of interest or, if a population rather than an individual is considered, the incidence of the disease in the population ( Box 31-3 ).

BOX 31-3 

Interpretation of a Test



Sensitivity = Pr (T+/D+) = Probability (Pr) the test (T) is positive given that the disease (D) is present



Sensitivity = Pr (T-/D-) = Probability the test is not positive given that the disease is not present



Predictive value of a positive test = Pr (D+/T-)



Predictive value of a negative test = Pr (D-/T+)



Prior probability and prevalence may be used interchangeably in these equations.

Rather than speculate on what a group of clinical findings suggests about the probability of MH susceptibility in an individual, one may use the test characteristics (sensitivity and specificity) to calculate the predictive value of the CHCT over a wide range of prior probabilities (Figs. 31-2 and 31-3 [2] [3]). For example, if a patient with a history of isolated masseter spasm is thought to have a less than 25% chance of having MH, then, if the sensitivity of the CHCT is 99% and the specificity is 85%, the positive predictive value of the CHCT in that individual is less than 69% and the negative predictive value is greater than 99%. In other words, the chance of that individual having a false-positive result of CHCT is at least 30% and the chance of a false-negative result is less than 1%. In contrast, if a patient with a strong family history of MH has many of the clinical signs of MH, it might be judged that the probability of that individual having MH, before obtaining the result of the CHCT, would be 80%. The positive and negative predictive value of the CHCT would be 96% and 99%, respectively, for such a patient. These statements are oversimplifications in that these calculations assume that the disease being tested for has similar manifestations in all affected individuals. Certainly this is not the case for MH. Nevertheless, appreciation of the concept of the predictive value of a test is important when questions arise regarding the meaning of clinical events and test results. These concepts have been used to argue that the index case should be the first person to undergo contracture testing, followed by first-degree relatives ( Loke and MacLennan, 1998 ; Larach and MacLennan, 1999 ).


FIGURE 31-2  The y-axis is the positive predictive value (PPV) of the caffeine-halothane contracture test (CHCT). This figure illustrates the fact that when the sensitivity is 95% and the specificity is 85%, the positive predictive value is less than 50% when the prior probability is less than 15%.




FIGURE 31-3  The y-axis is the negative predictive value (NPV) of the caffeine-halothane contracture test (CHCT). NPV is less altered by specificity than is positive predictive value (PPV) when prior probability is less than 50%. Thus the NPVs coincide for specificities from 85% to 95%. Figures 31-2 and 31-3 [2] [3] illustrate the relationship between the sensitivity and specificity of a test, the prior probability of the disease, and the predictive value of that test (see definitions in Box 31-3 ). The probabilities on the graphs are shown as decimals between 0 and 1. In both figures, the x-axis is prior probability of MH susceptibility in the individual under consideration. This may be thought of as the probability that the individual under examination is MH susceptible before the results of the CHCT are considered. This probability ranges from 0 to 0.5, or 50%, in these figures. In both figures, the sensitivity of the test is 0.95 or 95%. In both figures, the specificity of the CHCT varies between 0.95 (95%) and 0.15 (15%), as labeled on the dotted lines. The heavy line is the predictive value of the CHCT when sensitivity is 95% and specificity is 85%.



Currently, muscle biopsy for CHCT is the only way to evaluate the diagnosis of MH susceptibility in the absence of an episode of fulminant MH. For satisfactory in vitro testing, 1 g of muscle must be removed from the thigh. A child weighing less than 20 kg may be too small to undergo a muscle biopsy. In general, children younger than 10 years are too young to undergo CHCT.

Parents of an affected child may wish to have a muscle biopsy performed. The relatives of the parent whose findings are negative (assuming autosomal dominant inheritance) can then be reassured, without biopsy, that they have no increased risk of MH. Ideally, siblings and first cousins on the affected side should be informed and offered biopsy testing. Financial and geographic considerations often discourage families in these endeavors. At the very least, relatives of an MHS patient should be informed about the presence of MH susceptibility in their family and its implications.

A valuable self-help resource is the Malignant Hyperthermia Association of the United States (MHAUS, P.O. Box 1069, 11 East State St., Sherburne, NY 13460 (Fax 1-607-674-7910). This organization offers information, expert consultation, and referral and provides family counseling. Their newsletter contains up-to-date information and reviews of the recent professional literature on topics related to MH. MHAUS maintains a 24-hour, professionally staffed telephone line to provide information on diagnosis, treatment, and referral of patients with MH (telephone: 1-800-644-9737).


When a patient is referred preoperatively because of “possible MH,” one should determine how the diagnosis was made. At times, patients are erroneously told they “must have had an episode of MH” because a slight increase in temperature or transient ventricular arrhythmias occurred and no diligent effort was made to clarify the causes or to obtain biochemical evidence of hypermetabolism or rhabdomyolysis. Many cases of increased jaw tension, arrhythmia, or mild elevation of myoglobin or CK following the administration of succinylcholine occur in the absence of MH susceptibility. When the issue of MH susceptibility has been raised, the personal and family history should be examined for previous adverse sequelae to anesthetics, sudden cardiovascular collapse suggestive of arrhythmias or heatstroke, and any evidence of musculoskeletal disorders including cramping with exercise. A positive finding suggests that consultation with a neurologist, a muscle biopsy, and in vitro contracture testing may be warranted.

CK levels, at rest, are of no predictive value in the general population ( Britt et al., 1976 ; Paasuke and Brownell, 1986 ). If a relative of a patient known to be susceptible to MH has an elevated CK level, that individual has an increased likelihood of also being susceptible. This will not hold for patients with other problems producing CK elevations (e.g., Duchenne's muscular dystrophy). In some populations ( Ellis et al., 1975 ), more than 25% of the patients with elevated CK levels were not susceptible to MH on in vitro testing.


When it is clear that the suspected episode was MH and especially when contracture testing has already been done and shows a typical MH pattern, several decisions must be made. If it is at all possible, regional or local anesthesia should be chosen. Although some theoretic objections to amide-type local anesthetics exist, data in animals and humans have not shown any local anesthetic to trigger MH. Review of anesthesia during biopsy suggests that nerve blocks with small volumes of amide local anesthetics do not provoke an episode of MH ( Berkowitz and Rosenberg, 1985 ). Regional anesthesia with lidocaine, bupivacaine, ropivacaine, or another local anesthetic is an acceptable choice for the MHS patient.

One must decide whether the risks of preoperative prophylactic dantrolene (muscle weakness, disequilibrium, and nausea) ( Flewellen et al., 1983 ) justify its potential benefits. Because many muscle biopsies and other operations have been performed in patients with positive CHCT, without preoperative administration of dantrolene or postoperative complications ( Ording et al., 1991 ), it is considered acceptable to withhold preoperative dantrolene. These patients must be closely monitored during anesthesia with nontriggering agents. If there are no signs of increased metabolism or rhabdomyolysis and if no dantrolene was administered, then MHS patients may be safely discharged on the day of surgery ( Yentis et al., 1992 ).

When a very strong family or personal history of MH suggests that the risks of dantrolene may be acceptable, dantrolene can be given orally over several days or intravenously immediately before surgery. Treatment with what was expected to be adequate doses of oral dantrolene has not always prevented the development of hypermetabolism during anesthesia with nontriggering agents ( Fitzgibbons, 1980 ). It appears most appropriate to administer prophylactic dantrolene intravenously while monitoring muscle strength.

The dose-response relationship of dantrolene in children has not been reported. Available data suggest that the half-life of dantrolene in children is somewhat shorter than that in adults: 7.3 to 9.8 hours (Lietman et al., 1974 ; Lerman et al., 1989 ) ( Fig. 31-4 ) and 12.1 hours ( Flewellen et al., 1983 ), respectively. In adults, a cumulative dose of 2.2 to 2.5 mg/kg of dantrolene administered intravenously over 125 minutes produced a steady plasma concentration of dantrolene for longer than 5 hours ( Flewellen et al., 1983 ). Orally administered dantrolene, a total of 5 mg/kg in three or four divided doses administered every 6 hours to MHS adults, has also been shown to produce protective plasma concentrations of dantrolene for at least 6 hours after induction of anesthesia ( Allen et al., 1988 ). In children, intravenous administration of 2.4 mg/kg of dantrolene infused over 10 minutes produced stable blood levels of about 3.5 mcg/mL for 4 hours, after which a slow decline in plasma concentration occurred (Lerman et al., 1989 ). Hence, it may be reasonable to repeat doses of dantrolene in the range of 1 to 2 mg/kg every 5 to 7 hours for prophylaxis. The dose and timing are not rigid because they should be titrated to effect. It is likely that when plasma concentrations of dantrolene are sufficient to inhibit an episode of MH, the patient experiences weakness and possibly disequilibrium.


FIGURE 31-4  Dantrolene plasma concentration versus time in 10 children after intravenous administration of 2.4 mg/kg over 10 to 12 min.  (From Lerman J, McLeod ME, Strong HA: Pharmacokinetics of intravenous dantrolene in children. Anesthesiology 70:625, 1989.)




A dynamometer could be used to assess grip strength objectively, but this requires the patient's cooperation. In a study of adults, the dose of dantrolene that produced maximal depression of grip strength and evoked force of thumb contraction had no significant effect on vital capacity ( Flewellen et al., 1983 ). Similar studies have not been performed in children. Clinical experience (Brandom and Carroll, unpublished observations) suggests that less than 2 mg/kg of dantrolene administered intravenously to a child preoperatively can be associated with significant hypotonia in the postoperative period. If the patient is unable to maintain grasp, it is wise to stop dantrolene administration. Weakness induced by dantrolene could compromise the ability to swallow ( Flewellen et al., 1983 ) and even necessitate artificial protection of the airway and mechanical ventilation, although this has never been reported in the literature. Intravenous dantrolene should be administered in settings where support of airway and ventilation can be easily provided.


One may encounter patients who have had an anesthetic course or who have a family history that suggests MH susceptibility but who have not had that possibility evaluated by means of muscle biopsy and in vitro contracture testing. A reasonable approach to providing anesthesia for such patients is to administer a “nontriggering” anesthetic and monitor carefully for signs of MH. Dantrolene must be available but need not be administered prophylactically. It would be inappropriate to label an individual as MHS and administer dantrolene without obtaining some evidence of a hypermetabolic response to anesthesia in that individual or a similarly convincing history in a first-degree relative. There are many causes of perioperative muscle injury. It may not be possible to diagnose the underlying muscle disorder, but it is easy to demonstrate that there is no myoglobin in the urine. Urine should be examined prior to discharge if a diagnosis of MH or other occult muscle disease is suspected. If there is no myoglobin in the urine, the patient has little risk of renal injury.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Physiologic responses to stress may play a part in the initiation of an episode of MH in humans, as well as in pigs ( Gronert et al., 1980 ; Gronert and Theye, 1976a, 1976b [64] [65]). Anesthesia for the MHS patient should be designed to be as “stress-free” as possible, so that any tachycardia and arrhythmias that may occur are more likely to be associated with impending MH than with the stress of anesthetic, induction, or surgery.

There are many “nontriggering” techniques for general anesthesia ( Table 31-2 ). Local anesthetic cream can produce topical analgesia of the skin, which may facilitate intravenous catheter placement. Preoperative medication with midazolam 0.3 to 0.7 mg/kg orally or 0.2 to 0.3 mg/kg nasally often produces sedation adequate to facilitate the placement of an intravenous catheter in a child. Preoperative sedation is an important part of the anesthetic management for MHS patients in the opinion of some anesthesiologists. After placement of an intravenous catheter, anesthesia may be induced with barbiturates or propofol ( Raff and Harrison, 1989 ; Harrison, 1991 ) and narcotics as indicated by the planned surgery and other characteristics of the patient. Prior administration of benzodiazepine can reduce chest and truncal rigidity commonly observed after the administration of a synthetic narcotic. A nondepolarizing neuromuscular blocking agent may be administered if necessary. It is helpful to use a peripheral nerve stimulator when a neuromuscular blocker is administered so that the dose of drug can be titrated to the desired effect. Similarly, an anticholinesterase should be administered as indicated by the results of peripheral nerve stimulation.

TABLE 31-2   -- Malignant hyperthermia and drugs used during anesthesia

Drugs Likely to Trigger MH

Drugs that Do Not Trigger MH

Potent inhalation anesthetics: Halothane, isoflurane, enflurane, desflurane, sevoflurane, ether

Narcotics Benzodiazepines

Depolarizing neuromuscular blockers: Succinylch oline

Non depolarizing (competitive) neuromuscular blockers Anticholinesterases and anticholinergics
Local anesthetics
Nonsteroidal anti-inflammatory drugs



There are rare reports of changes compatible with MH occurring after the use of such “safe” general anesthetic drugs ( Fitzgibbons, 1980 ; Pollock et al., 1992 ). For susceptible patients, there is no “safe” general anesthetic technique, merely drugs that are less likely to trigger MH. It is advisable to avoid drugs that may affect temperature regulation and sympathetic tone to such an extent that it might be difficult to detect early signs of insidious MH. Furthermore, serotonergic agonists and some psychotropic drugs (MDMA [Ecstasy]) have produced MH episodes in susceptible pigs ( Wappler et al., 1997 ;Fiege et al., 2003 ). Large doses of phenothiazines and anticholinergics are not drugs of choice for the MHS patient. Atropine is administered only when there is significant risk of bradycardia. However, some anesthesiologists have found ketamine to be a useful anesthetic in patients susceptible to MH.

Monitoring and preparedness to treat acute MH are of the utmost importance. In addition to precordial heart tones, electrocardiogram, blood pressure, and oxygen saturation, end-tidal carbon dioxide concentrations should be monitored. Core temperature should be measured. Arterial and urinary bladder catheters are not needed for all surgery in MHS patients, but they are convenient for repeated blood sampling and close monitoring of hemodynamic stability and urine myoglobin. The anesthesia machine can be sufficiently flushed of potent inhalation agents by 12 minutes of 10 L/min oxygen flow (McGraw and Keon, 1989 ). Anesthesia workstations require 20 minutes of flushing if carbon dioxide absorbers and the respiratory circuit are not removed ( Schonell et al., 2003 ).

It is helpful to keep drugs (see Table 31-1 ) and supplies to treat MH in a portable container, such as a carryall or rolling cart that is immediately accessible in the operating room and recovery room and can easily be transported to other areas in the hospital. The necessary supplies include at least 5 to 10 mg/kg of dantrolene and liter quantities of sterile, preservative-free, distilled water in which to dissolve the dantrolene. Ice or cold packs should be ready, and large volumes of normal saline solution should be available in a nearby refrigerator. Water mattresses that can both cool and warm the patient should be placed under the MHS patient from the start of the anesthetic procedure.


The preceding recommendations for anesthetic care of patients with MH susceptibility apply to the patient undergoing diagnostic muscle biopsy except that prophylactic dantrolene is never given. Dantrolene may prevent the in vitro response to halothane and caffeine, causing a false-negative result. Biopsy for CHCT can be done only in one of the specialized centers that support the performance of this in vitro test. The list of currently active centers may be obtained from the Malignant Hyperthermia Association of the United States (

The child scheduled for a biopsy usually weighs more than 20 kg. Some biopsy center directors will test only children who are at least 10 years old. The patient may be mature enough to have regional anesthesia. In a cooperative child, the use of lateral femoral-cutaneous nerve block and intravenous sedation is often successful ( Berkowitz and Rosenberg, 1985 ). If the child cannot cooperate, general anesthesia may be induced and maintained with various agents, including benzodiazepines, narcotics, propofol or barbiturates, nondepolarizing relaxants, and nitrous oxide.

▪ postoperative care of the malignant hyperthermia-susceptible patient

If anesthesia has proceeded uneventfully and prophylactic dantrolene has not been administered, the patient should be transported to the recovery room for the usual monitoring of vital signs, electrocardiogram, mental status, and urine output and color. A dipstick should be used to check urine for blood. The reaction of heme with orthotolidine will occur if myoglobin, free hemoglobin, or red blood cells are present. If no sign of MH appears, the patient may be transferred to the floor after an ordinary length of stay in the recovery room. After observing such patients for 4 hours and finding no abnormalities, they may be discharged from the hospital. In this way, it is possible for a child who is susceptible to MH to be treated successfully as an outpatient ( Yentis et al., 1992 ; Pollock et al., 2004 ).

If there is any evidence of hypermetabolism or if continued treatment with intravenous dantrolene is contemplated, the patient should be cared for in an intensive care area. When preoperative prophylactic dantrolene has been administered but continuing treatment is not necessary and the patient is metabolically and hemodynamically stable, discharge from the recovery room is based on the same clinical criteria as for other patients who have been given muscle relaxants. Guidelines for heart rate, temperature, and other monitoring should be included in the postoperative orders. In a postoperative MH patient, the anesthesiologist should be called to evaluate fever or tachycardia. The causes are usually related to pain, mild dehydration, atelectasis, or bacteremia. Nevertheless, MH has been reported to occur several hours postoperatively. The patient must be examined carefully for signs of MH or altered mental status, venous blood gas tension and lactate should be measured, and urine should be tested for myoglobin. If signs of hypermetabolism or rhabdomyolysis are present, the patient should be treated with intravenous dantrolene and transferred to an intensive care unit.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


A number of disorders have been thought to be related to the MH syndrome because their presence appears to increase the risk of MH during anesthesia. A complete understanding of these syndromes could contribute to understanding the pathophysiology of MH.

The earliest large study of MH epidemiology ( Britt and Kalow, 1970 ) provided a review of the case histories of 89 MHS patients. Thirty-two of these patients had preexisting musculoskeletal abnormalities; most frequent were ptosis, strabismus, idiopathic kyphoscoliosis, and hernias—congenital inguinal hernia, umbilical hernia, and diaphragmatic hernia. A few patients also reported a tendency to have severe muscle cramps in the extremities unrelated to either cold or exercise. Other abnormalities noted included recurrent spontaneous dislocations of the hip, clubfoot, and pes excavatum.

Although not all myopathic patients are MHS, the presence of a known or suspected myopathy should alert the anesthesi-ologist that there may be increased potential for MH susceptibility and/or anesthetic complications that may mimic MH ( Heytens et al., 1992 ). It has been claimed that Duchenne's muscular dystrophy (DMD) coexists with MH susceptibility ( Heiman-Patterson et al., 1986 ). However, the genetic defect that produces DMD is distinct from genetic loci that have been associated with MH susceptibility. DMD is caused by a lack of dystrophin. The gene responsible for the production of normal dystrophin is located at chromosomal position Xp21. One genetic locus associated with MH is on chromosome 19q13.1. This gene codes the ryanodine receptor ( Thompson, 1994 ). There may be another genetic locus associated with MH on chromosome 17q ( Levitt et al., 1992 ).

Many patients with DMD have received potent inhalation anesthetics without MH occurring ( Peluso and Bianchini, 1992 ), but dystrophic muscle is fragile. Even mild exercise in DMD patients results in a marked egress of sarcoplasmic components into the plasma, most notably myoglobin, CK, and potassium ( Florence et al., 1985 ). These patients can have rhabdomyolysis during anesthesia with potent inhalation anesthetics even without the administration of succinylcholine ( Rubiano et al., 1987 ). It is not surprising that anesthetic complications with many of the qualities of MH occur in patients with abnormal dystrophin ( Kleopa et al., 2000 ) (see Chapter 32 , Systemic Disorders). Nevertheless, at least one patient with dystrophinopathy had a negative contracture test, ruling out MH susceptibility (Gronert et al., 1992 ).

Several extensive family studies of central core disease ( Shy and Magee, 1956 ; Byrne et al., 1982 ) have documented morphologically abnormal muscle, that is, central cores of oddly aligned fibers, in some patients with MH. The histologic abnormality of central core disease (CCD) is not a marker for MH. However, CCD is the only myopathy for which a definite genetic link to MH has been shown (Kausch et al., 1990 ). Several mutations in RYR1 cause CCD and/or MH susceptibility ( Loke and MacLennan, 1998 ; Tilgen et al., 2001 ). It is advisable to treat a patient with central core disease as MHS.

Another familial myopathy, the King-Denborough syndrome ( King and Denborough, 1973 ), is associated with MH susceptibility. Affected individuals have proximal muscle weakness, postural imbalances, cryptorchidism, webbed neck, pectus deformities, delayed development, and elevated levels of CK (Jurkatt-Rott et al., 2000).

In the past, other disorders in which patients appeared to have MH susceptibility included myotonia congenita, osteogenesis imperfecta ( Rampton et al., 1984 ), Schwartz-Jampel syndrome (dwarfism, craniofacial and skeletal abnormalities, blepharophimosis, and muscle stiffness), and possibly arthrogryposis ( Fowler et al., 1974 ; Baines et al., 1986 ). These syndromes may be associated with many of the symptoms of MH, but these symptoms are not specific for MH. Many patients with these and other muscular disorders have received inhalation anesthetics without complications. For example, a pyloromyotomy was performed in an infant with paramyotonia congenita during sevoflurane anesthesia ( Ay et al., 2004 ). Sometimes evaluation of suspect cases has found CHCT to be negative ( Hopkins et al., 1991 ).

The neurolept malignant syndrome (NMS) ( Guzé, 1985 ; Cohen et al., 1985 ; Mann et al., 2003 ) is a disorder recognized by psychiatrists that may clinically resemble MH. It occurs in one of 200 patients taking neuroleptic drugs that produce dopaminergic blockade. Most of the patients are young men with schizophrenia or mania treated with the potent piperazine phenothiazines or haloperidol, but more than 25 drugs have been implicated ( Heiman-Patterson, 1993 ). NMS may also occur when the administration of antiparkinsonian drugs is stopped. NMS may be fatal. Its manifestations are hypermetabolism with fever, tachycardia, muscle rigidity, and myoglobinuria. NMS has all the clinical features of MH, including acute renal failure and multiorgan failure, but it progresses over hours to days rather than minutes.

The inciting events of NMS are not the same as those for MH. There are several reasons that blockade of dopamine receptors can produce hyperthermia and rigidity ( Heiman-Patterson, 1993 ). Dantrolene has been used successfully for treatment of this syndrome ( Granati et al., 1983 ), as has bromocriptine, a dopamine agonist ( Caroff, 1980 ). The results of CHCT in patients with a history of NMS have been inconsistent ( Caroff et al., 1987 ; Adnet et al., 1989 ). Drugs that are known triggers of MH have been well tolerated in patients who have had NMS. However, repeated exposure of MHS pigs to a serotonin-2 receptor agonist can induce typical MH symptoms, without causing the same syndrome in normal animals ( Gerbershagen et al., 2003 ). This suggests that serotonin syndrome (tremor, diaphoresis, shivering, and myoclonus in the presence of serotoninergic medication) could be elicited more easily in MHS individuals ( Mann et al., 2003 ). Dantrolene can delay serotonin-induced contractures ( Wappler et al., 1997 ).

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The CHCT is the best laboratory test available to investigate susceptibility to MH. The methods for performance of the test have been standardized in North America ( Larach et al., 1989) . However, the European protocol differs from that in North America. Both tests provide consistent normal population values for comparison with diagnostic biopsies. In both North America and Europe, the CHCT is a concentration-response curve to caffeine alone, halothane alone, or their combination. Unlike usual concentration-response phenomena, differences between MHS and normal persons do not appear as altered ED50 or as a change in slope, but as a change in threshold. That is, when does a contracture begin to develop? At least three muscle strips are examined under each test condition ( Larach, 1989 ). These must be about the same weight, length, and thickness and start with equivalent baseline tension. Shorter muscle bundles deteriorate more rapidly due to the current of injury from the cut muscle end, and thicker bundles yield greater contractures. The upper limit of a normal contracture response is somewhat arbitrary. A muscle strip must respond with an active twitch to electrical stimulation; that is, it must be viable. The test should be completed within 5 hours of the excision of muscle from the patient's thigh. There are slight differences in European and North American protocols, which account for differences in threshold ( Ording and Bendixen, 1992 ).

The European protocol defines a positive caffeine contracture test as tension greater than 0.2g in the presence of 2 mmol/L caffeine or less. In this test, caffeine is added incrementally to concentrations of 0.5, 1, 1.5, 2, 3, 4, and 32 mmol/L to the bath surrounding the muscle strip. A positive halothane contracture test is the development of greater than 0.2g tension in the presence of 0.5%, 1.0%, or 2.0% halothane. In this test, muscle that has not been exposed to caffeine is bathed with Krebs—medium in which halothane concentrations have been verified. The combination of caffeine and halothane is not part of the European protocol. If one of the several strips tested has a positive response to caffeine and another strip has a positive response to halothane, the patient is considered MHS. If one muscle strip reacts to only one agent, the patient is MH equivocal by European standards.

The North American protocol includes exposure of muscle strips to 0.5, 1, 2, 4, 8, and 32 mmol/L caffeine. A positive caffeine contracture test is often defined as an increase in tension of 0.2g in the presence of 2 mmol/L caffeine or less. However, a cutoff of 0.3g or 0.4g may be preferred to increase the specificity of the test ( Larach, 1989 ). The caffeine-specific concentration (CSC) is the mmol/L concentration of caffeine at which a 1g increase in tension occurs. A CSC of less than 4 mmol/L is considered a positive response. A positive halothane contracture test is the development of more than 0.2gto 0.7g tension (depending on the controls in that laboratory) in the presence of 3% halothane ( Larach et al., 1989) . In the United States, if one muscle strip produces a positive reaction in either caffeine or halothane, the patient is said to be MHS.

The joint halothane-caffeine assay is an optional test that is not performed by all laboratories. To perform this test, muscle strips are exposed to 1% halothane for 10 to 15 minutes; then caffeine is added incrementally to the bath to a maximum concentration of 32 mmol/L. Normal muscle is expected to produce 1g of tension at greater than 1 mmol/L caffeine. The results of this test may be reported in terms of the halothane-caffeine specific concentration, or the concentration of caffeine, in the presence of halothane, at which greater than 1g of tension is produced.

Some patients whose muscle reacts normally to both caffeine and halothane alone may have an abnormally low halothane-caffeine specific concentration. This reaction is referred to as a type K response, using the initial of Kalow, who proposed that this response may indicate an intermediate genotype ( Kalow et al., 1979 ).

The significance of the type K response is controversial. About 20% of normal subjects exhibit a type K response; such individuals may respond normally to the clinical use of halothane and succinylcholine. There are some reports of MHS patients who had relatives whose muscle tested as type K. A similar phenomenon has been noted in the porcine model of MH.

Other laboratory tests have been evaluated for their diagnostic usefulness in MH; these include calcium uptake into frozen muscle, skinned fiber testing, platelet nucleotide depletion measurement, and the measurement of abnormal proteins in MH muscle. None of these is generally accepted, because none has been shown to reproduce the results of the in vitro muscle contracture tests ( Lee et al., 1985 ; Britt and Scott, 1986 ; Whistler et al., 1986 ; Nagarjan et al., 1987 ). Several of the proposed tests produced inconsistent results ( Ording et al., 1990 ; Quinlan et al., 1990 ).

Attempts have been made to develop relatively less invasive tests of MH susceptibility. The ryanodine receptor expressed on B-lymphocytes responds abnormally to agonists in the presence of mutations causative of MH ( Girard et al., 2001 ; Sei et al., 2002 ; Kraev et al., 2003 ; Loke et al., 2003 ). Cultured human muscle from MHS patients also has greater increases in intracellular calcium with exposure to halothane than does normal muscle ( Girard et al., 2002 ). Microdialysis of caffeine or halothane into muscle in vivo is being examined ( Anetseder et al., 2002 ; Bina et al., 2003 ; Textor et al., 2002 ). Abnormal force of contracture and abnormal rate of increase of force have been demonstrated in MHS pigs ( Quinlan et al., 1986 ). Studies of mechanical and electrical responses to repetitive nerve stimulation have been performed ( Balog et al., 2000 ; Hoyer et al., 2001, 2002 [78] [79]). A noninvasive in vivo test for MH susceptibility has been developed using phosphorus magnetic resonancespectroscopy (31P NMR) ( Olgin et al., 1988 ). This test is not specific for MH; it will yield a positive result, an elevated ratio of inorganic phosphate to phosphocreatine, in patients with mitochondrial myopathies ( Argov et al., 1987a ), muscular and myotonic dystrophies ( Younkin et al., 1987 ), metabolic myopathies associated with secondary atrophy ( Argov et al., 1987b ), polymyositis, hypothyroid myopathy ( Argov et al., 1987c ), advanced denervating muscle disorders ( Zochodne et al., 1986 ), and muscle injury ( McCully et al., 1987 ). Although 31P NMR is unlikely to be specific for MH, it could be useful as a screening test. An individual with a questionable clinical history could be evaluated by 31P NMR. If abnormal results were obtained, muscle biopsy and follow-up with a neurologist would definitely be indicated.

MH is a disorder of muscle that is subclinical until the muscle is stressed. Tests discern MH susceptibility only if they impose a stress on the intact tissue or organism or detect a genetic difference that has been demonstrated to be causative ( Urwyler et al., 2003 ). MH muscle testing is generally designed to avoid false-negative diagnoses; hence, there may be false-positive results of the CHCT. Findings suggest that, as with all tests, there are some rare false-negative contracture test results ( Larach, 1993 ). However, overall, MH contracture testing appears accurate, and patients with negative findings on CHCT can receive safe anesthetics with drugs that could trigger MH ( Ording et al., 1991 ). Failure to detect an RYR1 mutation does not imply that the patient is not MHS. If a patient undergoes genetic evaluation prior to contracture testing and no MH causative mutation is found, the patient must undergo contracture testing in order to support the diagnosis of not MHS. All patients should be monitored for signs of MH responses during anesthesia. It is possible that under certain conditions, an MH response to anesthesia may be acquired. Furthermore, MH can occur without the use of triggering drugs such as succinylcholine and potent inhalation anesthetics ( Fitzgibbons, 1980 ; Pollock et al., 1992 ).

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MH has been known for more than 40 years, yet many primary care physicians, dentists, and surgeons still are unaware of its life-and-death significance. Malignant Hyperthermia Association of the United States published a letter from a parent:

Your information will be most helpful for my married out-of-state, pregnant daughter—who tried to explain that MH existed in our family…. They told her nobody could be allergic to anesthetics, which was the same thing I was told 22 years ago when my son's tonsils were removed. We had lost many relatives to ether for minor surgery over the years. Trying to explain MH in places that don—t have large amounts of it is difficult. Some won—t liste….—Anonymous, 1986

Physicians who are aware of the potential seriousness of MH may ask what the implications of the diagnosis of MH susceptibility are for the patient's daily life. MH susceptibility has been associated with fourfold increases in plasma catecholamines with graded exercise ( Wappler et al., 2000 ) and rapid exhaustion after intense exercise ( Rueffert et al., 2004 ). However, MHS individuals have performed farm labor in the hot sun without precipitating an MH attack. Early studies of metabolic responses during noncompetitive, low-intensity, steady-state exercise found no difference between control and MHS patients ( Green et al., 1987 ). Slower recovery of muscle pH and phosphocreatine/inorganic phosphate ratios have been observed in MHS patients ( Allsop et al., 1991 , Olgin et al., 1991 ). MHS patients should be encouraged to refrain from strenuous exercise if they experience cramps or fever under such circumstances ( Davis et al., 2002 ). Some patients with exertional heat stroke are MHS ( Bendahan et al., 2001 ; Tobin, et al., 2001 ; Wappler et al., 2001 ). The psychoactive drug MDMA has been shown to trigger MH in susceptible swine ( Fiege et al., 2003 ). Dantrolene may be therapeutic when these symptoms occur ( Gronert, 1980 ).

Sudden death from undetermined cause may be part of the history of MHS families. In adults these sudden deaths may be due to arrhythmias. As of yet there are no published data regarding possible changes in muscle function with age in MHS patients, but it is noteworthy that in some MHS families the young adults are muscular and strong, whereas older adults may fatigue easily.

The North American Malignant Hyperthermia Registry, now at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania (Dr. Barbara W. Brandom, Director), collects data from practitioners and testing centers in Canada and the United States. This registry provides a database by which to define clinical MH and to study aspects of its presentation, treatment, and diagnostic methods. Because MH is a rare event, it is necessary to collect clinical reports from a large geographic area over an extended period of time to improve understanding of the clinical problem. Because MH is rare, all practitioners should have a responsibility to report such cases or suspected cases to the registry.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


MH is a potentially lethal pharmacogenetic syndrome. It has been of particular concern to pediatric anesthesiologists because succinylcholine and halothane are potent triggers of MH and have been popular drugs in the practice of pediatric anesthesia. With the advent of improved monitoring techniques and universal availability of intravenous dantrolene, mortality from MH has plummeted. However, the definitive diagnosis of MH is still not simple or easy. It falls to anesthesiologists to choose anesthetic agents and adjuvants that maximize the safety of the patient, to identify as potentially MHS those individuals who experience adverse reactions consistent with MH, and to counsel and refer those individuals and families to appropriate diagnostic centers. Anesthesiologists must also make fellow physicians and other health care providers aware of the existence and the seriousness of MH and of its effective treatment and prevention. When capnography, blood gas analysis, temperature monitoring, and dantrolene are available, patients with a history of MH susceptibility may safely receive routine anesthetic care with nontriggering anesthetics.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


We would like to acknowledge the extensive contributions of Joan Carroll, Henry Rosenberg, and Gerald Gronert to previous editions of this chapter and the editorial contribution of Philip Morgan to the current chapter.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


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