Malignant Hyperthermia.

[Kozack JK, MacIntyre DL. Malignant hyperthermia. Phys Ther. 2001;81:945-951.]

Key Words: Exercise, Heat stroke, Malignant hyperthermia, Physical therapy, Rhabdomyolysis.

Malignant hyperthermia (MH), a potentially fatal hypermetabolic reaction, is a genetic disorder of skeletal muscle.[1-8] The triggers for the hypermetabolic reaction are some anesthetics and muscle relaxants, or extreme stress in the form of heat or exercise.[4-6] If recognized early, the MH reaction can be reversed by the administration of dantrolene, a muscle relaxant, in addition to medical treatment such as cooling and hyperventilation.[1] Unfortunately, by the time the condition is recognized, the individual may have experienced extensive muscle damage (rhabdomyolysis) due to sustained muscle rigidity[9] and, therefore, have muscle pain and weakness and decreased range of motion (ROM) in the affected extremities.[10]

Physical therapists may encounter clients with MH in a variety of settings such as on sports fields, in the clinic, and in intensive care units. Understanding the etiology, pathophysiology, clinical presentation, and medical management of MH should provide the basis for physical therapy management of this complicated and intriguing disorder. There is a paucity of literature, however, regarding physical therapy treatment of MH. The purpose of this article is to increase awareness for physical therapy practitioners about MH in susceptible clients.

Etiology

Some inhalational anesthetics (eg, halothane, isoflurane, enflurane), depolarizing muscle relaxants such as succinylcholine,[1] or extreme stress in the form of heat or exercise are some of the triggers for an MH reaction.[4-7] Malignant hyperthermia is an autosomal dominant genetic mutation causing a disruption of intracellular calcium homeostasis in skeletal muscle during a reaction.[1,2,11] Problems with the ryanodine receptor, also known as the calcium release channel, gene on chromosome 19 are responsible for manifestations of this disorder in at least 50% of the people with MH.[11] Located in the triad junction of the sarcoplasmic reticulum, the ryanodine receptor is an integral component of the system that causes skeletal muscle contraction by acting as the main calcium release mechanism.[12] Working in conjunction with the ryanodine receptor, the dihydropyridine receptor is critical for initiating and terminating calcium release from the ryanodine receptor.[11,12] A mutation in the dihydropyridine receptor has also been linked to MH in some families.[8,11] Regardless of the underlying mechanism causing MH, intracellular calcium increases substantially during a reaction, initiating potentially irreversible muscle contracture and hypermetabolism.[1,2,5]

Pathophysiology

When the ryanodine receptor is stimulated in skeletal muscle that is susceptible to MH or in skeletal muscle that is not susceptible to MH, calcium is released from the sarcoplasmic reticulum (through the ryanodine receptor) into the myoplasm, causing muscle contraction.[1] During an anesthetic-induced MH reaction, excess quantities of calcium flood into the myoplasm, initiating muscle rigidity, increased heat production, and acidosis.[13] Heiman-Patterson explained in greater detail that

   [e]levated myoplasmic [Ca.sup.2+] stimulates phosphorylase kinase, leading
   to increased glycolysis resulting in lactic acid formation; initiates
   muscle contraction by binding to troponin; increases adenosine triphosphate
   (ATP) use through stimulation of myosin ATPase [adenosine triphosphatase];
   and causes mitochondria to sequester calcium in a process requiring ATP
   despite ATP depletion by other ongoing processes.... The sarcolemmal
   membrane integrity can no longer be maintained and additional [Ca.sup.2+]
   leaks into the muscle while CK [creatine kinase], potassium, and myoglobin
   leak out.[13(p483)]

This disruption in calcium homeostasis may result in muscle cell necrosis and rhabdomyolysis.[14] The [Na.sup.+]/[K.sup.+] pump also plays an important role in the development of rhabdomyolysis. If ATP production is not sufficient (as occurs during an MH reaction), the [Na.sup.+]/[K.sup.+] pump fails, allowing sodium, chloride, and water to flow freely into the cell. Due to osmosis, the muscle cell swells, causing further injury.[14]

According to Enzmann et al,[15] sensitivity to a number of drugs is enhanced in muscles that are susceptible to MH. Upon exposure to caffeine, succinylcholine (a muscle relaxant), and certain inhalational anesthetics, both the ryanodine receptor's threshold for calcium release and the membrane polarization are reduced,[1] setting off the cascade of events that underlie the serious clinical presentation.

The clinical features of exertional heat stroke (EHS) are similar to MH (eg, hyperthermia, rhabdomyolysis).[5] Bourdon and Canini theorized that "a myopathy [such as occurs with MH] would increase muscle caloric production for the same work done by decreasing muscular efficiency."[5(p269)] Therefore, the onset of EHS would occur more rapidly in individuals with MH compared with individuals who are not susceptible to MH. Sweating becomes inefficient for all individuals when humidity rises above 75%,[16] which is undesirable in warm temperatures because sweating serves as an evaporative cooling system. Alternatively, if excessive sweating occurs, a decrease in plasma volume (hypovolemia) can cause vasoconstriction, which reduces heat loss through the skin.[17] In EHS, metabolism increases and warms the body further.[16] Once heat production overrides the cooling mechanisms (as occurs in MH), the body's core temperature increases, disrupting homeostasis.[17] Like MH, a disruption in homeostasis leads to muscle breakdown and rhabdomyolysis.[16]

Associated Diseases and Disorders

Denborough stated that "everyone who is susceptible to MH has an underlying disorder of the muscle-cell membrane."[8(p1132)] Positive diagnoses (MH) and anesthetic-induced reactions with a presentation similar to MH have been reported in clients with neuroleptic malignant syndrome, central core disease, myotonia congenita, myotonic dystrophy, Duchenne muscular dystrophy, congenital muscular dystrophy, King-Denborough syndrome, osteogenesis imperfecta, myelomeningocele,[13] and hyperkalemic periodic paralysis.[18] However, Denborough contended that there are only 3 myopathies "in which the predisposition to MH has been established."[8(p1132)] These are Evans myopathy, King-Denborough syndrome, and central core disease.[8] The Table provides definitions for these terms.

Table 1. Definitions

Term                Definition

Central core        Genetic muscle disorder characterized by
disease             hypotonia and proximal muscle weakness(a)

Disseminated        "Overactivation of the clotting cascade ...
intravascular       leading to internal bleeding and excessive
coagulation         blood loss from wounds"(b) once the clotting
                    factors have been depleted

Evans myopathy      Genetic muscle disorder with possible muscle
                    wasting(c)

Hyperkalemia        Elevated levels of potassium in the blood(d)

Hyperkalemic        Genetic muscle disorder characterized by
periodic            episodic attacks of muscle weakness due to
paralysis           elevated levels of potassium in the serum(e)

Hyperphosphatemia   Elevated levels of phosphate in the blood(d)

Hypocalcemia        Decreased levels of calcium in the blood(d)

King-Denborough     Muscle disorder characterized by dysmorphic
syndrome            features such as webbed neck, kyphosis,
                    lordosis, pectus excavatum, and winged
                    scapula(e)

Myoglobinuria       Red- or brown-pigmented urine due to the
                    presence of myoglobin(d)

Neuroleptic         "Rigidity and hyperthermia during
malignant           administration of neuroleptics or the
syndrome            withdrawal of dopaminegic agents"(e)(p477)

Rhabdomyolysis      Disruption of the muscle cell membrane due
                    to extreme skeletal muscle injury(d)

(a) George AL. Molecular genetics of ion channel diseases. Kidney Int. 1995;48:1180-1190.

(b) Huston CJ. Disseminated intravascular coagulation. Am J Nurs. 1994;94:51.

(c) Denborough M. Malignant hyperthermia. Lancet. 1998;352:1131-1136.

(d) Poels PJE, Gabreels FJM. Rhabdomyolysis: a review of the literature. Clin Neurol Neurosurg. 1993;95:175-192.

(e) Heiman-Patterson TD. Neuroloeptic malignant syndrome and malignant hyperthermia: important issues for the medical consultant. Med Clin North Am. 1998;77: 477-492.

Epidemiology

The incidence of diagnosed anesthetic-induced MH is approximately 1 in 14,000 for the pediatric population and 1 in 50,000 for the adult population.[1] Sessler estimated that "susceptibility may be as high as one in two hundred patients."[1(p26)] The discrepancy between the incidence and susceptibility is due to several factors, the most important being that not all anesthetics administered trigger a reaction in people who have MH.[1]

Diagnosis

A biopsy sample of muscle tissue is taken to administer a contracture test, which "is the only recognized laboratory test to diagnose malignant hyperthermia."[19(p579)] The biopsy sample is tested for levels of contractibility while being immersed in baths of caffeine and halothane. This diagnostic test is known in North America as the Caffeine-Halothane Contracture Test and in Europe as the In Vitro Contracture Test.[20] Halothane is a triggering anesthetic, and caffeine causes muscle contraction in vitro.[1] The tissue obtained in the biopsy (most often removed from vastus lateralis muscle[6] or the quadriceps femoris muscle[21]) is immersed into the baths of caffeine and halothane, and the degree of tension generated from the muscle contraction is recorded.[22] Using the Caffeine-Halothane Contracture Test, 1 of 2 classifications can be made. Malignant hyperthermia susceptibility (MHS) is an abnormal response to caffeine or halothane, or a combination of caffeine and halothane. Malignant hyperthermia normal (MHN) is a normal response in both caffeine and halothane tests. The In Vitro Contracture Test has 3 classifications. Malignant hyperthermia susceptibility is diagnosed when an abnormal response is observed in each of 2 separate baths of caffeine and halothane. Malignant hyperthermia equivocal (MHE) is the diagnosis when muscle fibers contract abnormally to either caffeine or halothane, but not both. Malignant hyperthermia normal is the diagnosis when no abnormal responses are observed.[22]

Serum creatine kinase levels, determined by a simple blood test, have been used to screen clients for MH.[23] However, checking creatine kinase levels is no longer considered the diagnostic test of choice because of the lack of accuracy and the occurrence of both false positive and false negative results.[23] Only 70% of individuals susceptible to MH have elevated resting creatine kinase levels.[6] Creatine kinase levels may be elevated in individuals who are not susceptible to MH as a result of muscle injury unrelated to MH.[23]

Genetic testing for MH is possible, but difficult because over 16 point mutations in the human ryanodine receptor gene on chromosome 19 have been linked to MH.[8] In addition, markers on chromosomes 1, 3, 7, and 17 also have been demonstrated.[8] The abundant possibility for various mutations makes screening a challenge.

Phosphorus magnetic resonance spectroscopy ([sup.31]P-MRS) combined with a standardized exercise protocol is currently being investigated to detect metabolic abnormalities in the skeletal muscle of individuals with MH.[24,25] The goal of [sup.31]P-MRS research is to develop a noninvasive diagnostic test to differentiate clients with a diagnosis of MH from clients with a diagnosis of MHN.[24]

Anesthetic-Induced Reactions

Immediate Presentation

Hypermetabolism is the most common feature of an MH reaction, with a rise in end-tidal [CO.sub.2] as the first sign.[8] Typical indications of MH that a physical therapist should recognize are fever, tachycardia, cyanosis, generalized muscle rigidity, and cardiac arrhythmias.[8] Masseter muscle rigidity often occurs after the administration of succinylcholine in children who are susceptible to MH.[1] Masseter muscle rigidity is rare in adults.[1] Acidosis, hyperkalemia, hyperphosphatemia, and hypocalcemia may develop when the integrity of the muscle cell is lost due to hypermetabolism.[8] Sustained skeletal muscle contraction and its accompanying hypermetabolic state can result in rhabdomyolysis.[9] Rhabdomyolysis is detected by elevated levels of serum creatine kinase and myoglobinuria and may lead to compartment syndrome, renal failure,[14] or disseminated intravascular coagulation.[8] Seizures and acute pulmonary and cerebral edema may develop later in the reaction.[13] If the MH reaction is left untreated, the mortality rate is 65% to 70%, which is often due to ventricular arrhythmias.[13] Physical therapists may encounter individuals who have survived the complications of MH in an acute care facility and later may treat these individuals in an outpatient setting.

Long-term Presentation

Few descriptions of long-term symptoms following an MH reaction have been published. One case report details how a 27-year-old man was affected by prolonged muscle weakness following an anesthetic-induced MH reaction.[26] Detailed manual muscle testing of his upper and lower extremities was performed 1 month, 2 months, and 3 months following the reaction. Although he had received "muscle rehabilitation"[26(p426)] (which the authors did not define), weakness was still pronounced, ranging from 3/5 to 4/5, one month after the reaction. At the 3-month mark, manual muscle test scores had increased to 5/5 for all of the muscles tested.[26] Although few reports have been published on postoperative muscle weakness following an MH reaction,[26] weakness may occur in some cases.

Non-Anesthetic-induced Reactions

With regard to non-anesthetic-induced reactions, Denborough stated that "the MH myopathy has varied clinical presentations, including heatstroke, gross rhabdomyolysis after a variety of triggers [such as a military march, 200-m sprint training, an influenza-like illness, or a gas from fire extinguishers[8]], a chronically raised serum CK, muscle pain, neuroleptic malignant syndrome (NMS), and sudden infant death (SID)."[8(p1132)] In the remainder of this update, we will focus on heat stroke and rhabdomyolysis because they may relate most to physical therapy practice.

Exertional Heat Stroke

Physical therapists working with athletes should be aware of the precipitating events and the clinical signs indicative of EHS. This is particularly important because there appears to be a relationship between MH and EHS.[4,5,17,27,28] Exertional heat stroke may occur during high-intensity exercise and is more likely to occur when warm and humid conditions are present.[5,17] Hyperthermia, dizziness, loss of consciousness, and rhabdomyolysis are common features of EHS.[5] Studies of individuals who have survived EHS have shown that greater than 40% are diagnosed as having either MHS or MHE, as determined with the In Vitro Contracture Test.[5] This finding raises 2 questions: (1) Are individuals with MH predisposed to EHS? and (2) Do many individuals who develop EHS have an underlying muscle disorder that portrays sensitivity to the In Vitro Contracture Test? Bourdon and Canini[5] recommended that individuals who experience EHS should be considered to have MH until proven otherwise by the Caffeine-Halothane Contracture Test or the In Vitro Contracture Test. Dantrolene has been used successfully to treat heat stroke in some clients.[17]

Rhabdomyolysis

Strenuous exercise also can induce rhabdomyolysis in individuals with MH,[4,21,29] and, as with EHS, physical therapists should be aware of the signs and precipitating conditions of rhabdomyolysis. Randall et al explained that "[p] oar conditioning, a dramatic increase in activity level, and high levels of motivation may place an individual at risk for developing rhabdomyolysis."[29(p565)] Rhabdomyolysis results from a disruption of the muscle cell membrane that causes cellular contents such as myoglobin and creatine kinase to leak into the plasma, leading to myoglobinuria.[14] If not managed appropriately by a medical team, muscle cell necrosis may occur in addition to other complications such as renal failure or cardiac arrest.[14] Severe muscle pain, swelling, weakness, and stiffness often occur.[14] Differentiation of rhabdomyolysis from exertional muscle injury, which results in the common presentation of delayed-onset muscle soreness, may, at times, be difficult. However, the presence of myoglobin in the urine is a key feature of rhabdomyolysis and may, but not always, result in red- or brown-tinged urine.[14] Myoglobinuria warrants an immediate referral to an emergency medical service. Along with myoglobin, creatine kinase is another laboratory marker used in the detection of rhabdomyolysis.[29] Elevated levels of serum myoglobin and creatine kinase, as well as myoglobinuria, indicate the degree of skeletal muscle damage and suggest the diagnosis of rhabdomyolysis.[29]

Medical Management

For anesthetic-induced MH reactions, discontinuation of the triggering drugs and hyperventilation with oxygen are believed to be essential in an attempt to arrest the progression of the MH reaction.[1] Intravenous administration of dantrolene is the next critical step.[1] Additional therapy with drugs (eg, procainamide) and cooling is required to reverse the metabolic abnormalities.[9] If compartment syndrome secondary to rhabdomyolysis develops, surgical fasciotomies may be required to relieve the intracompartmental pressures and to prevent nerve damage and ischemic necrosis in the affected compartments.[14]

Dantrolene is an antiarrhythmic drug[1] and a skeletal muscle relaxant that acts to reverse muscle contraction by blocking calcium release from the sarcoplasmic reticulum.[6] Dantrolene has dramatically decreased the mortality rate of anesthetic-induced MH reactions from approximately 70% in the 1970s[30] (when dantrolene was not available) to 5% today.[8] For some individuals, intravenous dantrolene is used for prophylaxis prior to their receiving an anesthetic.[31] Oral dantrolene has also been used as a prophylactic drug[31] and is occasionally prescribed to treat the MH-like syndrome in some people who are affected by non-anesthetic-induced MH-like symptoms.[6,17]

Physical Therapy Management

Postoperative

There is a paucity of literature regarding physical therapy management of a client following an MH reaction. We believe that physical therapists, based on the biology of the condition, should intervene for the following conditions or symptoms after an MH reaction: pain, weakness, and decreased range of motion secondary to muscle rigidity and/or rhabdomyolysis.[10] Any nerve damage or ischemic muscular necrosis (secondary to compartment syndrome) that may have been surgically treated with a fasciotomy may also require physical therapy intervention.[14] Muscle weakness secondary to the muscle damage that occurs during an MH reaction may require at least 2 to 3 months for complete resolution.[26]

In the previously described case report of the 27-year-old man who was affected by prolonged postoperative muscle weakness, it is important to note that "muscle weakness did not return to normal even by 1 month after the episode, despite muscle rehabilitation."[26(p426)] It took 3 months for the muscles, which had sustained severe rigidity, to reach a grade of 5/5 on manual muscle testing. Pathohistological studies have demonstrated differing levels of skeletal muscle damage in people following MH reactions.[26]

Physical therapists should understand the side effects of oral and intravenous dantrolene, which may affect mobilization, ambulation, and exercise. Muscle weakness, disequilibrium, and drowsiness have been reported in subjects taking intravenous dantrolene prophylactically. Allen et al[31] found that prophylactic oral dantrolene caused weakness and drowsiness in some subjects.

Education

Because an acute MH-like syndrome may occur as a result of strenuous exercise, particularly in hot and humid conditions, physical therapists may want to educate people who may be susceptible to MH. Kochling et al believe that "[it] is still a matter of debate whether or not human MH can be triggered by physical or emotional stress."[4(p316)] Some case reports, however, describe athletes with MH who are affected by an MH-like syndrome following exercise.[4,6,17,21,28] In addition, epidemiological studies have revealed that the frequency of exercise-induced symptoms (eg, muscular cramps, pain, stiffness, fever) is greater in individuals who are susceptible to MH than in individuals who are not susceptible to MH.[21,28]

In one report, an athlete was described who, despite adequate hydration and calcium and potassium supplements, was affected by "severe muscle cramping after strenuous exercise in hot, humid weather."[6(p49)] After determining that the athlete had MH, oral dantrolene was prescribed to prevent further muscle cramping.[6] In the event that questions arise regarding the efficacy of oral dantrolene prior to participating in sports, it should be recognized that athletic performance may be negatively affected by dantrolene's effects, leading to muscle weakness.[31] The cost of strength loss versus the benefit of preventing MH-like symptoms would need to be assessed by a physician for each individual's situation.

Exercise-induced rhabdomyolysis is a more severe symptom of MH-like syndromes and has been reported in some athletes with MH following strenuous exercise.[4,21,28] Myoglobinuria is one of the features that helps to differentiate rhabdomyolysis from mild exercise-induced muscle injury. Anyone with the darkened urine indicative of myoglobinuria should seek an immediate medical referral. A myopathy, often related to MH, that causes a predisposition to rhabdomyolysis should be suspected if the serum creatine kinase level exceeds 10,000 U/L after exercise.[21] Serum creatine kinase levels usually return to normal (less than 100 U/L[29]) within 3 to 7 days following a rhabdomyolytic event.[21]

Exercise

Olgetree et al stated, "Little is known about the safety of exercise in malignant hyperthermia-susceptible individuals who are seen with exercise-related symptoms."[6(p51)] Even less is known about the risks and benefits of exercise following an MH reaction. With regard to exercise in the absence of an MH reaction, Abraham et al contended that "Is]port is safe provided heat stroke is prevented"[9(p16)] in individuals with MH. Until further research has been conducted into the effects of exercise in individuals with MH, educating susceptible individuals on both the environmental triggers (strenuous exercise in warm and humid conditions) and the signs and symptoms of a developing MH reaction is essential. Immediate referral to an emergency medical team is warranted when a person has typical signs and symptoms of an MH reaction.

Rehabilitation Following Rhabdomyolysis

A MEDLINE search from 1966 to 1999 (using the key words "rhabdomyolysis," "physical therapy or physiotherapy," and "malignant hyperthermia") revealed no reports on physical therapy rehabilitation following rhabdomyolysis as a consequence of an MH reaction. Therefore, only rehabilitation following exertional rhabdomyolysis is discussed.

A study by Randall et al[29] outlined the rehabilitation of 10 soldiers who had experienced exertional rhabdomyolysis. Rhabdomyolysis resulted after the soldiers performed over 100 push-ups over many hours, including isometric contractions in the "up" position for prolonged periods. In the 24 to 48 hours following this activity, the soldiers "experienced severe pain in the upper extremities, loss of range of motion in one or both arms, and darkening of the urine."[29(p565)] Four of these soldiers were hospitalized due to fear of acute renal failure. Serum creatine kinase levels rose above 20,000 U/L, indicating rhabdomyolysis. Rehabilitation began immediately and progressed from active and gentle passive range of motion, to low-intensity exercise using a stationary cycle modified for the upper extremities, to daily weight training (including push-ups), to modified workouts with their units. At a mean of 24.6 days following the rhabdomyolysis, unmodified workouts began.[29] The authors did not state whether any of the 10 soldiers were susceptible to MH.

Conclusion

Research about physical therapy intervention for individuals with MH is minimal. We believe the following questions need to be answered for individuals with MH in order for them to lead a healthy and active lifestyle:

1. What sports and conditions place these individuals at risk for developing MH?

2. Can individuals with MH be educated to safely perform "at-risk" athletic activities?

3. Should an exercise program be developed for individuals with MH?

4. What would be the benefits of such an exercise program?

5. How do the underlying myopathies of MH affect health and lifestyle?

6. What are the best physical therapy interventions for people with MH following exercise-induced reactions (cramping, pain, stiffness, rhabdomyolysis)?

7. Are modalities safe and useful in individuals with MH?

8. What are the safe progressions back to exercise following an MH reaction (both anesthetic-induced and non-anesthetic-induced)?

In addition, the typical course of recovery following an MH reaction needs to be assessed. Once the signs and symptoms of the recovery period are determined, a physical therapy-based postoperative rehabilitation program could be developed to facilitate the recovery process.

Olgetree et al pointed out an important fact: "Little is known about the safety of exercise in malignant hyperthermia-susceptible individuals."[6(p51)] In addition, little is known about physical therapy interventions for people with MH. We contend that, when working with athletes in the field or educating clients in the clinic, physical therapists should inquire whether they have ever felt ill following exercise or have experienced heat stroke. They should always advise clients to maintain hydration during exercise and avoid hot, humid environments. Asking clients about the presence of darkened urine if they report exercise-induced reactions may assist in the identification of individuals who are susceptible to MH.

References

[1] Sessler DI. Malignant hyperthermia. Acta Anaesthesiol Scand Suppl. 1996;109:25-30.

[2] Allen GC. Malignant hyperthermia: recognition and management of susceptible patients. Curr Opin Anaesthesiol. 1996:9:271-275.

[3] Lynch PJ, Krivosic-Horber R, Reyford H, et al. Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Anesthesiology. 1997;86:620-626.

[4] Kochling A, Wappler F, Winkler G, Schulte am Esch JS. Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care. 1998;26:315-318.

[5] Bourdon L, Canini F. On the nature of the link between malignant hyperthermia and exertional heatstroke. Med Hypotheses. 1995;45: 268-270.

[6] Ogletree JW, Antognini JF, Gronert GA. Postexercise muscle cramping associated with positive malignant hyperthermia contracture testing. Am J Sports Med. 1996;24:49-51.

[7] Allsop P, Jorfeldt L, Rutberg H, et al. Delayed recovery of muscle pH after short duration, high intensity exercise in malignant hyperthermia susceptible subjects. Br J Anaesth. 1991;66:541-545.

[8] Denborough M. Malignant hyperthermia. Lancet. 1998;352: 1131-1136.

[9] Abraham RB, Cahana A, Krivosic-Horber RM, Perel A. Malignant hyperthermia susceptibility: anaesthetic implications and risk stratification. QJM. 1997;90:13-18.

[10] Arrington ED, Miller MD. Skeletal muscle injuries. Orthop Clin North Am. 1995;26:411-422.

[11] Leong P, MacLennan DH. The cytoplasmic loops between domains II and III and domains III and IV in the skeletal muscle dihydropyridine receptor bind to a contiguous site in the skeletal muscle ryanodine receptor. J Biol Chem. 1998;273:29958-29964.

[12] Wagenknecht T, Radermacher M, Grassucci R, et al. Locations of calmodulin and FK506-binding protein on the three-dimensional architecture of the skeletal muscle ryanodine receptor. J Biol Chem. 1997;272:32463-32471.

[13] Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia: important issues for the medical consultant. Med Clin North Am. 1993;77:477-492.

[14] Poels PJE, Gabreels FJM. Rhabdomyolysis: a review of the literature. Clin Neurol Neurosurg. 1993;95:175-192.

[15] Enzmann NR, Balog EM, Gallant EM. Malignant hyperthermia: effects of sarcoplasmic reticulum [Ca.sup.2+] pump inhibition. Muscle Nerve. 1998;21:361-366.

[16] Powers JH, Scheld WM. Fever in neurologic diseases. Infect Dis Clin North Am. 1996;10:45-66.

[17] Dickinson JG. Heat-exercise hyperpyrexia. J R Army Med Corps. 1989;135:27-29.

[18] Moslehi R, Langlois S, Yam I, Friedman JM. Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. Am J Med Genet. 1998;76:21-27.

[19] Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test. The North American Malignant Hyperthermia Registry of MHAUS. Anesthesiology. 1998;88:579-588.

[20] Loke JCP, MacLennan DH. Bayesian modeling of muscle biopsy contracture testing for malignant hyperthermia susceptibility. Anesthesiology. 1998;88:589-600.

[21] Kojima Y, Oku S, Takahashi K, Mukaida K. Susceptibility to malignant hyperthermia manifested as delayed return of increased serum creatine kinase activity and episodic rhabdomyolysis after exercise. Anesthesiology. 1997;87:1565-1567.

[22] Ball SP, Johnson KJ. The genetics of malignant hyperthermia. J Med Genet. 1993;30:89-93.

[23] Ording H. Diagnosis of susceptibility to malignant hyperthermia in man. Br J Anaesth. 1988;60:287-302.

[24] Bendahan D, Kozak-Ribbens G, Rodet L, et al. [sup.31]Phosphorus magnetic resonance spectroscopy characterization of muscular metabolic anomalies in patients with malignant hyperthermia. Anesthesiology. 1998;88:96-107.

[25] Monsieurs K, Heytens L, Kloeck C, et al. Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible individuals assessed by [sup.31]P-MR spectroscopy. J Neurol. 1997;244:651-656.

[26] Maeda H, Iranami H, Hatano Y. Delayed recovery from muscle weakness due to malignant hyperthermia during sevoflurane anesthesia. Anesthesiology. 1997;87:425-426.

[27] Hopkins PM, Ellis FR, Halsall PJ. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet. 1991;338: 1491-1492.

[28] Hackl W, Winkler M, Mauritz W, et al. Muscle biopsy for the diagnosis of malignant hyperthermia susceptibility in two patients with severe exercise-induced myolysis. Br J Anaesth. 1991;66:138-140.

[29] Randall T, Butler N, Vance AM. Rehabilitation of ten soldiers with exertional rhabdomyolysis. Mil Med. 1996;161:564-566.

[30] Wedel DJ, Quinlan JG, Iaizzo PA. Clinical effects of intravenously administered dantrolene. Mayo Clin Proc. 1995;70:241-246.

[31] Allen GC, Cattran CB, Peterson RG, Marcel L. Plasma levels of dantrolene following oral administration in malignant hyperthermia-susceptible patients. Anesthesiology. 1988;69:900-904.

JK Kozack is an undergraduate physical therapist student, School of Rehabilitation Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

DL MacIntyre, PT, PhD, is Assistant Professor, School of Rehabilitation Sciences, University of British Columbia, T325-2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5 ([e-mail]). Address all correspondence to Dr MacIntyre.

Dr MacIntyre provided the idea for this update. Ms Kozack provided writing. Elizabeth Dean, PT, PhD, provided consultation (including review of manuscript before submission).