Muscle physiology

Normal Muscle Physiology

The propagation of an action potential down a motor nerve fiber produces depolarization of that fiber and release of acetylcholine (ACh) at the neuromuscular junction. When two molecules of ACh interact with the ACh receptor, the channel opens, allowing sodium to enter the cell and potassium to flow out. This initiates a wave of depolarization along the muscle cell membrane or sarcolemma. The propagated depolarization wave spreads internally via transverse tubules that abut onto the sarcoplasmic reticulum (SR) (Fig. 37-1). The SR is an internal cellular structure and a major storage site for calcium ions. The wall of the transverse tubule contains the dihydropyridine receptor, a voltage-dependent calcium channel that interacts with the calcium-sensitive ryanodine receptor (RYR), the footplate between the transverse tubule and the SR. Within a voltage window, calcium is released from the SR (Melzer and Dietze, 2001) into the sarcoplasm through RYR type 1 (RYR1). Increased calcium in the sarcoplasm also induces further calcium release from the SR.

FIGURE 37-1 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; modified from Peachey LD: The sarcoplasmic reticulum and transverse tubules of the frog’s sartorius, J Cell Biol 25:209, 1965.)

Furthermore, when calcium has been depleted from the SR, a process known as store-operated calcium entry (SOCE) allows calcium entry into the sarcoplasm from the extracellular milieu (Fig. 37-2) (Zhao et al., 2006). Excitation-coupled calcium entry (ECCE) refers to the process by which extracellular calcium enters the sarcoplasm through the plasma membrane after depolarization (Cherednichenko et al., 2004; Lyfenko and Dirksen, 2008). The RYR has influence on both SOCE and ECCE.

FIGURE 37-2 This diagram illustrates movement of calcium through the muscle cell after depolarization of the sarcolemma. Note several processes that contribute to elevation of calcium in the sarcoplasm during excitation-contraction coupling.

(Modified from Parness J et al.: The myotonias and susceptibility to malignant hyperthermia, Anesth Analg 109:1054, 2009.)

Type 1 RYRs are found in all skeletal muscle, smooth muscle, neurons, and B lymphocytes. Type 2 RYRs are found in cardiac muscle, brain, and some hematopoietic cells. Type 3 RYRs are found in skeletal and smooth muscle and to a lesser extent in the brain. The function of RYR1 is modified by other proteins and by the redox state of the cell (Fig. 37-3) (Aracena-Parks et al., 2006; Goonasekera et al., 2007; Durham et al., 2008; Cornea et al., 2009; Protasi et al., 2009).

FIGURE 37-3 This cryoelectron microscopic model illustrates the shape of the ryanodine receptor (RYR1) and indicates areas where two other proteins interact with RYRY1. On the left is a side view of RYR1. The red dashed circle is the FK506 protein-binding site. The dashed blue oval is the approximate binding site of Ca²⁺ calmodulin (CaM) binding, between RYR1 cytoplasmic domains 3 and 8. On the top right is an atomic model of Ca²⁺ CaM in complex with RYR1 amino acids 3614-3640. The lower row is a space filling representation of CaM-RYR1 interaction from the side and from the cytoplasmic face of RYR1.

(From Cornea RL et al: FRET-based mapping of calmodulin bound to the RyR1 Ca²⁺ release channel, Proc Natl Acad Sci USA 106:6128, 2009.)

Calcium released from the SR combines with troponin, allowing cross-bridges to form between actin and myosin filaments and muscle to contract. When the wave of depolarization ceases, calcium ions dissociate from troponin and are removed from the sarcoplasm by adenosine triphosphate (ATP), requiring calcium pumps in the SR and other organelles. Thus, coupling of the excitation of the muscle membrane and contraction of the muscle cell entails changes in intracellular calcium concentration. Calcium increase in the sarcoplasm also initiates the breakdown of ATP and metabolic processes that support the energy needed for muscle contraction (e.g., glycolysis).

Mechanism of Action of Dantrolene

Since dantrolene was introduced in the 1970s, its use has remarkably improved the treatment and survival of patients with MH. It has been claimed that dantrolene inhibits the release of calcium from the SR by limiting the activation of the calcium-dependent RYR1, but more recently it was shown that dantrolene blocks ECCE across the plasma membrane (Fruen et al., 1997; Cherednichenko et al., 2008). 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 who have been given dantrolene have normal neuromuscular transmission and depressed force of muscle contraction. The protective effects of dantrolene against MH require significant depression of the force of contraction (Flewellen et al., 1983). Dantrolene can produce clinically significant weakness and decreased metabolism in normal muscle as well as in MH-susceptible muscle (Flewellen et al., 1983). It can reduce elevated creatine kinase (CK) in diseased muscle, independent of the presence of RYR1 mutations (Bertorini et al., 1991; Kamper and Rodemann, 1992).

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 and 12.1 hours, respectively (Fig. 37-4) (Lietman et al., 1974; Flewellen et al., 1983; Lerman et al., 1989). 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 3 or 4 divided doses administered every 6 hours to adults with MH susceptibility, 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 1 mg/kg of dantrolene every 5 to 7 hours for prophylaxis. Alternatively, pharmacokinetic modeling with parameters derived in adults recommends a continuous infusion of dantrolene (Podranski et al., 2005). 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 37-4 Plasma decay of dantrolene in children.

(From Lerman J et al: 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 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 (Brandom and Carroll, unpublished observations). Weakness induced by dantrolene could compromise the ability to swallow and even necessitate artificial protection of the airway and mechanical ventilation, although this has never been reported in the literature (Flewellen et al., 1983). Intravenous dantrolene should be administered in settings where support of airway and ventilation can be easily provided.

Clinical presentation

The initial clinical signs of an impending episode of MH are nonspecific. The most commonly reported initial signs are hypercarbia, sinus tachycardia, and masseter spasm or jaw rigidity (Larach et al., 2010). Arrhythmias and tachypnea may be present (Box 37-1). Increased or rapidly increasing temperature is often an early sign of MH, and metabolic acidosis is often not observed before treatment of MH (Larach et al., 2010).

Rigidity of the extremities and the entire body are signs of fulminant MH. When MH is fulminant, there is severe metabolic acidosis (base deficit often greater than 8 mEq/L), respiratory acidosis (arterial carbon dioxide tension [Paco₂] of greater than 60 mm Hg), tachycardia with arrhythmias, a rapid increase in body temperature to 39.5° C or greater, hyperkalemia, myoglobinuria, and often, but not always, a marked increase in serum CK (Gronert, 1980; Newmark et al., 2007). 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, help to differentiate fulminant MH from other metabolic crises such as porphyria, thyroid storm, untreated pheochromocytoma, and Ecstasy exposure (Allen and Rosenberg, 1990). Some other conditions that produce signs similar to MH are sepsis, allergic drug reactions, intracranial trauma, and hypoxic encephalitis.

Ideally, MH should be recognized and treated before it becomes fulminant. Treatment is more likely to be successful the earlier it is started, but because the signs of MH are not highly specific it is difficult for anesthesia practitioners to distinguish between early MH and many other complications. If there are 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), yet evidence is later obtained that the patient is indeed susceptible to MH, this constellation of clinical findings could be called abortive MH. In such cases, masseter spasm may or may not occur (Ellis et al., 1990). There may be a moderate increase in CK and serum myoglobin. When considering the implications of these tests, note that myoglobin appears in the plasma within minutes of muscle injury by succinylcholine. However, CK continues to increase for 8 to 20 hours after a transient injury, even in patients who are not susceptible to MH (Florence et al., 1985). The incidence of abortive MH is as high as 1:4200 anesthesias when succinylcholine is used in combination with potent inhalation anesthetics (Ording, 1985). However, in the first decade of the 21st century, the incidence of MH cases identified by hospital discharge diagnosis codes was estimated to be about 1:100,000 anesthesias (Brady et al., 2009).

The diagnosis of MH may be mistakenly applied to patients suffering hyperkalemic cardiac arrest or sudden exacerbation of chronic rhabdomyolysis, which has occurred in pediatric patients after the administration of succinylcholine (Kovarik and Morray, 1995; Larach et al., 1997; Piotrowski and Fendler, 2007). In this condition, the sudden severe increase in plasma potassium can be fatal, but metabolic abnormalities are secondary to cardiac failure and not increased metabolism in skeletal muscle, as in MH (Delphin et al., 1987; Rosenberg and Gronert, 1992; Tang et al., 1992; Larach et al., 2001).

In a group of 48 children, 17 of whom later proved to be susceptible to MH 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). However, 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 is not an absolute predictor of MH susceptibility. Three of 24 patients, who were referred for muscle-contracture testing to evaluate MH susceptibility and 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, and increase in tension of the masseter muscle may be observed in the normal pediatric patient who is given halothane or sevoflurane and succinylcholine (Van der Spek et al., 1987; 1988; Lanier et al., 1990). Larach and others (1987) could not identify the patient with MH susceptibility on the basis of these signs (Hackl et al., 1990). Therefore, when MH is suspected clinically, after treating the patient arrangements should be made for confirmatory testing (see related sections in this chapter).

If events during the induction of anesthesia require explanation beyond light anesthesia, transient rigidity and tachycardia during inhalation of sevoflurane, or hypoventilation, further investigation to rule out the diagnosis of MH must be undertaken immediately, before surgery begins. The anesthesiologist must document the presence of increased metabolic rate, rather than the decreased metabolic rate that usually follows induction of anesthesia. Venous or arterial blood should be obtained for measurement of partial pressure of carbon dioxide [Pco₂], lactate, potassium, and CK. Mixed venous blood is most likely to show significant alterations in Pco₂, but it may not be readily available (Gronert and Theye, 1976a, 1976b). 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 Pco₂ and worsening base deficit before these changes are found in arterial blood. Increasing end-tidal carbon dioxide concentrations, particularly with increased minute ventilation, supports the presumptive diagnosis of MH. 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. With anesthesia techniques common in the 21st century, MH may not be recognized until the second or third hour of anesthesia. MH may first be recognized in the postoperative recovery room. Fatal MH can occur without exposure to anesthetics (Brown et al., 2000). Once a hypermetabolic state is recognized, appropriate actions must be taken without delay, as described later.

Masseter spasm

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 et al., 1987, 1988). 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 muscle rigidity and trismus. In masseter muscle rigidity, the mouth cannot be fully opened even with firm pressure on the incisors, but the mouth can be opened far enough to permit intubation of the trachea. In trismus, the mouth cannot be opened enough to permit intubation of the trachea. Using these definitions, Hannallah and Kaplan (1994) noted rigidity in 0.2% of 500 children anesthetized with halothane and administered succinylcholine, but none of these 500 patients experienced trismus. It may be that the several-fold greater incidence of masseter spasm noted in the 1980s included 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. 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 and in cases in which it was not observed. It may be that when masseter spasm is accompanied by rigidity of the entire body, MH is 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; Plumley et al., 1990). Increase in masseter muscle tension occurs in normal mammals after the administration of succinylcholine with 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; Takamatsu et al., 1996). Masseter spasm 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 when the clinical presentation of MH is 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 (O’Flynn et al., 1994).

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 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 units/L were observed in many. However, there were 11 children who experienced generalized rigidity in combination with masseter muscle spasm. Anesthesia was aborted for four of these children and continued without inhalation agents in three of the children. 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 CK was 40,000 IU. Nine years later, this healthy adolescent had completed extensive evaluation for neuromuscular disorders, including in vitro testing for MH with the caffeine-halothane contracture test (CHCT). The patient and family remained without signs, symptoms, or diagnosis of any myopathy. If this patient had been labeled as susceptible to MH, it would have been a misdiagnosis. 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; however, if rigidity does not abate when deep neuromuscular block was produced with nondepolarizing blockers, muscle must be abnormal. Either fulminant MH is occurring or the patient may have occult myotonia (Neuman and Kopman, 1993).

Inhalation anesthesia without succinylcholine was associated with fewer episodes of both fulminant (2 vs. 8) and abortive (17 vs. 110) MH than was succinylcholine with potent inhalation anesthetics in a Danish population (Ording, 1985). Thus, avoiding succinylcholine administration to pediatric patients anesthetized with 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, strong indications for this drug have been identified.

Treatment of an acute episode of malignant hyperthermia

When the diagnosis of MH is 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 several-fold with 100% oxygen at the highest possible flow rate, check core temperature, and alert the surgeon that the procedure must be concluded promptly. Other anesthesiologists, paramedical personnel, or both should be called in at once for assistance. If core temperature is higher than 39° C, cooling measures should be applied until temperature is below 38° C (see www.mhaus.org).

Dantrolene must be diluted with sterile, preservative-free, distilled water that should be stored in large quantities with the drug (Table 37-1). 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. New formulations of dantrolene may go into solution faster than did dantrolene manufactured before 2008. The initial intravenous dantrolene dose should be 2.5 mg/kg, although more than 10 mg/kg may be needed to control the episode (Larach et al., 2010). Repeated dosing 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, tachycardia and stiffness have resolved. The usual upper limit of 10 mg/kg may be exceeded as necessary. The most common side effects of this drug are muscle weakness and phlebitis.

TABLE 37-1 Drugs and Dosages Used to Treat an Acute Episode of Malignant Hyperthermia

* 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 all signs of MH, including muscle stiffness, have abated and creatine kinase has decreased consistently. If the patient is metabolically stable, vital signs are normal, and muscle weakness is present, the interval between dantrolene doses can be increased to 8 hours.

The anesthesia machine need not always be switched to a standby unit that has been kept free of inhalation anesthetics. However, because of both the increased internal gas volume of and the increased anesthetic solubility in modern anesthesia work stations, more time may be required to eliminate traces of anesthetic. For example, over 100 minutes of 10 L/min fresh gas flow (10 L/min FGF) was needed to reduce residual inhalation anesthetic to 5 ppm in the Drager Fabius anesthesia machine, whereas after 20 minutes residual sevoflurane was less than 5 ppm in the Drager Narcomed GS machine (Gunter et al., 2008; Whitty et al., 2009). Isoflurane washout can require more than 45 minutes of 10 L/min FGF in the Drager Primus machine, more than 50 minutes in the Datex-Ohmeda machine, and more than 75 minutes in the Aestiva machine (Crawford et al., 2007; Birgenheier et al., 2009). If the carbon dioxide absorber and circuit tubing are not changed, 30 minutes of 10 L/min FGF is needed to reach 2 ppm isoflurane in the Datex-Ohmeda work station (Schonell et al., 2003). In summary, replacement of all exposed elements, including the ventilator diaphragm and breathing system with autoclaved or new parts, provides the fastest preparation of the anesthetic work station without the addition of charcoal filters. Continuation of 10 L/min FGF for the duration of the anesthesia has been recommended to avoid increasing concentrations of agent (Crawford et al., 2007; Whitty et al., 2009). If MH occurs after the first hour of exposure to an inhalation anesthetic, there is a substantial volume of the anesthetic trigger agent in the patient’s body. It is likely that placement of a charcoal filter on the inspiratory limb of the anesthesia circuit and administration of 10 L/min FGF could greatly speed elimination of potent anesthetic from the breathing circuit (Gunter et al., 2008; Birgenheier et al., 2009.)

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). Furthermore, a temperature that is higher than normal may accelerate an MH episode in humans, as has been observed in animals (Chelu et al., 2006; Dainese et al., 2009). Drapes should be removed, heated humidifiers and hot air blowers should be turned off, and water mattresses should be turned to cooling temperatures. Room temperature normal saline solution should 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.

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 allows 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 of the patient’s acid-base status than arterial blood. 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.

Hyperkalemia results when cell membranes are disrupted and when acidosis is severe. This is recognized on the electrocardiogram as increased T-wave amplitude in the early stages and later by widening QRS complexes, intraventricular conduction delays and blocks, and finally no organized rhythm at all. Intravenous calcium is appropriate emergency treatment of the hyperkalemia associated with MH (Gronert et al., 1986). Glucose and insulin (10 units of 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.

Large losses of intravascular volume should be anticipated; evaporative loss of fluid may be great, and edema formation may occur in muscles 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. Alkaline osmotic diuresis is induced by mannitol in the current formulation of dantrolene (150 mg of mannitol/mg of dantrolene in Dantrium). This protects renal tubule function in the presence of myoglobinuria and promotes acute intravascular volume loss. The management of the acute MH episode is summarized in Box 37-2.

Because calcium channel blockers might interfere with excitation-contraction coupling and conserve energy reserves, it is reasonable to ask what effects such drugs might have on MH-susceptible muscle (Lynch et al., 1986). Not all calcium channel-blocking drugs have the same effects in subjects with MH susceptibility. Diltiazem inhibits halothane-induced contracture in MH-susceptible pig muscle, thus confirming a single similar observation in human muscle (Illias et al., 1985). Verapamil, however, is not a therapeutic agent in porcine MH (Gallant et al., 1985). Furthermore, verapamil and dantrolene can 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 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 have been recommended (Lynch et al., 1986; Rubin and Zablocki, 1987).

Prophylactic management

Indications for Muscle Biopsy and Genetic Evaluation of Type 1 Ryanodine Receptor

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 and CHCT. Others prefer to advise that this invasive test be performed only when the predictive value of the test is likely to be helpful for patient management. The CHCT is currently the only method that can rule out MH susceptibility. The Clinical Grading Scale (CGS) was developed using the Delphi process to provide clinical definition of a case that is almost certain to be MH for the purpose of defining the diagnostic criteria of the CHCT (Larach et al., 1994). Box 37-1 contains many of the elements of the CGS. The five processes evaluated by the CGS (rigidity, muscle breakdown, respiratory acidosis, temperature increase, and cardiac involvement) each contribute a limited number of points to the score. Scores are further divided into categories of likelihood of the patient having MH. Category 6 is almost certain MH; category 5 indicates that MH is very likely; category 4 means that MH is somewhat greater than likely; category 3 indicates that MH is somewhat less than likely; category 2 implies that MH is unlikely; and in category 1, the chance of a patient having MH is almost none. If the total score of the CGS is 50 or more, the case is category 6, almost certain to be MH. If the score is between 35 and 49 the case is category 5, very likely to be MH. The CGS must be applied with medical judgment to estimate the probability that a given anesthesia event was MH. It is important to document the adequacy of minute ventilation when interpreting carbon dioxide tensions. Increased minute ventilation may be the only sign of MH. This produces a category 3 score on the CGS, indicating that MH is somewhat less than likely and might suggest that further testing is not warranted. However, if the anesthesiologist feels that carbon dioxide production was increased and this was reversed by elimination of potent anesthetic, the patient should be referred for testing of MH susceptibility. On the other hand, a child who has sepsis with cerebral palsy, or one of many other medical conditions, may have a high score on the CGS. Referral of a patient whose illness is explained by other processes for evaluation of MH susceptibility would be a costly waste of effort.

A new benefit of undergoing CHCT is that patients with contracture tests indicating MH susceptibility are candidates for genetic study. Initial studies of the RYR1 gene in these subjects with MH susceptibility were limited to the three hot spots in RYR1. However, as a larger proportion of the RYR1 gene is studied, the percentage of patients who have MH susceptibility with RYR1 mutations or variants of unknown significance (VUS) has increased to 50% or more (Robinson et al., 2003; Sambuughin et al., 2005; Ibarra et al., 2006; Levano et al., 2009). 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) after an RYR1 mutation has been identified in the proband. Because fewer than 50% of all people who undergo contracture testing may be diagnosed as susceptible to MH by this test, if evaluation of MH status begins with screen of RYR1, the yield of positive diagnoses will be low (Girard et al., 2004).

A panel of 17 RYR1 exons, encompassing all the acknowledged MH mutations, is available as a clinically useful genetic test of MH susceptibility (Sei et al., 2004) (see www.mhaus.org for the addresses of the diagnostic laboratories). It may detect a RYR1 abnormality in about 30% of North American patients who would be diagnosed as susceptible to MH by CHCT. With this test, genetic counseling is available at the University of Pittsburgh, Center for Medial Genetics (800-54-8155). It is expected that genetic testing of MH susceptibility will be less sensitive but also less invasive and less costly than muscle biopsy and CHCT, because the genetics of MH susceptibility is not completely known (Nelson et al., 2004). Therefore, clinical genetic testing is of most value for determining affected family members in a family in which an RYR1 mutation has been found in an individual who experienced severe MH or had a positive CHCT. The incidence of compound heterozygotes is relatively high when the entire RYR1 gene is examined. Therefore, if an individual does not have the familial RYR1 variant, contracture testing must be performed to prove that the patient is not susceptible to MH.

Individuals who have had positive muscle contracture tests after experiencing MH episodes should undergo genetic screening and document the result in the MH Registry (www.mhreg.org; 888-74-7899). If no abnormality is found in the RYR1 gene in such patients, these are important subjects for experimental study of MH genetics.

The sensitivity and specificity of the CHCT have been determined; therefore, general statements about the predictive value of this test can be made (Larach et al., 1992; Larach, 1993; Ording et al., 1997; Allen et al., 1998). The clinician needs to know the predictive value of the test because the clinician can obtain the results of the diagnostic test. Before applying the test, the clinician cannot be sure whether or not the patient really has the disease.

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). The sensitivity of a diagnostic test 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 definition of a positive result of the CHCT was set to make this test sensitive, so that fewer than 1% of the people who would be at risk of MH events would fail to be identified by the CHCT. Therefore, the CHCT could not also be highly specific. To apply Bayes Theorem and estimate the PPV or NPV, given the sensitivity and specificity of the CHCT, a clinician also has to make a decision about the probability that the patient is MH susceptible before the diagnostic results are known (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 37-3).

Box 37-3 Interpretation of a Test

Sensitivity = Pr (T⁺/D⁺): The sensitivity of a test is the probability (Pr) that the test result is positive (T⁺) given that the disease is present (D⁺).

Specificity = Pr (T^–/D^–): The specificity of a test is the probability (Pr) that the test result is not positive (T^–) given that the disease is not present (D^–)

Predictive value of a positive test = Pr (D⁺/T⁺): The predictive value of a positive test, also known as the positive predictive value (PPV), is the probability that the disease is present given that the test result was positive.

Predictive value of a negative test = Pr (D^–/T^–): The predictive value of a negative test, also known as the negative predictive value (NPV), is the probability that the disease is present given that the test result was positive.

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, it is possible to use the test characteristics (sensitivity and specificity) to calculate the predictive value of the CHCT over a wide range of prior probabilities (Fig. 37-5, A and B). For example, if a patient with a history of isolated masseter spasm is thought to have less than a 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 values 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, 1998a; Larach and MacLennan, 1999). The same order of testing is appropriate for genetic analysis.

FIGURE 37-5 A, The y-axis is the PPV of the 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%. B, The y-axis is the NPV of the CHCT. NPV is less altered by specificity than PPV when prior probability is less than 50%. Thus, the NPVs coincide for specificities from 85% to 95%. These two images 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 37-3). 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 susceptible to MH 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 and contracture testing of viable muscle is the only method that can confirm the diagnosis of not MH susceptible. The procedure can be viewed at www.mhaus.org. 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 muscle biopsy for CHCT. In general, children younger than 10 years of age are too young to undergo CHCT. Diagnostic standards were developed in adults.

Parents of an affected child may wish to have a muscle biopsy and contracture test performed (Figs. 37-6 and 37-7 and www.mhaus.org). The relatives of the parent whose findings are negative (assuming autosomal dominant inheritance) can then be reassured, without further testing, that they have no increased risk of MH. Ideally, siblings and first cousins on the affected side should be informed and offered diagnostic testing. Financial and geographic considerations often discourage families in these endeavors. However, the costs are less for genetic testing than for muscle contracture testing. Clinical genetic testing does not require travel to the location of the testing lab, as is necessary for CHCT. At the very least, relatives of an patient with MH susceptibility should be informed about the presence of MH susceptibility in their family and its implications.

FIGURE 37-6 The muscle fiber contraction in response to an electrical stimulus and subsequent relaxation produces a black mark on the polygraph. Time is increasing from left to right. At the arrow, 3% halothane is added to the bath surrounding the fiber. The strength of normal muscle contraction (top) increases, but the muscle still relaxes to baseline. The MH susceptible muscle (bottom) does not relax back to baseline after exposure to halothane. In this case the contracture, the increase in baseline tension is over 2.5 g.

(Courtesy of Dr. Muldoon and the MH Diagnostic Laboratory at the Uniformed Services of the Health Sciences.)

FIGURE 37-7 The muscle fiber contraction in response to an electrical stimulus and subsequent relaxation produces a black mark on the polygraph. Time is increasing from left to right. At the arrows increments of caffeine are added to the bath surrounding the fiber. The strength of normal muscle contraction (top) increases, but the muscle still relaxes to baseline until exposed to 8 mmol caffeine. The MH-susceptible muscle (bottom) does not relax back to baseline after exposure to low concentrations of caffeine. In this case the contracture, the increase in baseline tension is over 0.6 g in the presence of 2 mmol caffeine.

(Courtesy of Dr. Muldoon and the MH Diagnostic Laboratory at the Uniformed Services of the Health Sciences.)

A valuable self-help resource is the Malignant Hyperthermia Association of the United States (MHAUS; PO Box 1069, 11 East State St., Sherburne, NY 13460; fax 1-607-674-7910). This organization offers information, expert consultation and referral, and many useful resources for families and health care providers. The MHAUS 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 (1-800-644-9737). See www.mhaus.org for addresses of the clinical laboratories at which genetic testing and muscle contracture testing are performed.

Anesthesia techniques

Physiologic responses to stress may play a part in the initiation of an episode of MH in humans, as well as in pigs (Gronert and Theye, 1976a, 1976b; Gronert et al., 1980). Anesthesia for the patient who is susceptible to MH 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 (see Table 37-2). 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. In the opinion of some anesthesiologists, preoperative sedation is an important part of the anesthetic management for patients who are susceptible to MH. After placement of an intravenous catheter, anesthesia may be induced with barbiturates or propofol. narcotics, and α₂-agonists (e.g., dexmedetomidine), as indicated by the planned surgery and other characteristics of the patient (Raff and Harrison, 1989; Harrison, 1991). Intramuscular administration of general anesthetics may be an alternative. 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.

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; Shukry et al., 2006). For susceptible patients, there is no absolutely 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 (e.g., 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 patient who is susceptible to MH. Atropine is administered only when there is significant risk of bradycardia. However, some anesthesiologists have found ketamine to be a useful anesthetic in patients who are susceptible to MH.

Monitoring and preparedness to treat acute MH are of the utmost importance. In addition to precordial heart tones, electrocardiogram, blood pressure, minute ventilation, and oxygen saturation, end-tidal oxygen and carbon dioxide concentrations should be monitored. Core temperature should be measured. Arterial and urinary bladder catheters are not needed for all surgery in patients with susceptibility to MH, but they are convenient for repeated blood sampling and close monitoring of hemodynamic stability and urine myoglobin.

It is helpful to keep drugs and supplies to treat MH in a portable container, such as a carry-all or rolling cart that is immediately accessible in the operating room and recovery room and can easily be transported to other areas of the hospital (see Table 37-1). 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 available, and large volumes of normal saline solution should be available in a nearby refrigerator.

Disorders associated with malignant hyperthermia

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, but solid evidence is often lacking (Table 37-3) (Davis and Brandom, 2009). A complete understanding of these syndromes could contribute to understanding the pathophysiology of MH. Although not all myopathic patients are susceptible to MH, the presence of a known or suspected myopathy should alert the anesthesiologist that there may be increased potential for MH susceptibility or anesthesia complications that may mimic MH (Heytens et al., 1992).

TABLE 37-3 Association of Various Diseases with Malignant Hyperthermia

From Davis PJ, Brandom BW: The association of malignant hyperthermia and unusual disease: when you are hot you are hot or maybe not, Anesth Analg 109:1001, 2009.

Many patients with DMD have received potent inhalation anesthetics without occurrence of MH, but dystrophic muscle is fragile and can have RYR1 dysfunction (Peluso and Bianchini, 1992; Bellinger et al., 2009). Even mild exercise in patients with DMD 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, there has been at least one patient who had dystrophinopathy and a negative contracture test, which ruled out MH susceptibility in that patient (Gronert et al., 1992).

Less common than dystrophinopathy, enzyme deficiencies and mitochondrial disease in muscle may also produce rhabdomyolysis, which can be easily exacerbated. Nonspecific signs of MH may occur during anesthesia (Hogan and Vladutiu, 2009). If the patient has a history of recurrent rhabdomyolysis, blood-based genetic testing of carnitine palmitoyltransferase II (CTP2), myophosphorylase (PYGM; deficiency of PYGM is McArdle disease), and myoadenylate deaminase (AMPD1) may determine the cause. When these blood tests are not diagnostic, muscle biopsy may be useful for diagnosis of these enzyme deficiencies as well as deficiencies in the glycolytic pathway and mitochondrial diseases.

Several extensive family studies of central core disease (CCD) have documented morphologically abnormal muscle—i.e., central cores of oddly aligned fibers—in some patients with MH (Shy and Magee, 1956; Byrne et al., 1982; Jeong et al., 2008). CCD is the first myopathy for which a definite link to MH was shown. Multiminicore disease is a different histologic diagnosis that has also been associated with susceptibility to MH and may be related to CCD (Ferreiro et al., 2002; Jeong et al., 2008). Several mutations in RYR1 cause both CCD and MH susceptibility; therefore, it is advisable to treat a patient with CCD as susceptible to MH (Loke and MacLennan, 1998b; Tilgen et al., 2001; Robinson et al., 2006). The risk of MH in CCD, multiminicore disease, and nemaline rod myopathy was recently reviewed by Klinger and colleagues (2009).

Another familial myopathy, the King-Denborough syndrome, is associated with MH susceptibility (King and Denborough, 1973). Affected individuals have proximal muscle weakness, postural imbalances, cryptorchidism, webbed neck, pectus deformities, delayed development, and elevated levels of CK (Jurkat-Rott et al., 2000). Variants in the RYR1 gene have been found in some patients with King-Denborough syndrome.

In the past, other disorders in which patients appeared to have MH susceptibility included myotonia congenita, osteogenesis imperfecta, Schwartz-Jampel syndrome (dwarfism, craniofacial and skeletal abnormalities, blepharophimosis, and muscle stiffness), and possibly arthrogryposis (Fowler et al., 1974; Rampton et al., 1984; 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). A recent review of myotonias concluded that with the exception of hypokalemic periodic paralysis (hypoKPP), the risk of MH in myotonic patients is not increased (Parness et al., 2009). For theoretic reasons, although there are no published case reports of MH-like adverse events in patients with hypoKPP, risk of MH may be increased in this condition. Definitive diagnosis of myotonias and other channelopathies (including MH) should be pursued, because specific treatment may be available (Lehmann-Horn et al., 2008).

The neuroleptic malignant syndrome (NMS) is a potentially fatal disorder recognized by psychiatrists that may clinically resemble MH (Cohen et al., 1985; Guzé and Baxter, 1985; Mann et al., 2003). It occurs in 1:200 patients taking neuroleptic drugs that produce dopaminergic blockade. A 24-hour consultant service is available through the Neuroleptic Malignant Syndrome Information Service (NMSIS; www.nmsis.org; 888-667-8367). Most patients with NMS 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. The manifestations of NMS are altered mental status, hypermetabolism with fever, tachycardia, muscle rigidity, and myoglobinuria. NMS has all of 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 differ from those of MH. Blockade of dopamine receptors can produce hyperthermia and rigidity, and bromoscriptine, (dopamine agonist) as well as dantrolene and benzodiazepines have been used to successfully treat this syndrome (Caroff, 1980; Granati et al., 1983; Heiman-Patterson, 1993). 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. Repeated exposure of pigs with MH susceptibility to a serotonin-2 receptor agonist can also induce typical MH symptoms without causing the same syndrome in normal animals (Gerbershagen et al., 2003). Mann et al. (2003) demonstrated that in humans the serotonin syndrome (tremor, diaphoresis, shivering, and myoclonus in the presence of serotonergic medication) could be elicited easily in individuals susceptible to MH. Dantrolene can delay serotonin-induced contractures (Wappler et al., 1997).

Contracture test

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 and slightly differently in Europe (Larach et al., 1989; Ording and Bendixen, 1992). 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 and halothane alone. Unlike usual concentration-response phenomena, differences between persons susceptible to MH and those who are not do not appear as altered (median effective dose) ED₅₀ or as a change in slope, but as a change in threshold. Patients must travel to the MH diagnostic center where this bioassay can be performed. The muscle strips to be tested must respond with active twitch to electrical stimulation (i.e., they must be viable). The test should be completed within 5 hours of the excision of muscle from the patient’s thigh.

The North American protocol includes exposure of muscle strips to 0.5, 1, 2, 4, 8, and 32 mmol/L caffeine. A positive CHCT is often defined as an increase in tension of 0.2 g in the presence of 2 mmol/L caffeine or less. However, a cutoff of 0.3 g or 0.4 g may be preferred to increase the specificity of the test (Larach, 1989). A positive halothane contracture test is the development of more than 0.2 g to 0.7 g 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 susceptible to 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).

MH is a disorder of muscle that is usually 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 susceptible to MH. If a patient undergoes genetic evaluation before contracture testing and no MH-causative mutation is found, the patient must undergo contracture testing in order to support the diagnosis of not susceptible to MH. All patients should be monitored for signs of MH during anesthesia. Furthermore, MH can occur without the use of triggering drugs such as succinylcholine and potent inhalation anesthetics (Fitzgibbons, 1980; Pollock et al., 1992; Shukry et al., 2006).

Anesthesiologists’ responsibility to other physicians

MH has been known for more than 40 years, yet many primary care physicians, dentists, and surgeons are still unaware of its life-and-death significance. In 1986 the Malignant Hyperthermia Association of the United States published a letter from a parent:

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 and rapid exhaustion after intense exercise; however, individuals susceptible to MS have performed farm labor in the hot sun without precipitating an MH attack (Wappler et al., 2000; Rueffert et al., 2004). Early studies of metabolic responses during noncompetitive, low-intensity, steady-state exercise found no difference between control and patients with MH susceptibility (Green et al., 1987). Slower recovery of muscle pH and phosphocreatine/inorganic phosphate ratios have been observed in patients with MH susceptibility (Allsop et al., 1991; Olgin et al., 1991). Patients who are susceptible to MH should be encouraged to refrain from strenuous exercise if they experience cramps or fever under such circumstances (Davis et al., 2002). Some people with MH susceptibility are unable to sustain exercise in the heat as well as they do in cool environments, and some patients with exertional heat stroke are actually susceptible to MH (Bendahan et al., 2001; Tobin et al., 2001; Wappler et al., 2001). Dantrolene may be therapeutic when these symptoms occur (Gronert, 1980).

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

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 health care providers, affected families, and testing centers in Canada and the United States. This registry provides a database through 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 health care providers have a responsibility to report such cases or suspected cases to the Registry.

Summary

MH is a potentially lethal pharmacogenetic syndrome. It has been of particular concern to pediatric anesthesiologists because succinylcholine and inhalation anesthetics are potent triggers of MH and may be administered often 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 susceptible to MH 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 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.

Acknowledgments

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