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Department of Anesthesiology - Residents Section
Anesthesia Knowledge - Malignant Hyperthermia
Pathophysiology, Molecular Biology, Genetics, Dantrolene
Malignant hyperthermia is a myopathy, usually subclinical, that features an acute loss of control of intracellular calcium (Ca2+ ). Normally, the wave of depolarization from end plate to transverse tubule (T tubule) is transferred to the sarcoplasmic reticulum (SR), resulting in release of Ca2+. The dihydropyridine receptor (DHPR), which is located in the wall of the transverse tubule, functionally couples the T tubule membrane to the SR membrane. A physical link between DHPR and Ry1 is thought to transmit a signal across the triadic junction to promote the release of Ca2+ necessary to activate the contractile apparatus. The free ionized unbound intracellular Ca2+ concentration within the muscle cell increases from the relaxed level of 10-7 M to about 5 - 10-5 M. This increase in Ca2+ removes the troponin inhibition from the contractile proteins, resulting in muscle contraction. The intracellular Ca2+ pumps rapidly transfer Ca2+ back into the SR, and relaxation occurs when the concentration is restored to less than mechanical threshold. Both contraction and relaxation require adenosine triphosphate (ATP) (i.e., both are energy-related processes that consume ATP)
The clinical and laboratory data in swine and humans indicate decreased control of intracellular Ca2+, resulting in a release of free unbound ionized Ca2+ from storage sites that normally maintain muscle relaxation. Aerobic and anaerobic metabolism increases to provide more ATP to drive the Ca2+ pumps that maintain Ca2+ homeostasis across the sarcolemma into extracellular fluid and into the SR and mitochondria. Virtually all of these reactions are exothermic, that is, they produce heat. Rigidity occurs when unbound myofibrillar Ca2+ approaches the contractile threshold. Dantrolene is therapeutic because it reduces Ca2+ release from the SR without altering Ca2+ reuptake.
Figure 27-1 The key ion channels involved in neuromuscular transmission and excitation contraction coupling. Nerve impulses arriving at the nerve terminal activate voltage-gated Ca2+ channels (1). The resulting increase in cytoplasmic Ca2+ is essential in exocytosis of acetylcholine. Binding of acetylcholine to postsynaptic nicotinic cholinergic receptors activates an integral nonselective cation channel, which depolarizes the sarcolemmal membrane (2). Depolarizing the sarcolemma to threshold activates voltage-gated Na+ channels (3), which propagate action potential impulses deep into the muscle via the transverse tubule system. Within the transverse tubule system, L-type voltage-gated Ca2+ channels sense membrane depolarization and undergo a conformational change (4). A physical link between the a1-subunit and the ryanodine receptor is thought to transfer the signal to sarcoplasmic reticulum to induce the release of stored Ca2+ (5).
The onset of MH can be acute and rapid, particularly during induction of anesthesia with an inhaled anesthetic or with the use of SCh. On rare occasions, the onset can be delayed for some hours and may not become overt until the patient is in the recovery room. Regardless of the time of onset, once initiated, the course of MH can be extraordinarily rapid. When clinical signs, such as increased expired carbon dioxide, muscle rigidity, tachycardia, and fever, suggest the presence of MH, the association is not strong unless more than one abnormal sign is noted. When there is but a single suggestive adverse sign, the diagnosis is usually not MH.
The volatile anesthetics and SCh cause affected subjects to undergo a striking increase in metabolism, both aerobic and anaerobic, resulting in intense production of heat, carbon dioxide, and lactate and an associated respiratory and metabolic acidosis. ,  These reactions markedly alter whole-body acid-base balance and temperature because of the large proportion of skeletal muscle to body weight (40-50%) and are magnified as temperature increases. Whole-body rigidity occurs in almost all pigs and in most humans. Temperature may exceed 43°C (109.4°F), PaCO2 may exceed 100 mm Hg, and pHa may be less than 7.00. Associated with this is increased permeability of muscle with increased serum levels of potassium, ionized calcium, CK (although MH-related changes do not differ overall from CK changes observed during surgery  ), myoglobin, and serum sodium.  Later, serum potassium and calcium levels decrease; muscle edema may occur. Sympathetic hyperactivity occurs early as a sign of increased metabolism (tachycardia, sweating, hypertension). With metabolic exhaustion, cellular permeability in general may increase, with whole-body edema, including acute cerebral edema. As MH progresses, disseminated intravascular coagulation and cardiac or renal failure may develop. MH is a disorder of increased metabolism — it need not involve increased temperature, for example, if heat loss is greater than production, or if cardiac output plummets early.
The clinical MH syndrome can occur as a "final common path" in situations that may not involve susceptibility to MH. This is somewhat analogous to observing Raynaud's phenomenon in the absence of Raynaud syndrome. Examples include exaggerated heat stroke, the neuroleptic malignant syndrome (NMS), thyroid storm,  diabetic coma,  alcohol therapy for limb arteriovenous malformation,  free blood in cerebrospinal fluid, ,  hypokalemic periodic paralysis,  and various myopathies involving constantly and precariously altered permeability of cellular membranes and intracellular organelles, such as Duchenne's muscular dystrophy. 
Anesthetic drugs that trigger MH include halothane, enflurane, isoflurane, desflurane, and sevoflurane, as well as SCh. The onset may be explosive if SCh is used. Inbred susceptible swine are identified predictably during an inhalation induction with a potent volatile anesthetic; they develop pronounced hindlimb rigidity within 5 minutes. Prior exercise even an hour before induction of anesthesia - increases the severity and hastens the onset of these attacks in swine. Mild hypothermia, depressants such as barbiturates and tranquilizers, and nondepolarizing relaxants delay the onset of MH. , , 
Susceptible humans respond less predictably than swine to these triggers. Many affected humans have previously tolerated potent triggers without visible difficulty.  This unpredictability might in part be related to the delaying effects described earlier, as well as to the brevity of short-duration anesthetics. Some patients have experienced MH episodes during anesthesia that did not involve recognized triggering agents  ; fortunately, all have responded appropriately to dantrolene. Obviously, the mechanism of anesthetic triggering in humans is unsolved.
Succinylcholine has several variant responses that can occur singly or in combination: (1) a muscle contracture, also noted in muscle that is myotonic or denervated 81 ; (2) a change in muscle membrane permeability without contracture, resulting in the release of CK and myoglobin from muscle (even in normal patients, SCh releases CK and myoglobin from muscle in small amounts; this is exaggerated in the presence of halothane and attenuated by curare,  and myoglobin release can be fairly marked even in the absence of obviously discolored urine  ); and (3) an increase in metabolism, as in MH, usually associated with both muscle contracture and increased membrane permeability. 
Nitrous oxide has been proposed as a weak trigger of human MH.  This is most unlikely because it has been used repeatedly as the basic anesthetic in MH-susceptible humans and swine without triggering MH. Hyperbaric nitrous oxide does not produce MH in susceptible swine, even in concentrations causing apnea. 89
Nondepolarizing muscle relaxants block the effects of SCh in triggering MH. They attenuate the effects of the volatile anesthetics. ,  d-Tubocurarine has been incriminated as an MH trigger because it produced fever in two susceptible children.  d-Tubocurarine has been associated with greater lactate production in susceptible pigs exposed to environmental stress,  but it has not been shown to be a trigger of MH in susceptible swine; it does produce a contracture in denervated muscle, suggesting that it may have a mild depolarizing action that is not apparent under usual conditions.  Reversal of a nondepolarizing neuromuscular blockade has been performed without untoward events in humans with MH susceptibility.
Episodes of MH have been reported during various operative procedures, with general or regional anesthesia, and in extremes of ages. Although rare, prolonged and recurrent MH can still occur despite the absence of triggering agents.  Prior fever or SCh-induced trismus should not be ignored, even if the patient survived without obvious mishap.  The youngest probable case of MH involved an episode of SCh-related muscle rigidity occurring in utero just before birth.  Presumably, the fetus inherited susceptibility from his father that was triggered by anesthetic agents given to his mother.
Volatile agents reportedly stimulate MH Ca2+ release in site-specific channel gating actions that occur at lower concentrations than in normal muscle, and perhaps even at subclinical concentrations (see Pathophysiology). It was previously believed that amide local anesthetics, such as lidocaine, could trigger MH. However, the evidence for this effect is weak. Animal data demonstrating Ca2+ release from the SR by amide anesthetics involve millimolar concentrations, which can only be achieved clinically by doses of about 2 g.  MH is not triggered in the most susceptible species, inbred swine, even if enormous doses of lidocaine are administered intravenously. It is ironic that Kalow et al 6 first commented about the possible efficacy of intravenous local anesthetics in treating MH, when one of the two cases the investigators were referring to involved treatment with intravenous lidocaine. Finally, amide anesthetics are now routinely used without untoward events for nerve block anesthesia in susceptible patients undergoing muscle biopsy.
It has been suggested that long-term propofol infusions in pediatric intensive care may induce MH-type reactions.  However, propofol has been demonstrated as safe in patients with MH syndrome,  and its effects on membranes of MH-affected skeletal muscle are stabilizing and opposite to those of volatile triggers.