Malignant hyperthermia

PHARMACOLOGY

Malignant hyperthermia

Learning objectives

Philip M Hopkins After reading this article, you should be able to: C describe the major processes involved in skeletal muscle myoplasmic calcium regulation C list the principal cellular structures implicated in the aetiology of malignant hyperthermia C understand how the pathophysiology of an MH reaction relates to its clinical features C describe the treatment of an MH reaction C describe the principles of the diagnosis of MH susceptibility

Abstract Malignant hyperthermia (MH) is a pharmacogenetic disorder. Indeed, it was among the first group of pharmacogenetic conditions reviewed in the anaesthetic literature. Most patients who are susceptible to MH have no overt manifestations of the condition until they are exposed to the triggering drugs, which comprise the potent inhalational anaesthetics and suxamethonium. There is currently no valid population screening test for MH and the key to avoiding mortality or chronic morbidity rests with anaesthetists recognizing the early features of a developing MH reaction and then intervening appropriately. There are no clinical pathognomonic features of MH but an understanding of the cellular and systemic events underlying the reaction is most useful in making the provisional diagnosis. This article will focus on these pathophysiological mechanisms and the rationale for published management guidelines. As MH is fundamentally a disorder of skeletal muscle calcium regulation it is necessary first to summarize the physiology of skeletal muscle calcium release and reuptake.

release channel of the sarcoplasmic reticulum (SR), the principal intracellular calcium store. The SR calcium-release channel, which is known as the ryanodine receptor protein (RyR, a term coined through the pharmacological agent used to isolate the protein from cell homogenates), becomes activated, enabling calcium ions to be released from the SR, interact with the myofilaments and thus lead to muscle contraction. Calcium ions released into the cytoplasm under physiological conditions are very efficiently removed by reuptake into the SR by the action of an ATP-dependent pump.

Keywords Dantrolene; excitation-contraction coupling; skeletal muscle Calcium release during a malignant hyperthermia reaction The triggering anaesthetics have a direct effect on the DHPR-RyR complex to cause release of SR calcium. This means that a malignant hyperthermia (MH) reaction can develop irrespective of the presence of neuromuscular blockade because action potential generation is not required for the reaction to

Skeletal muscle intracellular calcium release and sequestration Intracellular calcium is the mediator of excitation-contraction (EC) coupling e the process whereby the muscle action potential is transduced into contractile activity.1 The muscle action potential relies on impulses from the motor neurone arriving at the neuromuscular junction. This causes the release of acetylcholine, which binds to postjunctional receptors, thereby causing the opening of the associated ion channel to generate the motor end-plate potential. When the end-plate potential is of sufficient magnitude, voltage-activated sodium channels in the periend-plate sarcolemmal membrane are activated, resulting in the generation of a muscle action potential that spreads across the sarcolemma and also along continuations of the sarcolemma that invaginate the muscle and are known as the t-(transverse) tubules. Within the t-tubular membrane are the voltage-sensing structures of the EC coupling process (Figure 1). These were pharmacologically characterized by their binding affinity to dihydropyridine compounds and hence they are known as dihydropyridine receptors (DHPRs). Unlike the DHPRs found in the heart and vascular smooth muscle, skeletal muscle DHPRs do not function as calcium channels. Rather, the change in conformation they undergo when the t-tubular membrane depolarizes seems to affect principally an intracellular projection of the protein. This in turn causes a change in conformation of the closely apposed large cytoplasmic projection of the calcium-

Structures involved in skeletal muscle excitation-contraction coupling Outside

Inside

DHPR SR

RyR

ATP T-tubule

Mitochondria Contractile apparatus The action potential is sensed by the dihydropyridine receptor (DHPR), causing opening of the ryanodine receptor (RyR) and resultant release of calcium from the sarcoplasmic reticulum (SR). The calcium activates the contractile apparatus before being sequestered by the SR ATP-dependent calcium pump. AP, action potential; ATP, adenosine triphosphate.

Philip M Hopkins MD FRCA is Professor of Anaesthesia at the University of Leeds, UK. Conflicts of interest: none.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:6

AP

Figure 1

263

Ó 2011 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

proceed. When muscle is inactive the closed state of the RyR protein appears to be stabilized by magnesium (Mg2þ) ions. During EC coupling the change in conformation of the DHPR overrides the inhibitory effect of Mg2þ; in MH muscle, the triggering anaesthetics seem to mimic this effect. The calcium ion pore of the RyR remains open in MH individuals in the presence of sufficiently high concentrations (within the clinical range) of triggering anaesthetic. This results in supraphysiological levels of SR calcium release with a compensatory increase in activity of the SR calcium reuptake pump. If SR calcium release is sustained, additional calcium sequestration mechanisms become operational. These include a sarcolemmal ATP-dependent calcium pump and several mitochondrial calcium uptake mechanisms. Indeed the first clinical signs of MH can be apparent before there is any demonstrable increase in intracellular calcium ion concentration, and these signs result from increased utilization of adenosine triphosphate (ATP) by the various calcium pumps. ATP utilization produces ADP, which directly stimulates intermediary metabolism, to increase oxygen consumption and carbon dioxide production and sympathetic stimulation. As intracellular calcium ions increase in the face of maximal calcium sequestration failing to keep pace with calcium release (Figure 2), the contractile myofilaments interact to cause increased muscle tone, utilizing further ATP in the cyclical binding and unbinding of actomyosin and generating heat (muscle contraction is only 15e20% energy efficient). Muscle activity increases the permeability of the sarcolemmal membrane and this is exaggerated in MH where the activity is sustained and uncoordinated: hyperthermia compounds the muscle contraction

and increases membrane permeability. The result is rhabdomyolysis with hyperkalaemia (cardiac arrhythmias) and myoglobinaemia (renal failure). Hyperthermia also directly activates endothelial clotting factors that may initiate disseminated intravascular coagulation (DIC).

Summary of clinical features of an MH reaction The early features result from increased carbon dioxide production (e.g. increasing end-tidal carbon dioxide in mechanically ventilated patients, tachypnoea in spontaneously ventilating patients), increased oxygen consumption and sympathetic stimulation (tachycardia).2 If the reaction is not halted, there will be progressive muscular rigidity, hyperthermia, rhabdomyolysis and DIC. In the very earliest stages, arterial blood gases may reveal an isolated respiratory acidosis, but a mixed respiratory-metabolic acidosis is usually apparent by the time the diagnosis is made. The most frequent exception to this typical pattern of clinical features is when suxamethonium is administered to facilitate tracheal intubation at induction of anaesthesia. In patients susceptible to MH, suxamethonium frequently causes an exaggeration of the degree and duration of the initial spasm of the jaw muscles (masseter muscle spasm) or even generalized muscular rigidity that precedes the metabolic features of the ‘classical’ MH reaction.

Treatment of an MH reaction It is worth re-emphasizing that successful treatment of an MH reaction depends on early diagnosis. This requires an understanding of the nature of the condition and due vigilance during the conduct of every anaesthetic. Once the diagnosis is made, extra assistance should be summoned because a coordinated team approach will lead to the most efficient implementation of the recommended interventions. As many as possible of these interventions should be made simultaneously, rather than in the sequence they must inevitably be described in an article such as this.

Role of calcium in producing the primary features of an MH reaction: metabolic stimulation, excessive contractile activity, heat and rhabdomyolysis Extracellular

Measures to halt the MH process Remove triggering drugs e administration of potent inhalational anaesthetics should be discontinued by turning off the vaporizer, and elimination accelerated by application of increased minute ventilation using high flows of 100% oxygen through a non-rebreathing circuit. Cooling e In addition to preventing the adverse consequences of hyperthermia per se, reducing the body temperature appears to have a direct effect in limiting the MH reaction. Indeed, in a study of the porcine model of MH, cooling the animals to below 35 C before administration of triggering anaesthetics delayed or even prevented the onset of MH. The exact cooling techniques used will depend on the equipment available, but the loss of heat is aided by the avoidance of measures that will cause generalized vasoconstriction and by maintaining intravascular hydration. Dantrolene sodium is the only licensed therapeutic agent with efficacy in the management of MH.3 It is a lipophilic hydantoin derivative that is prepared in vials containing 20 mg dantrolene powder and 3 g mannitol to aid water solubility. To prepare for intravenous administration each 20 mg needs to be solubilized in 60 ml water: mixing of the drug is slow and at least one member of the team should have the dedicated role of preparing dantrolene for

Cell membrane Cytoplasm Heat

+

K+ Myoglobin Glucose

+ Ca

+

2+

+

ATP

ATP

SR

ADP

+

Pyruvate

Krebs cycle

ADP, adenosine diphosphate; ATP, adenosine triphosphate; MH, malignant hyperthermia; SR, sarcoplasmic reticulum. Figure 2

ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:6

264

Ó 2011 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

administration. The initial aim of dantrolene therapy should be to administer 2.5e3.0 mg/kg as rapidly as possible. If there is not a progressive fall in core temperature, decreasing heart rate and evidence of reduced carbon dioxide production within 5 minutes of the initial dose, a further 1 mg/kg dantrolene should be administered and repeated every 5 minutes until there is a response. The site of action of dantrolene has been much debated in the literature. An important binding site on the RyR protein has been identified, although other evidence suggests dantrolene may also exert effects on other proteins involved in skeletal muscle calcium regulation. Once treatment has reversed the adverse trends, further dantrolene should not be given unless recrudescence of MH occurs, so as to limit the side effects of dantrolene (especially weakness, dizziness, nausea) and to avoid hypothermia. The elimination half-life of dantrolene is 10e12 hours, and therapeutic concentrations are maintained after initial intravenous dosing probably for 4e5 hours, although some of the metabolites are also active. Recrudescence of MH is associated with the most severe cases and may also be associated with those patients with a large muscle mass: it invariably occurs within 12 hours of the initial reaction.

Cardiac arrhythmias were such a common feature of early reports of MH that some workers considered heart muscle to contain the MH defect in addition to skeletal muscle. We now know that there are distinct RyR protein isoforms in cardiac and skeletal muscle, and that arrhythmias occur secondary to the metabolic disturbance and increased sympathetic outflow. In addition to correcting the underlying metabolic abnormalities, the choice of anti-arrhythmic should be based mostly on standard protocols for the specific arrhythmia identified. The main exception to this is a recommendation that calcium-channelblocking drugs should be avoided as there are reports from animal work that the combination of verapamil and dantrolene can have a marked negative inotropic effect.

Diagnostic testing for MH susceptibility The implications of a diagnosis of MH susceptibility for the individual patient and their family are such that confirmation of a provisional clinical diagnosis is almost always warranted. Currently the only sufficiently sensitive tests (>99% sensitivity) involve in vitro pharmacological challenge of muscle bundles excised at open muscle biopsy. Although these tests are conceptually straightforward, they are conducted in dedicated laboratories because of the quality control required. The basis of the tests is that the drugs used (halothane and caffeine, applied in separate tests) cause muscle contracture in MH muscle at lower concentrations than in normal muscle.

Treatment of the effects of MH Hypoxaemia and acidosis e hyperventilation with 100% oxygen has already been mentioned. In the presence of profound acidosis, which should be anticipated, administration of sodium bicarbonate is useful. Hyperkalaemia e in the presence of life-threatening arrhythmias associated with hyperkalaemia, intravenous calcium chloride should be administered despite the possibility that entry of extracellular calcium down an increased concentration gradient into store-depleted skeletal muscle may exacerbate the MH reaction. Otherwise, measures to promote movement of potassium into cells (sodium bicarbonate, glucose and insulin) should be used to control hyperkalaemia. If these measures fail to maintain safe serum potassium concentrations, haemodialysis may be necessary. Myoglobinaemia e the mechanisms of myoglobin-induced renal damage are not fully elucidated, but there appear to be contributions from renal vasoconstriction, direct toxicity from lipid peroxidation and tubular obstruction. There is evidence that urine alkalinization limits lipid peroxidation and tubular aggregation. In MH, an alkaline diuresis should be established and maintained unless it can be confirmed that significant rhabdomyolysis has not occurred. The goals of therapy are to produce a urine output of 2e3 ml/kg/hour and a urinary pH of greater than 7.0. Crystalloid, bicarbonate and mannitol infusions are recommended. Disseminated intravascular coagulation e clotting studies should be ordered on diagnosis of MH, but the presence of DIC invariably becomes apparent clinically before the results of investigations are available. DIC is a poor prognostic indicator in MH and treatment should be aggressive and empirical, using cryoprecipitate, platelets and fresh-frozen plasma.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:6

Prospects for tests using DNA The genetics of MH are more complicated than initially assumed. Although the inheritance appears to follow an autosomal dominant pattern in most MH families, several genes are implicated. The most important of these is the RYR1 gene that encodes the skeletal muscle RyR isoform. More than 180 RYR1 variants have been identified but these may account for only 75% of cases. Furthermore, in at least 5% of these cases there appears to be another factor contributing to the MH phenotype. In most of the approximately 25% of MH cases where RYR1 is not involved the gene, or genes, involved have not been identified. We are still, therefore, some way off from the prospect of DNA-based routine preoperative screening for MH risk. In the meantime, in families where a RYR1 mutation has been identified, testing for this mutation has a role in limiting the number of individuals who require the traditional tests on muscle biopsy tissue. A

REFERENCES 1 Hopkins PM. Skeletal muscle physiology. Cont Educ Anaesth Crit Care Pain 2006; 6: 1e6. 2 Hopkins PM. Malignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth 2000; 85: 118e28. 3 Krause T, Gerbershagen MU, Fiege M, et al. Dantrolene e a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004; 59: 364e73.

265

Ó 2011 Elsevier Ltd. All rights reserved.