Malignant hyperthermia: advances in clinical management and diagnosis

Abstract

Br J Anaesth 2000; 85: 118–28 Malignant hyperthermia (MH) was the name given to a type of severe reaction under general anaesthesia that was first described in 1960.21Denborough MA Lovell RRH Anaesthetic deaths in a family.Lancet. 1960; ii: 45Abstract Scopus (319) Google Scholar Monitoring during anaesthesia at that time was based on clinical observation and physical signs, without the luxury of today's advanced equipment. The apparent features of the reactions were, therefore, dominated by a progressive pyrexia that usually led to death,11Britt BA Gordon RA Three cases of malignant hyperthermia with special consideration of management.Can Anaesth Soc J. 1969; 16: 99-105Crossref PubMed Scopus (28) Google Scholar 19Cullen WG Malignant hyperpyrexia during general anaesthesia; a report of two cases.Can Anaesth Soc J. 1966; 13: 437-443Crossref PubMed Scopus (16) Google Scholar 21Denborough MA Lovell RRH Anaesthetic deaths in a family.Lancet. 1960; ii: 45Abstract Scopus (319) Google Scholar 22Denborough MA Foster JFA Lovell RRH Maplestone DA Villiers JD Anaesthetic deaths in a family.Br J Anaesth. 1962; 34: 395-396Crossref PubMed Scopus (244) Google Scholar hence the name malignant hyperpyrexia or hyperthermia. The ‘malignant’ part of the name MH has proved useful in emphasizing the potentially fatal nature of the reaction. The ‘hyperthermia’ component is, perhaps, less useful because it identifies a relatively late feature of a reaction in which early intervention is important. From this point of view, it might be useful for the anaesthetist to think of MH as ‘malignant hypermetabolism’, because the earliest clinical features (rising end-tidal carbon dioxide concentration and tachycardia) are indicative of the metabolic nature of the reaction. In 1988, a postgraduate educational issue of the British Journal of Anaesthesia33Ellis FR Hopkins PM Halsall PJ Christian AS Masseter muscle spasm and the diagnosis of malignant hyperthermia susceptibility.Anesth Analg. 1992; 75: 143-146Crossref PubMed Scopus (4) Google Scholar was devoted to a series of review articles on the subject of MH. Since then, MH research has benefited from the rapid advances in molecular genetics stemming from development of the polymerase chain reaction.101Mullis KB Faloona FA Specific synthesis of DNA in vitro via a polymerase catalyzed chain reaction.Methods Enzymol. 1987; 155: 335-350Crossref PubMed Scopus (3848) Google Scholar Elucidation of the molecular genetic basis of MH carries the prospect of presymptomatic diagnosis and a complete understanding of the aetiology of the disorder and is likely to contribute to our understanding of skeletal muscle pathology and molecular mechanisms of inhalational anaesthetics. These prospects have, however, been made less tangible by the apparent complexity of the molecular genetics of MH.65Hopkins PM Halsall PJ Ellis FR Diagnosing malignant hyperthermia susceptibility.Anaesthesia. 1994; 49: 373-375Crossref PubMed Scopus (15) Google Scholar 111Robinson R Curran JL Hall WJ et al.Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.J Med Genet. 1998; 35: 196-201Crossref PubMed Scopus (32) Google Scholar Contrary to an earlier view that DNA-based screening could be applied readily,57Healy SJ Heffron JJ Lehane M Bradley DG Johnson K McCarthy TV Diagnosis of susceptibility to malignant hyperthermia with flanking DNA markers.BMJ. 1991; 303: 1225-1228Crossref PubMed Scopus (19) Google Scholar the complexity of the disorder has required a re-examination of the criteria for the clinical diagnosis of MH, refinement of in vitro muscle contracture tests (IVCTs) used for laboratory diagnosis and functional analysis of potential subcellular targets of the MH defect(s).65Hopkins PM Halsall PJ Ellis FR Diagnosing malignant hyperthermia susceptibility.Anaesthesia. 1994; 49: 373-375Crossref PubMed Scopus (15) Google Scholar In this review, I will focus on these aspects of MH, along with developments in the clinical management of MH since 1988. I will not discuss the management of an MH reaction following its diagnosis, as this is essentially unchanged from earlier reviews.33Ellis FR Hopkins PM Halsall PJ Christian AS Masseter muscle spasm and the diagnosis of malignant hyperthermia susceptibility.Anesth Analg. 1992; 75: 143-146Crossref PubMed Scopus (4) Google Scholar MH is a manifestation of exposure of susceptible individuals to triggering drugs. Without such exposure, it is usually impossible to identify the MH-susceptible patient unless there is a personal or family history suggestive of MH. Even then, further questioning about the details of the history will often lead to the exclusion of MH. Various musculoskeletal abnormalities, such as scoliosis, hernias or strabismus, have been associated with MH susceptibility,10Britt BA Preanesthetic diagnosis of malignant hyperthermia.Int Anesthesiol Clin. 1979; 17: 63-96Crossref PubMed Scopus (23) Google Scholar 115Strazis KP Fox AW Malignant hyperthermia: a review of published cases.Anesth Analg. 1993; 77: 297-304Crossref PubMed Scopus (122) Google Scholar but an analysis of >2500 patients tested for MH susceptibility could find no evidence to support such associations.52Halsall PJ Clinical presentation of malignant hyperthermia.in: Hopkins PM Ellis FR Hyperthermic and Hypermetabolic Disorders. Cambridge University Press, Cambridge1996: 107-118Google Scholar In 1988, Brownell concluded that, of the muscle diseases associated with MH, only central core disease appeared to be truly linked.13Brownell AK Malignant hyperthermia: relationship to other diseases.Br J Anaesth. 1988; 60: 303-308Crossref PubMed Scopus (122) Google Scholar More recent studies have indicated that not even this link is consistent.20Curran JL Hall WJ Halsall PJ et al.Segregation of malignant hyperthermia, central core disease and chromosome 19 markers.Br J Anaesth. 1999; 83: 217-222Crossref PubMed Scopus (40) Google Scholar 54Halsall PJ Bridges LR Ellis FR Hopkins PM Should patients with central core disease be screened for malignant hyperthermia?.J Neurol Neurosurg Psychiatry. 1996; 61: 119-121Crossref PubMed Scopus (7) Google Scholar 71Islander G Henriksson KG Ranklev-Twetman E Malignant hyperthermia susceptibility without central core disease (CCD) in a family where CCD is diagnosed.Neuromusc Disord. 1995; 5: 125-127Abstract Full Text PDF PubMed Scopus (13) Google Scholar Some syndromes with features similar to those of MH have been investigated for common aetiology. Neuroleptic malignant syndrome is discussed in the accompanying review by Adnet;5Adnet PJ Lestavel P Krivosic-Horber R Neuroleptic malignant syndrome.Br J Anaesth. 2000; 85: 129-135Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar these patients need not be considered at risk of developing MH under anaesthesia. There is less certainty concerning those with a history of exertional heat stroke or exercise-induced rhabdomyolysis. Our group and others have demonstrated muscle abnormalities similar to those found in MH in some patients with such a history.50Hackl W Winkler M Mauritz W Sporn P Steinbereithner K Muscle biopsy for diagnosis of malignant hyperthermia susceptibility in two patients with severe exercise-induced myolysis.Br J Anaesth. 1991; 66: 138-140Crossref PubMed Scopus (50) Google Scholar 62Hopkins PM Ellis FR Halsall PJ Evidence for related myopathies in exertional heat stroke and malignant hyperthermia.Lancet. 1991; 338: 1491-1492Abstract PubMed Scopus (92) Google Scholar In our cases, the same muscle abnormality was found in relatives, but was probably not identical to that found in MH.62Hopkins PM Ellis FR Halsall PJ Evidence for related myopathies in exertional heat stroke and malignant hyperthermia.Lancet. 1991; 338: 1491-1492Abstract PubMed Scopus (92) Google Scholar There are undoubtedly ‘non-muscle’ causes of heat stroke, such as obesity, concurrent viral illness or recent alcohol consumption,25Dickinson JG Exertional heat stroke: predisposing factors, clinical features, treatment and prevention.in: Hopkins PM Ellis FR Hyperthermic and Hypermetabolic Disorders. Cambridge University Press, Cambridge1996: 20-41Google Scholar but if these are excluded, I would advise that a patient with a history of exertional heat stroke or exercise-induced rhabdomyolysis, especially more than one episode, be investigated for MH. Occasionally, a ‘routine’ preoperative biochemical screen will reveal an increased raised serum creatine kinase concentration in an apparently asymptomatic patient. This could be indicative of MH, but investigation for MH need be done only if more common causes of creatine kinase elevation and uncommon causes requiring less invasive diagnostic techniques than MH (Table 1) are excluded.Table 1Causes of increased serum creatine kinase concentration. These can be divided into ‘identifiable’ and ‘idiopathic’ according to how easy the underlying cause is to diagnose. Hypothyroidism is by far the commonest cause, followed by myopathies‘Identifiable’Hypothyroidism, myopathies, exercise, malignancy (always BB isoenzyme), denervation syndromes, myocardial infarction, rhabdomyolysis (trauma, drugs)‘Idiopathic’Malignant hyperthermia susceptibility, Duchenne dystrophy carriers, idiopathic paroxysmal rhabdomyolysis, haemolytic syndromes, previous neuroleptic malignant syndrome Open table in a new tab There is no clinical feature that is specific for MH. Diagnosis depends on a knowledge of features that can occur during an MH reaction (Table 2), recognition of these features occurring in a pattern (including temporal relationships between individual manifestations) consistent with an evolving MH reaction, and exclusion of other causes of these clinical features (Table 3). Early diagnosis is important, as prompt, appropriate treatment is associated with the best outcome.Table 2Clinical features of malignant hyperthermia. The changes are grouped according to their timing of onset in the reaction. The time periods (early, succeeding and late) cannot be quantified because they vary greatly between patients; they do indicate a consistent temporal relationship in the onset of clinical features. Features in brackets may have their onset at any stage of the reaction. SV=spontaneous ventilationTimingClinical signsChanges in monitored variablesBiochemical changesEarlySustained jaw rigidity after succinylcholineTachypnoea (SV)Increased minute ventilation (SV)Rapid exhaustion of soda limeRising end-tidal carbon dioxideIncreased Paco2Hot soda lime canisterHigh pulse rateTachycardiaDecreased pH(Irregular pulse)(Ventricular ectopics)(Increased [K+])(Peaked T waves on ECG)SucceedingPatient hot to touchRising core body temperatureCyanosisFalling SpoDecreased PaoDark blood in wound(Irregular pulse)(Ventricular ectopics)(Increased [K+])(Peaked T waves on ECG)LateGeneralized muscle rigidityProlonged bleedingDark urineIncreased creatine kinase, myoglobinuriaOliguria(Irregular pulse)(Ventricular ectopics)(Peaked T waves on ECG)(Increased [K+])Death Open table in a new tab Table 3Differential diagnoses of a suspected malignant hyperthermia reactionInadequate anaesthesia or analgesiaInappropriate breathing circuit, fresh gas flow or ventilationInfection or sepsisTourniquet ischaemiaAnaphylaxisPhaeochromocytomaThyroid stormCerebral ischaemiaOther muscle diseases Open table in a new tab (i) Masseter spasm. In the absence of a family history of MH, the first indication that an individual may be susceptible to the condition is the development of an exaggerated initial response to succinylcholine, i.e. an increase in tension of the jaw muscles.17Christian AS Ellis FR Halsall PJ Is there a relationship between masseteric muscle spasm and malignant hyperpyrexia?.Br J Anaesth. 1989; 62: 540-544Crossref PubMed Scopus (34) Google Scholar If sufficiently sensitive measuring equipment is used, jaw stiffness after administration of succinylcholine can be detected in most individuals.81Leary NP Ellis FR Masseteric muscle spasm as a normal response to suxamethonium.Br J Anaesth. 1990; 64: 488-492Crossref PubMed Scopus (53) Google Scholar It is often more pronounced in children.123van der Spek AF Fang WB Ashton-Miller JA Stohler CS Carlson DS Schork MA The effects of succinylcholine on mouth opening.Anesthesiology. 1987; 67: 459-465Crossref PubMed Scopus (73) Google Scholar When the jaw stiffness is severe, and especially when it is prolonged, the condition is called masseter spasm. Doubt has been expressed as to the validity of masseter spasm as an indicator of potential MH susceptibility,86Littleford JA Patel LR Bose D Cameron CB McKillop C Masseter muscle spasm in children: implications of continuing the triggering anesthetic.Anesth Analg. 1991; 72: 151-160Crossref PubMed Scopus (63) Google Scholar 122van der Spek AF Triggering agents continued after masseter spasm: there is proof in this pudding.Anesth Analg. 1991; 73: 364-365Crossref PubMed Google Scholar but this doubt was based on a false premise.33Ellis FR Hopkins PM Halsall PJ Christian AS Masseter muscle spasm and the diagnosis of malignant hyperthermia susceptibility.Anesth Analg. 1992; 75: 143-146Crossref PubMed Scopus (4) Google Scholar 60Hopkins PM Masseter muscle spasm.in: Goldstone JC Pollard BJ Handbook of Clinical Anaesthesia. Churchill Livingstone, London1996: 646-647Google Scholar Interestingly, several of the patients included in the report by Littleford and colleagues86Littleford JA Patel LR Bose D Cameron CB McKillop C Masseter muscle spasm in children: implications of continuing the triggering anesthetic.Anesth Analg. 1991; 72: 151-160Crossref PubMed Scopus (63) Google Scholar have been proven subsequently to be susceptible to MH. A further illustration of the need to consider a patient developing masseter spasm following succinylcholine as potentially susceptible to MH is presented by Ramirez and colleagues.109Ramirez JA Cheetham ED Laurence AS Hopkins PM Suxamethonium, masseter spasm and later malignant hyperthermia.Anaesthesia. 1998; 53: 1111-1116Crossref PubMed Scopus (19) Google Scholar These workers reported the case of a trauma victim in whom tracheal intubation in the accident and emergency department was difficult because of increased resistance to mouth opening following the use of succinylcholine. Anaesthesia was maintained using an infusion of propofol during transfer to the CT scanner and from there to the operating theatre. Once in the operating theatre, for fixation of a humeral fracture, isoflurane was substituted for propofol and subsequently the typical metabolic features of MH developed.109Ramirez JA Cheetham ED Laurence AS Hopkins PM Suxamethonium, masseter spasm and later malignant hyperthermia.Anaesthesia. 1998; 53: 1111-1116Crossref PubMed Scopus (19) Google Scholar (ii) Hypermetabolism. MH occurs because the triggering drugs cause an imbalance in Ca2+ homeostasis within skeletal muscle cells.87Lopez JR Allen PD Alamo L Jones D Sreter FA Myoplasmic free [Ca2+] during a malignant hyperthermia episode in swine.Muscle Nerve. 1988; 11: 82-88Crossref PubMed Scopus (75) Google Scholar 113Ryan JF Lopez JR Sanchez VB Sreter FA Allen PD Myoplasmic calcium changes precede metabolic and clinical signs of porcine malignant hyperthermia.Anesth Analg. 1994; 79: 1007-1011Crossref PubMed Scopus (25) Google Scholar The increased intracellular Ca2+ concentration stimulates metabolism both directly, through activation of phosphorylase to increase glycolysis, and indirectly, because of an increased demand for ATP production. ATPases are important components of myofilament relaxation and the Ca2+ sequestration pumps of the sarcoplasmic reticulum and sarcolemma. Metabolic stimulation leads to increased carbon dioxide production (tachypnoea and increased end-tidal carbon dioxide concentration) and early lactic acidosis (possibly related to acute intracellular inorganic phosphate deficiency). The resulting mixed respiratory and metabolic acidosis stimulates sympathetic outflow, leading to tachycardia. In humans, changes in arterial pressure are not usually marked in the early phases of MH; this may reflect opposing effects of increased sympathetic drive and locally mediated peripheral vasodilation secondary to tissue acidosis. Increasing body temperature is a relatively late indicator of the hypermetabolic response.109Ramirez JA Cheetham ED Laurence AS Hopkins PM Suxamethonium, masseter spasm and later malignant hyperthermia.Anaesthesia. 1998; 53: 1111-1116Crossref PubMed Scopus (19) Google Scholar (iii) Muscle rigidity and breakdown. Generalized muscle rigidity can occur in association with masseter spasm following succinylcholine and usually indicates MH susceptibility.31Ellis FR Halsall PJ Christian AS Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands.Anaesthesia. 1990; 45: 838-841Crossref PubMed Scopus (47) Google Scholar As with masseter spasm, it resolves spontaneously, usually within 5 min. A more insidious development of generalized skeletal muscle rigidity during maintenance of anaesthesia with potent inhalational anaesthetics is a sinister feature of MH. It indicates that the ability of the muscle to produce ATP, a function crucial to the reversal of the MH process even if Ca2+ release can be halted, is almost exhausted. Sustained rigor also restricts the circulation to the muscle beds, resulting potentially in accumulation of toxic metabolic products and heat, and failure of delivery of oxygen and therapeutic agents to the muscle. Evidence of rhabdomyolysis can usually be obtained by measuring serum creatine kinase and urinary (or serum) myoglobin concentrations. The time-course of changes in the serum concentrations of these proteins has been described.80Laurence AS Vanner GK Collins W Hopkins PM Serum and urinary myoglobin following an aborted malignant hyperthermia reaction.Anaesthesia. 1996; 51: 958-961Crossref PubMed Scopus (17) Google Scholar The magnitude of these changes following MH reactions is, however, quite variable. In some cases, the changes may be indistinguishable from those resulting from surgery,79Laurence AS Serum myoglobin and creatine kinase following surgery.Br J Anaesth. 2000; 85: 763-766Crossref PubMed Scopus (61) Google Scholar but in others, especially when succinylcholine and a potent inhalational anaesthetic have been used in combination, the creatine kinase concentration may be a thousand times normal. Rhabdomyolysis also leads to extrusion of K+ from the damaged muscle. Hyperkalaemia and sympathetic stimulation are the main causes of cardiac arrhythmias in MH. The onset of MH varies in its speed. In some cases, metabolic stimulation will be evident clinically within 10 min of the administration of a potent inhalational anaesthetic; in others, several hours may elapse. It is plausible that the speed of onset reflects the rate of increase in intracellular Ca2+ concentration, which will depend on the particular drug used, the concentration of the drug in the muscle and any number of physiological variables that dictate the efficiency of Ca2+ homeostatic processes in the individual. Considered together with the complete range of duration of surgical procedures, this variability in timing of onset and rate of development of MH dictates that a procedure may conclude just before the symptoms of MH become apparent. In this situation, the reaction will progress while trigger drug concentrations in the muscle remain above a threshold value. It is possible that lower concentrations of trigger drugs are needed to maintain a reaction than to initiate it because an increased intracellular Ca2+ concentration stimulates sarcoplasmic reticulum Ca2+ release through the mechanism known as Ca2+-induced Ca2+ release.73Kawana Y Iino M Horiuti K et al.Acceleration in calcium-induced calcium release in the biopsied muscle fibers from patients with malignant hyperthermia.Biomed Res. 1992; 13: 287-297Crossref Scopus (26) Google Scholar 129Yamazawa T Takeshima H Sakurai T Endo M Iino M Subtype specificity of the ryanodine receptor for Ca2+ signal amplification in excitation–contraction coupling.EMBO J. 1996; 15: 6172-6177PubMed Google Scholar Similarly, if very high intracellular Ca2+ concentrations are reached, Ca2+-induced Ca2+ release may sustain an MH reaction even when the trigger drug has been eliminated, especially if Ca2+ sequestration is compromised by a reduced capability for ATP production. This is probably why recrudescence of signs can occur after their initial control. MH reactions that begin soon before or after the end of surgery do, however, present with the same features as intraoperative reactions. This is important because it means that postoperative pyrexia, in the documented absence of tachypnoea, raised end-tidal partial pressure of carbon dioxide and tachycardia, is not indicative of MH.53Halsall PJ Ellis FR Does postoperative pyrexia indicate malignant hyperthermia susceptibility?.Br J Anaesth. 1992; 68: 209-210Crossref PubMed Scopus (21) Google Scholar It is important to stress that MH cannot be excluded as the cause of postoperative pyrexia if records of anaesthesia and the immediate postoperative period do not detail variables indicative of hypermetabolism. Occasionally, no metabolic features of an MH reaction are recognized during the perioperative period (they may, for example, be attributed to sepsis) and the patient will present 2–4 days after the operation in acute renal failure secondary to rhabdomyolysis.12Britt BA Webb GE LeDuc C Malignant hyperthermia induced by curare.Can Anaesth Soc J. 1974; 21: 371-375Crossref PubMed Scopus (20) Google Scholar None of the clinical features of MH is specific to MH (Table 2) and a variety of differential diagnoses exists (Table 3). Several attempts have been made to analyse clinical features of MH reactions for their use in diagnosis.31Ellis FR Halsall PJ Christian AS Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands.Anaesthesia. 1990; 45: 838-841Crossref PubMed Scopus (47) Google Scholar 49Hackl W Mauritz W Schemper M Winkler M Sporn P Steinbereithner K Prediction of malignant hyperthermia susceptibility: statistical evaluation of clinical signs.Br J Anaesth. 1990; 64: 425-429Crossref PubMed Scopus (24) Google Scholar 76Larach MG Rosenberg H Larach DR Broennle AM Prediction of malignant hyperthermia susceptibility by clinical signs.Anesthesiology. 1987; 66: 547-550Crossref PubMed Scopus (17) Google Scholar 78Larach MG Localio AR Allen GC et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology. 1994; 80: 771-779Crossref PubMed Scopus (437) Google Scholar Each of these studies used a different approach and three will be discussed further. Ellis and colleagues,31Ellis FR Halsall PJ Christian AS Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands.Anaesthesia. 1990; 45: 838-841Crossref PubMed Scopus (47) Google Scholar based on a suggestion by Ording and Ranklev (see 52Halsall PJ Clinical presentation of malignant hyperthermia.in: Hopkins PM Ellis FR Hyperthermic and Hypermetabolic Disorders. Cambridge University Press, Cambridge1996: 107-118Google Scholar), defined eight categories of clinical presentation. Three of these included reactions that were predominantly metabolic, but of different severity; a further three categories were for masseter spasm, either alone, with other ‘muscle’ features (high creatine kinase, generalized muscle rigidity) or with metabolic signs; the other categories were unexplained anaesthetic death or cardiac arrest and ‘other presentations’, e.g. postoperative pyrexia or renal failure.31Ellis FR Halsall PJ Christian AS Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands.Anaesthesia. 1990; 45: 838-841Crossref PubMed Scopus (47) Google Scholar Four hundred and two index patients were assigned to these categories; for each category, the proportion of patients diagnosed as susceptible to MH using IVCTs was calculated. This approach has proved useful in providing a rough estimate of the likelihood of MH (and the need for definitive testing) in patients who have experienced an adverse reaction which was thought to be MH. Further use of these data is limited because they were inevitably dependent on contemporary anaesthetic practice and the referral pattern to our unit. For example, I suspect that patients with lesser degrees of masseter spasm are referred now, compared with 15–20 years ago, because of the prevalence of articles on this subject in the intervening period. Hackl and colleagues49Hackl W Mauritz W Schemper M Winkler M Sporn P Steinbereithner K Prediction of malignant hyperthermia susceptibility: statistical evaluation of clinical signs.Br J Anaesth. 1990; 64: 425-429Crossref PubMed Scopus (24) Google Scholar also compared results of IVCTs with clinical signs in index cases, but with a more sophisticated statistical approach. They generated logistic regression models in an attempt to predict MH susceptibility. However, the best model could correctly classify only 78% of subjects, highlighting the difficulty in predicting MH susceptibility from clinical features. Rather than analysing data from a sample of patients, Larach and colleagues used the Delphi process to generate iteratively a consensus clinical grading scale for MH.78Larach MG Localio AR Allen GC et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology. 1994; 80: 771-779Crossref PubMed Scopus (437) Google Scholar Eleven experts responded to a series of questionnaires in which they were asked to score the relative importance of potential clinical indicators of MH, with feedback and anonymous comments from the other members of the expert panel. Scoring was ultimately used to generate a qualitative indication of likelihood of MH susceptibility.78Larach MG Localio AR Allen GC et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology. 1994; 80: 771-779Crossref PubMed Scopus (437) Google Scholar This study has proved invaluable in validating the laboratory diagnostic techniques for MH susceptibility7Allen GC Larach MG Kunselman AR The sensitivity and specificity of the caffeine–halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS.Anesthesiology. 1998; 88: 579-588Crossref PubMed Scopus (171) Google Scholar 103Ording H Brancadoro V Cozzolino S et al.In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group.Acta Anaesthesiol Scand. 1997; 41: 955-966Crossref PubMed Scopus (278) Google Scholar because ‘true’ diagnosis of MH susceptibility obtained using the ‘almost certain’ descriptor of the clinical grading scale78Larach MG Localio AR Allen GC et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology. 1994; 80: 771-779Crossref PubMed Scopus (437) Google Scholar was derived totally independently of contracture test results. However, the clinical grading scale can be criticized. First, no weighting is given to the temporal relationship of events, which can be used to exclude MH in some situations. Second, the score will be influenced greatly by missing data. Most importantly, the scores and rules for their application are somewhat ambiguous, leading to considerable variability in scoring, even among the 11 experts used to generate the clinical grading scale.78Larach MG Localio AR Allen GC et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology. 1994; 80: 771-779Crossref PubMed Scopus (437) Google Scholar The potent inhalational anaesthetic drugs are the most commonly implicated pharmacological triggers of MH. Indeed, there are no verified cases of death from MH where a potent inhalational anaesthetic has not been used. There remains uncertainty over some groups of drugs because of the potential limitation in extrapolating in vitro data to exclude a drug, that has been implicated on the basis of a clinical report, as a trigger. Over the past 30 years, many groups of drug have been implicated when one of their number was used as part of a combination of drugs providing anaesthesia for patients who subsequently developed an MH reaction during surgery. The situation is complicated further by a lack of verification that the clinical reaction was a true MH response rather than being caused by other factors, such as sepsis, inadequate anaesthesia or analgesia or, more rarely, thyrotoxicosis or phaeochromocytoma. Although MH was not recognized until the introduction of halothane, it is likely that the classical anaesthetic vapours, diethyl ether and chloroform, in addition to other now unused ether derivatives, accounted for many fatal cases of MH.22Denborough MA Foster JFA Lovell RRH Maplestone DA Villiers JD Anaesthetic deaths in a family.Br J Anaesth. 1962; 34: 395-396Crossref PubMed Scopus (244) Google Scholar 55Harrison GG Isaacs H Malignant hyperthermia. An historical vignette.Anaesthesia. 1992; 47: 54-56Crossref PubMed Scopus (16) Google Scholar In vitro studies have demonstrated that ether and chloroform cause contracture in MH muscle (unpublished observations) and it is probable that these early MH reactions went unnoticed, because of the lack of routinely available monitoring systems and, perhaps, because death under anaesthesia was relatively common. Of the contemporary