Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group.

Survival from a malignant hyperthermia (MH) crisis is highly dependent on early recognition and prompt action. MH crises are very rare and an increasing use of total i.v. anaesthesia is likely to make it even rarer, leading to the potential risk of reduced awareness of MH. In addition, dantrolene, the cornerstone of successful MH treatment, is unavailable in large areas around the world thereby increasing the risk of MH fatalities in these areas. The European Malignant Hyperthermia Group collected and reviewed all guidelines available from the various MH centres in order to provide a consensus document. The guidelines consist of two textboxes: Box 1 on recognizing MH and Box 2 on the treatment of an MH crisis.

Analysis of RYR1 haplotype profile in patients with malignant hyperthermia.

This study represents a new approach to characterising patients at risk of malignant hyperthermia (MH) through the use of a recently published method for identifying high-risk haplotypes in candidate genes. We present analysis based upon the largest standardised and genotyped database of MH patients worldwide. We used unphased RYR1 SNP data directly to (1) assess RYR1 haplotype frequency differences between susceptible cases and control groups and (2) analyse population-based association via clustering of RYR1 haplotypes based on disease risk. Our results show a significant difference in RYR1 haplotype frequency between susceptible cases and UK Caucasian population controls. Furthermore we identify a high-risk cluster of haplotypes that is associated with the commonest UK MH mutation p.G2434R/c.7300G>A. These results demonstrate the applicability of this new and practical method for population based association analysis.

Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility.

BACKGROUND: Tissue-specific monoallelic silencing of the RYR1 gene has been proposed as an explanation for variable penetrance of dominant RYR1 mutations in malignant hyperthermia (MH). We examined the hypothesis that monoallelic silencing could explain the inheritance of an MH discordant phenotype in some instances. METHODS: We analysed parent-offspring transmission data from MH kindreds to assess whether there was any deviation from the expected autosomal dominant Mendelian inheritance pattern. We also evaluated informative single-nucleotide polymorphism (SNP) genotypes in a cohort of unrelated MH patients using genomic DNA (gDNA, prepared from leucocytes) and coding DNA (cDNA, prepared from skeletal muscle). Finally, we examined the segregation of specific mutations at the gDNA and cDNA level within MH families where positive RYR1 gDNA genotype/normal MH phenotype discordance had been observed. RESULTS: In 2113 transmissions from affected parents, there was a consistent parent-of-origin effect (P<0.001) with affected fathers having fewer affected daughters (20%, 95% CI 17-22%) than affected sons (25%, 95% CI 23-26%) or unaffected daughters (27%, 95% CI 25-30%). No discrepancies were observed between the RYR1 SNP genotypes recorded at the gDNA and cDNA levels. In 14 MH negative individuals from 11 discordant families, the familial mutation was detected in skeletal muscle cDNA in all cases. CONCLUSIONS: Epigenetic allele silencing may play a role in the inheritance of MH susceptibility, but this is unlikely to involve silencing of RYR1.

Genetic variation in RYR1 and malignant hyperthermia phenotypes.

BACKGROUND: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype. METHODS: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype. RESULTS: We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001). CONCLUSIONS: The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.

Effects of atropine and glycopyrrolate on cognitive function following anaesthesia and electroconvulsive therapy (ECT).

Memory changes are known to be associated with electroconvulsive therapy (ECT). The anticholinergic drugs used prior to the procedure have also been suspected of causing cognitive deficits. The present study was designed to assess memory and concentration in depressed patients receiving 0.6 mg atropine, 0.2 mg glycopyrrolate or placebo before anaesthesia and ECT. Glycopyrrolate is an anticholinergic agent lacking central nervous system effects. Anaesthesia and bilateral ECT resulted in significant short-term memory deficit, but this was seen equally in each of the groups of patients irrespective of which premedication was given. As no regimen was superior, as far as effect on memory is concerned, premedication for ECT should be chosen according to other criteria.

Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia.

BACKGROUND: In normal resting muscle, cytosolic Mg(2+) exerts a potent inhibitory influence on the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR1). Impaired Mg(2+)-regulation of RyR1 has been proposed as a causal factor in malignant hyperthermia (MH). The aim of this study was to compare the effects of cytosolic Mg(2+) on SR Ca(2+) release induced by halothane or sevoflurane in normal (MHN) and MH susceptible (MHS) human skeletal muscle fibres. METHODS: Samples of vastus medialis muscle were obtained from patients under investigation for MH susceptibility. Single fibres were mechanically skinned and perfused with solutions mimicking the intracellular milieu. Changes in [Ca(2+)](i) were detected using fura-2 fluorescence after application of equimolar halothane or sevoflurane. RESULTS: In MHN fibres, concentrations of sevoflurane or halothane as high as 10 mM typically failed to induce SR Ca(2+) release at physiological free [Mg(2+)] (1 mM). However, when [Mg(2+)] was decreased to 0.4 mM, SR Ca(2+) release occurred in 51% (16/33) and 6% (2/33) of MHN fibres after the addition of 1 mM halothane or 1 mM sevoflurane, respectively. Further decreases in [Mg(2+)] increased the proportion of responsive fibres. In the presence of 0.1 mM [Mg(2+)], Ca(2+) release occurred in all fibres (33/33) after the introduction of 1 mM halothane or 1 mM sevoflurane. In MHS fibres, 1 mM halothane or 1 mM sevoflurane-induced Ca(2+) release in 54% (7/13) or 15% (2/13) of fibres, respectively, at 1 mM Mg(2+). A decrease in [Mg(2+)] to 0.2 mM Mg(2+) was sufficient to render 100% of MHS fibres (13/13) responsive to 1 mM halothane or 1 mM sevoflurane. CONCLUSIONS: In both MHS and MHN fibres (i) halothane is a more potent activator of SR Ca(2+) release than sevoflurane and (ii) as with halothane, the efficacy of sevoflurane-induced SR Ca(2+) release exhibits a marked dependence on cytosolic [Mg(2+)]. The marked potentiation of SR Ca(2+) release after a moderate reduction in cytosolic [Mg(2+)] suggests that conditions which cause hypomagnesaemia will increase the probability and possibly severity of an MH event. Conversely, maintenance of a normal or slightly increased cytosolic [Mg(2+)] may reduce the probability of MH.

Does postoperative pyrexia indicate malignant hyperthermia susceptibility?

We are frequently asked if patients, in whom only postoperative pyrexia has been observed, should be considered as potentially susceptible to malignant hyperthermia (MHS). Of 30 patients of this type studied in this Unit, none was shown to be MHS. We consider that postoperative pyrexia alone is unlikely to signify MH.

The control of muscle contracture by the action of dantrolene on the sarcolemma.

Although dantrolene reverses the muscle contracture seen during a malignant hyperpyrexia (MH) crisis, its site of action is not known. It has been inferred from previous work that the major abnormality in MH is in the sarcoplasmic reticulum, and that dantrolene must act on this organelle. In the present study the ability of dantrolene to control drug-induced muscle contraction was tested. The drugs were chosen because their sites of action were known for inducing contracture. Dantrolene had no effect on contractures induced by 2:4 dinitrophenol, exerted only a minor effect on caffeine contractions, but reduced significantly the contracture produced by K+. It is postulated that the major action of dantrolene is on the sarcolemma, which may be the site of the MH abnormality.

A screening test for the malignant hyperpyrexia phenotype using suxamethonium-induced contracture of muscle treated with caffeine and its inhibition by dantrolene.

Suxamethonium induced a contracture in caffeine pretreated human muscle in vitro. The contracture was significantly greater (P less than 0.001) with MHS muscle compared with muscle from normal subjects. This reaction is now used as an additional screening test for the MHS phenotype. The contracture was prevented by pretreatment with dantrolene.

Suxamethonium spasm. A differential diagnostic conundrum.

Spasm of muscle in association with suxamethonium is not uncommon. As an accepted early sign of malignant hyperpyrexia (MH), patients have been referred for MH screening who have shown only this abnormality. Case histories of 277 probands have been analysed and grouped according to final diagnosis, depending on results of muscle biopsy and in vitro screening. When muscle spasm is induced with suxamethonium, malignant hyperpyrexia must be considered a probable diagnosis.

Comparison of in vitro contracture testing with ryanodine, halothane and caffeine in malignant hyperthermia and other neuromuscular disorders.

In vitro exposure of living skeletal muscle to ryanodine has been proposed as a potentially specific test for malignant hyperthermia (MH). In this study we have compared in vitro contracture responses to halothane, caffeine and ryanodine in skeletal muscle specimens obtained from 155 patients attending for diagnosis of susceptibility of MH and also from six patients having muscle biopsy for diagnosis of other neuromuscular disorders. Although the ryanodine contracture test was not specific for MH, the results suggest it may greatly aid (in conjunction with the standard halothane and caffeine contracture tests) the accurate phenotyping of individuals that is essential for the further genetic analysis of MH.

The effects of benzamil on in vitro contracture responses of human skeletal muscle to halothane.

1. Inhibition of sodium-calcium exchange using 100 microM benzamil caused contracture development of in vitro skeletal muscle samples from humans susceptible to malignant hyperthermia, but not of samples from normal individuals. 2. This dose of benzamil increased the contracture response of both types of muscle to halothane. 3. At a concentration of 1 microM, benzamil significantly reduced the contracture response to halothane of muscle from malignant hyperthermia individuals. 4. The implications for the role of sodium-calcium exchange in skeletal muscle calcium homeostasis and the pathophysiology of malignant hyperthermia are discussed.

Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia.

In vitro contracture tests used currently for malignant hyperthermia (MH) do not possess absolute specificity. This is potentially a great problem in the study of the genetic approach which offers the best prospect for the development of a non-invasive diagnostic test for the condition. The calcium release channel of the sarcoplasmic reticulum has been proposed as the site of the MH defect. Ryanodine, which binds avidly to this channel, was shown to differentiate between muscle of MH susceptible and normal patients in terms of in vitro contracture response. This ryanodine contracture response is proposed as a potentially specific in vitro diagnostic test for MH.

Evaluation of local anaesthetic blockade of the lateral femoral cutaneous nerve.

An assessment of local anaesthetic blockade of the lateral femoral cutaneous nerve using a standard technique was made. The rate of successful blockade was high, but the area of sensory loss was inconsistent between patients and was more anterior and distal than described in textbooks of anatomy.

Hypermetabolism in arthrogryposis multiplex congenita.

Two patients who developed hypermetabolic reactions during anaesthesia and surgery and who were suffering from arthrogryposis multiplex congenita are reported and it is proposed that the reaction is distinct from malignant hyperthermia and independent of the anaesthetic agents used. The implications for anaesthetists involved in the management of patients with arthrogryposis multiplex congenita are discussed.

Malignant hyperpyrexia and sudden infant death syndrome.

This paper reports three investigations of the suggested relationship between sudden infant death syndrome (SIDS) and malignant hyperpyrexia (MH). In the first study 151 MH-susceptible families completed a questionnaire designed to identify the incidence of SIDS within their own pedigree. In the second study 106 SIDS families completed a questionnaire designed to identify the incidence of anaesthetic related problems. In the third study, 14 SIDS parents were subjected to muscle biopsy and in vitro halothane contracture and caffeine contracture screening for susceptibility to MH. From the results of the three studies it can be concluded that there is no association between SIDS and MH.

The work of the Leeds Malignant Hyperpyrexia Unit, 1971-84.

A detailed account of the procedure of muscle biopsy for screening patients suspected of being susceptible to malignant hyperpyrexia is given, together with a review of the results obtained from 1127 patients screened over the last 14 years. The information should help anaesthetists to discuss the investigation fully with probands and other members of their families before referral for further specific investigation.

Is the "K-type" caffeine-halothane responder susceptible to malignant hyperthermia?

The "K-type" designation is used to describe a patient being investigated for malignant hyperthermia (MH) when concurrent administration of caffeine and halothane induces muscle contracture (rigidity, spasm) in vitro, but when halothane and caffeine given separately produce a normal response. It is accepted in some centres that K-type individuals are susceptible to malignant hyperthermia (MHS). In this paper, the K-type is shown not to correlate with the MH susceptible (MHS) status as accepted by the European MH group.

Evaluation of spin resonance spectroscopy of red blood cell membranes to detect malignant hyperthermia susceptibility.

We have evaluated a spin labelled electron spin resonance technique to identify malignant hyperthermia susceptible (MHS) patients. We studied 19 patients, 10 MHS and nine MHN (normal), using the standard European procedure. We were unable to obtain any evidence that this technique could be used to diagnose MH susceptibility. Furthermore, there was no significant difference in the fluidity of the red blood cell membranes between the two groups, which would have been indicative of a generalized membrane abnormality in MH.

Evaluation of "3 in 1" lumbar plexus block in patients having muscle biopsy.

Winnie and co-workers described a technique of blocking the lateral cutaneous nerve of thigh, femoral and obturator nerves using one injection of local anaesthetic into the fibrous sheath surrounding the femoral nerve. We studied 40 patients undergoing biopsy of vastus medialis for investigation of malignant hyperpyrexia, for onset, quality and recovery from this block. The patients were assigned in a random double-blind fashion to receive 0.6 ml kg-1 of one of two anaesthetic solutions: 1% lignocaine with 1 in 100,000 noradrenaline or 0.25% bupivacaine. Bupivacaine produced a similar onset time but longer duration of action compared with lignocaine. Median peak plasma concentrations of six patients in each group did not approach values associated with toxicity. This study demonstrated a 12.5% and 87.5% partial and complete femoral nerve block, respectively, and a 67.5% success rate for lateral cutaneous nerve of thigh using Winnie's technique. There was no clinical evidence of obturator nerve block.