It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.

Over the past 50 yr, many drugs have been implicated as triggers of malignant hyperthermia (MH), a potentially fatal pharmacogenetic disorder of skeletal muscle calcium regulation. This review discusses the potent inhalation agents as the principal triggers and evidence that the modern agents, desflurane, sevoflurane, and isoflurane, can cause florid MH reactions in the same way as halothane but also are associated with reactions whose onset is delayed for several hours into anaesthesia. There is evidence that the triggering of MH by drugs is dose-dependent but the minimum dose that will trigger the condition is unknown. This has implications for the preparation of anaesthetic machines when used for known or suspected MH patients. While succinylcholine enhances the response of potent inhalation anaesthetics, its role as an inherent trigger of the condition is controversial. Non-depolarizing neuromuscular blocking drugs appear to protect against the development of MH and this may be by blocking excitation-coupled calcium entry—a recently described route of skeletal muscle calcium entry that may also explain the mechanism of the effect of succinylcholine in MH. Another mechanism for extracellular calcium influx, store-operated calcium entry, is activated in MH muscle and may explain how a triggered reaction is sustained. Finally, reports of drugs that have been implicated as additional triggers of MH over the past 10 yr are discussed.

© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com1A01, 2A06, 3I00...Key pointsA previous apparently uneventful general anaesthetic does not exclude the possibility of a malignant hyperthermia (MH) reaction on subsequent exposure to MH triggering drugs.The time course of the clinical presentation of MH under anaesthesia is highly variable: hypermetabolic features may recur up to 14 h after initial resolution.Early diagnosis is the key to successful management of an MH crisis.Activated charcoal filters are an efficient way to reduce the concentration of volatile agents in inspired gases during an MH reaction.Genetic testing alone cannot currently exclude susceptibility to MH.In this article, we will first describe the epidemiology, pathophysiology, diagnosis, and differential diagnosis of malignant hyperthermia (MH). We will then discuss the perioperative management, referral, and...

Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the α1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK. We investigate the CACNA1S locus in detail in 50 independent MH patients, the largest study to date, to identify novel variants that may predispose to disease and also to characterise the haplotype structure across CACNA1S. We present CACNA1S cDNA sequencing data from 50 MH patients in whom RYR1 mutations have been excluded, and subsequent mutation screening analysis. Furthermore we present haplotype analysis of unphased CACNA1S SNPs to (1) assess CACNA1S haplotype frequency differences between susceptible MH cases and a European control group and (2) analyse population-based association via clustering of CACNA1S haplotypes based on disease risk. The study identified a single potentially pathogenic change in CACNA1S (p.Arg174Trp), and highlights that the haplotype structure across CACNA1S is diverse, with a high degree of variability.

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. 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. 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). 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.

It is now just over 2 yr since Marhofer and colleagues,¹ in this journal, reviewed the use of ultrasound in regional anaesthesia. They concluded with the hope that the availability of portable ultrasound systems with high-frequency probes would promote the routine use of ultrasound guidance in regional anaesthesia. This review, however, was accompanied by an editorial that queried the evidence base for preferring ultrasound guidance to other techniques of nerve localization.² With the widespread availability to anaesthetists of high-resolution portable ultrasound machines,³ it is timely to consider if sufficient evidence has accumulated to quell the doubts expressed by Denny and Harrop-Griffiths.²