Malignant hyperthermia is recognised as a potentially fatal hypermetabolic disorder triggered by volatile anaesthetics and depolarising muscle relaxants. In this issue of the journal, two studies raise the potential for improving the management of rare problems in anaesthesia – presymptomatic screening of malignant hyperthermia susceptibility and treatment with dantrolene.1,2
The observation that freshly biopsied muscle strips from patients who have survived malignant hyperthermia were more sensitive to caffeine and halothane in in-vitro challenges compared to muscle strips from patients with no history of malignant hyperthermia prompted the use of in-vitro muscle contracture testing (IVCT) for presymptomatic screening of susceptibility to malignant hyperthermia.3,4 Freshly biopsied muscle strips from the quadriceps muscle, about 2 cm long and 2–3 mm thick, are mounted for measurement of isometric contractions in a tissue bath with an isotonic solution aerated with oxygen containing 5% CO2. Challenging muscle strips with caffeine, halothane and various other drugs in vitro causes a shift of the dose–response curve to the left in specimens from malignant hyperthermia susceptible (MHS) individuals compared to malignant hyperthermia normal (MHN) individuals. This phenomenon is used for diagnostic purposes by setting drug concentration thresholds for abnormal muscle contractures.5 Despite the evaluation of different drugs, caffeine and halothane have remained the ‘gold standard’ for presymptomatic malignant hyperthermia screening for more than 25 years.
Because the licence for the clinical use of halothane expired in 2005, there is speculation that halothane could become commercially unavailable in the near future. Therefore, Metterlein et al.1 have investigated the commercially available alternative volatile anaesthetics enflurane, isoflurane, desflurane and sevoflurane for their effect on in-vitro muscle contraction. Their data confirm previous research and show that halothane remains the best volatile anaesthetic drug for the in-vitro diagnosis of malignant hyperthermia susceptibility; the best discrimination between contractions of muscle specimens from MHN and MHS individuals was obtained using halothane rather than other volatile anaesthetics, because halothane caused the strongest contractions.
The clinical usefulness of IVCT has been questioned several times, particularly because the diagnostic sensitivity of the test is only 99%.6 Sceptical anaesthetists and experts will question whether the findings of Metterlein et al. are of any relevance, because they would never use volatile anaesthetics in a patient with even a minimal risk of malignant hyperthermia based on clinical history.7 This group of people would never accept an MHN diagnosis obtained using IVCT as clinically relevant because of the lack of a 100% diagnostic sensitivity. Although this is a safe strategy to reduce the potential risk for a malignant hyperthermia reaction in such a patient, this is not a balanced view of the problem. We use many other biological tests with a much lower level of accuracy, and there are further aspects that must be taken into account if the value of IVCT is questioned.
Contracture results of potentially MHS individuals obtained by IVCT and genetic research in known MHS individuals have led to the identification of various causative genetic mutations in the ryanodine receptor gene (RYR1), the gene encoding the calcium channel of the sarcoplasmic reticulum, in 70–80% of MHS families, and in a few cases in the α1-subunit of the dihydropyridine-sensitive L-type voltage-dependent calcium channel of skeletal muscle.8,9
IVCT has been shown to be an effective tool for screening potentially MHS individuals and remains the ‘gold standard’ for malignant hyperthermia diagnosis in patients with unknown familial causative genetic mutations or to confirm MHN diagnosis if a previously identified causative familial genetic mutation is not present in an individual of such a malignant hyperthermia pedigree.10 The presence of a causative genetic mutation in a malignant hyperthermia family allows non-invasive genetic screening for malignant hyperthermia susceptibility in family members who would not be able to undergo IVCT (e.g. babies or the elderly).11
Non-triggering anaesthetics are not 100% safe (e.g. awareness, propofol infusion syndrome), whereas volatile anaesthetics have unique benefits for some groups of patients (e.g. induction of anaesthesia in paediatrics, myocardial protection).12
According to the experiences of malignant hyperthermia investigation units and malignant hyperthermia patient organisations, many individuals from malignant hyperthermia families are keen to establish a diagnosis because they are concerned about being treated incorrectly during anaesthesia or because they have been told that they cannot be anaesthetised until they have been tested for malignant hyperthermia. Experts who are exclusively in favour of or against IVCT have a paternalistic view, which may not be appropriate in many circumstances. There is evidence that genetic screening for malignant hyperthermia will be implemented in future concepts of personalised medicine.13
Metterlein et al.1 demonstrate that there are differences among the investigated volatile anaesthetics used to induce contractures in muscle strips from MHS individuals. However, it is important to note that these findings cannot be used to conclude that some volatile anaesthetics are less potent malignant hyperthermia triggers. The findings support the view that the present IVCT protocol for the diagnosis of malignant hyperthermia susceptibility does not need a revision in favour of the use of a more modern volatile anaesthetic, because halothane is the best drug for diagnostic discrimination. Therefore, halothane should continue to be used for IVCT as long as it is available, even if the licence for clinical use has expired. If halothane becomes unavailable, there are alternative drugs. The RYR1 activators ryanodine and 4-chloro-m-cresol have already been evaluated in multicentre studies of the European Malignant Hyperthermia Group.14,15 However, due to the heterogeneity of malignant hyperthermia susceptibility, the diagnostic approach using a combination of IVCT and malignant hyperthermia-specific genetic investigations is likely to be the most powerful tool for advising potentially MHS patients and anaesthetists for several years.
In the second article, Schütte et al.2 present data from a malignant hyperthermia swine model comparing a new dantrolene suspension with regular dantrolene sodium. The new drug, a nanocrystalline suspension of dantrolene, is 150 times more concentrated than regular dantrolene (50 compared to 0.33 mg ml−1). The authors demonstrate that the time needed to prepare the new drug for intravenous administration is about 17 times shorter than for regular dantrolene. The time reduction to prepare the solution, as well as the positive therapeutic effect in MHS swine, demonstrates that the new drug has the potential to improve the treatment of malignant hyperthermia. However, the crucial question is whether the new dantrolene product will soon be available for clinical use. Malignant hyperthermia is a rare disorder, and the cost of launching a new drug is high. Keeping in mind the increasing financial pressure on the healthcare system, it is unclear whether the new drug will become available. However, there are arguments in favour of making drugs for rare disorders available due to recent political plans to support research and drug development for rare diseases with public funding.16
In summary, both studies are important contributions to improving knowledge about presymptomatic malignant hyperthermia testing and for better treatment of malignant hyperthermia.1,2 At present, cornerstones for prevention and successful treatment of malignant hyperthermia are careful evaluation of the history given by patients before anaesthesia, presymptomatic family screening in suspected MHS individuals, early detection and immediate and correct treatment of malignant hyperthermia episodes, and availability of dantrolene.17 New findings, the power of information technology, such as worldwide open access to literature, the use of checklists, and specific applications on computers and on the iPhone (e.g. MHApp) have the potential to improve the prevention and treatment of malignant hyperthermia.
1 Metterlein T, Schuster F, Kranke P, et al.
In-vitro contracture testing for susceptibility to malignant hyperthermia: can halothane be replaced? Eur J Anaesthesiol
2 Schütte JK, Becker S, Burmester S, et al.
Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs. Eur J Anaesthesiol
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