Malignant hyperthermia

Malignant hyperthermia (MH) is a life-threatening condition characterized by signs of hypermetabolism during general anaesthesia. There is a wide variability in the magnitude of these signs. Early recognition and immediate management are essential in preventing morbidity and mortality. A MH crisis is a rare reaction caused by abnormal calcium movement within the skeletal muscle cells on exposure to volatile anaesthetic agents and/or succinylcholine. Diagnosing this condition preoperatively can be a challenge as a history of an uneventful exposure to the triggering agents does not exclude the possibility of developing the reaction. Despite the autosomal dominant pattern of inheritance, genetic testing is not a definitive diagnostic tool. The gold standard diagnostic test is the in-vitro contracture test (IVCT) that is usually performed in specialist MH centres using fresh muscle biopsies. A MH crisis can be fatal if mismanaged. Dantrolene is the only specific treatment available; it is crucial to ensure its availability in areas where triggering agents are administered. This article summarizes the pathophysiology and the safe perioperative approach in managing patients with MH. Both the European Malignant Hyperthermia Group (EMHG) and the Association of Anaesthetists have published comprehensive guidelines on the safe management of this condition.     

Malignant hyperthermia

Malignant hyperthermia (MH) is a rare but potentially life-threatening emergency characterized by a hypermetabolic state which leads to pyrexia and muscle rigidity. It is a genetic disorder that displays autosomal dominant inheritance. Defects of the RyR1 and CACNA1S genes cause dysregulated calcium release within skeletal myocytes on exposure to triggering agents, causing tetanic contraction of the myocyte. Triggering agents are the halogenated volatile anaesthetic agents and suxamethonium chloride. Diagnosing MH involves genetic testing and an in-vitro contracture test. This is performed at specialist MH centres.An unexplained rise in end-tidal CO₂ and tachycardia should prompt the anaesthetist to consider an MH crisis. This can occur at any time during an anaesthetic or within the ensuing hours. A previous uneventful general anaesthetic does not rule out a crisis happening on subsequent anaesthetics. Crisis management comprises of stopping the offending triggering agent and provision of a clean volatile-free anaesthetic circuit. Activated charcoal filters are useful for the sequestration of halogenated vapours. Dantrolene is the only available treatment and should be immediately available in every area providing anaesthetic assistance. Active body cooling should be implemented to target core body temperatures below 38.5°C. Supportive measures should be instigated until the reaction has subsided. Guidelines produced by the Association of Anaesthetists of Great Britain and Ireland and the European Malignant Hyperpyrexia Group are available to aid in the management of the MH-susceptible patient and an MH crisis.     

Malignant hyperthermia

Malignant hyperthermia (MH) is an uncommon, life-threatening, acute pharmacogenetic disorder of the skeletal muscle cell. It manifests in susceptible individuals as a hypermetabolic response on exposure to halogenated volatile anaesthetics and depolarizing muscle relaxants. There may also be a relationship between susceptibility to MH, heat stroke and exercise-induced rhabdomyolysis. The pathophysiology of the crisis involves an uncontrolled release of cytoplasmic free calcium from the sarcoplasmic reticulum leading to activation of energy-producing biochemical pathways. Organ system failure and rhabdomyolysis may occur as a result of high fever, hyperkalaemia and acidosis. The ryanodine receptor, the calcium-release channel of the sarcoplasmic reticulum, is the primary locus for malignant hypothermia susceptibility. Multiple mutations in the gene for the ryanodine receptor protein are causative. Other genes may also be involved.A classical fulminant crisis presents with a rising end-tidal carbon dioxide, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Mortality may be as high as 70% if the syndrome is not recognized and treated. Immediate discontinuation of triggering agents, oxygenation, and correction of acidosis and electrolyte abnormalities, cooling and dantrolene are essential for treatment of the syndrome. Thanks to clinical and research investigations, widespread education and the introduction of dantrolene sodium, the mortality from MH is less than 5%. This chapter provides an overview and an update of MH.     

Malignant hyperthermia in the early days of pediatric anesthesia: an interview with anesthesiology pioneer,Dr. John F. Ryan

Dr. John F. Ryan (1935 ‐ ), Associate Professor of Anaesthesia at the Harvard Medical School, influenced the careers of hundreds of residents and fellows‐in‐training while instilling in them his core values of resilience, hard work, and integrity. His authoritative textbook, A Practice of Anesthesia for Infants and Children, remains as influential today as it did when first published decades ago. Although he had had many accomplishments, he identified his experiences caring for patients with malignant hyperthermia and characterizing the early discovery of this condition as his defining contribution to medicine. Based on a series of interviews with Dr. Ryan, this article reviews a remarkable career that coincides with the dawn of modern pediatric anesthetic practice.     

Hyperthermia in the pediatric intensive care unit – is it malignant hyperthermia?

Objective:  To determine the characteristics of calls made to the Malignant Hyperthermia Association of the United States (MHAUS) Hotline regarding pediatric patients in the intensive care unit setting.
Aim:  Retrospective, cohort study conducting analysis of included cases to identify the cause of elevated temperature in the pediatric intensive care unit.
Background:  The etiology of hyperthermia in the pediatric intensive care unit (ICU) is multifactorial and often difficult to diagnose.
Methods/materials:  Review of all MHAUS logs for the years 1997–2005 for children, 18 years of age and younger, with elevated temperature presenting in the intensive care setting.
Results:  Sixty-three of 1883 (3.3%) calls met inclusion criteria and these cases were characterized. Patient temperature values ranged from 38.0 to 45.0°C. Malignant hyperthermia (MH) was considered 'definite' in five cases and 'probable' in three cases. An infectious diagnosis was given to 16 cases, and a central fever was diagnosed in nine cases. The diagnosis was unknown in the remaining 30 cases. Dantrolene was administered prior to the Hotline call in 32 cases. The recommendation to continue or stop dantrolene varied according to the clinical situation. In six cases, the Hotline expert recommended initiation of dantrolene. In 17 cases, the Hotline expert recommended initiation or continuation of dantrolene as a nonspecific antipyretic, even though MH was not considered as a leading diagnosis.
Conclusions:  Cases of elevated temperature in children in an intensive care unit setting reported to the MHAUS Hotline were rarely considered to be MH related. Although MH does not represent a significant portion of diagnoses related to hyperthermia, when hyperthermia occurs in children exposed to anesthetic agents, MH should be considered in the differential diagnosis.     

Malignant hyperthermia during isoflurane anaesthesia. A case report

A case of malignant hyperthermia during isoflurane anaesthesia without the use of muscle relaxants in a healthy 7-year-old girl is presented. In this case only premedication and nitrous oxide were used together with isoflurane. Thus isoflurane by itself can trigger malignant hyperthermia, even in the absence of muscle relaxants.     

Malignant hyperthermia: clinical course and metabolic changes in two patients

Two cases of malignant hyperthermia (MH) are presented. One patient was treated symptomatically for the first 6 h until she was given dantrolene. Her clinical course was complicated and the catecholamine and cortisol concentrations were still elevated 24 h after start of treatment. In the second patient an early diagnosis was made and treatment promptly instituted. Only minor endocrine-metabolic changes were seen in this patient. However, in spite of the early successful treatment with dantrolene the MH reaction recurred 12 h after the initial symptoms. These two cases demonstrate the importance of early treatment including dantrolene. Successful treatment with dantrolene does not, however, preclude a recurrence of MH, and thus subsequent doses of dantrolene should be given.     

Rewarming following hypothermic cardiopulmonary bypass in the malignant hyperthermia-susceptible patient: Implications for diagnosis and perioperative management

A 55-year-old, malignant hyperthermia-susceptible patient underwent myocardial revascularization without incident. Six hours postoperatively, he developed what was initially diagnosed as an MH crisis, for which he received intravenous dantrolene. The resultant muscle weakness prolonged the duration of postoperative mechanical ventilation and likely contributed to the development of a postoperative pneumonia. Plasma dantrolene levels were measured for the first 48 hours postoperatively and correlated with clinical findings. On reviewing the patient's perioperative course, it was felt that the hypermetabolic state was not due to MH. The patient's pattern of rewarming following hypothermic cardiopulmonary bypass was similar to non-MH-susceptible patients. Because of the difficulty in diagnosing a MH crisis after hypothermic bypass, it is recommended that patients receive prophylactic dantrolene preoperatively and after bypass. Nondepolarizing muscle relaxants should be given postoperatively to prevent shivering and respiratory acidosis while patients rewarm.     

Malignant hyperthermia susceptibility

A case of pregnancy complicated by malignant hyperthermia susceptibility is reported. Serum CPK and electrolyte concentrations were measured during pregnancy and labour. Labour and delivery were managed successfully under epidural analgesia using plain bupivacaine 0.5%.     

Comparison of North American and European malignant hyperthermia group halothane contracture testing protocols in swine

Different in vitro halothane testing procedures have been used in the European malignant hyperthermia (MH) Group Protocol (EMHGP) and the North American MH Group Protocol (NAMHGP), whereas the caffeine-testing protocols are very similar. The present study compares the two halothane-testing protocols in ten MH susceptible swine and in four control swine. Halothane contracture testing was conducted in vitro 12-52 days following the barnyard challenge that established the MH susceptibility of the swine. There was one false positive and one false negative halothane test by the EMHGP. The MH-equivocal category in the EMHGP, which is treated clinically as MH-susceptible, affords a margin of safety in such cases. In contrast, there were no false halothane tests by the NAMHGP. While some skeletal muscle strips from MH pigs were normal by both protocols (NAMHGP 30%; EMHGP 10%), the outcome of halothane testing by the NAMHGP was unaffected. The response to halothane 3% is reduced if preceded by the EMHGP, suggesting that simply adding halothane 3% to the end of the EMHGP does not permit a direct quantitative comparison to the NAMHGP. However, the diagnostic outcomes of the two approaches are similar.     

Malignant hyperthermia and central core disease causative mutations in Swedish patients

BACKGROUND: Malignant hyperthermia (MH) susceptibility is a pharmacogenetic disorder of intracellular calcium homeostasis. In susceptible individuals, halogenated anaesthetics and/or suxamethonium may trigger an MH reaction. The diagnosis of MH susceptibility is made by an in vitro contracture test of biopsied muscle strips. METHODS: In 27 MH susceptible (MHS) probands and four MH negative (MHN) probands, exons 17, 39, 40, 45 and 46 of the RYR1 gene were screened for MH causative mutations. In addition, in three patients with established central core disease (CCD), exons 17, 39, 40, 45 and 46 and exons 95, 100, 101 and 102 were screened for MH and CCD causative mutations. All screenings were performed by direct sequencing of the entire exons. RESULTS: MH causative mutations were found in five of the 27 MHS probands (19%). CCD causative mutations were found in two of three CCD patients in the C-terminal exons. None of the CCD patients showed a mutation in N-terminal exon 17 or in the central exons. CONCLUSIONS: In a Swedish population, screening of N-terminal exon 17 and the central exons for MH causative mutations in the RYR1 gene covers 19% of families. Thus, other mutations must also be responsible for MH susceptibility in Sweden. Although the number of CCD patients in this study was small, screening of the C-terminal exons for CCD causative mutations seems to be a promising tool in the process of making a diagnosis.     

Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and moderate hypothermia

A 56-year old man was admitted for elective mitral valve repair and coronary artery bypass surgery due to mitral valve leakage and unstable angina. After induction of anaesthesia he developed a combined metabolic and respiratory acidosis. Different diagnosis were considered and we decided to treat the patient with dantrolene due to suspicion of malignant hyperthermia (MH). The patient received one dose of dantrolene 2,5 mg/kg during cardiopulmonary bypass (CPB) and a second dose of dantrolene 2,5 mg/kg during weaning from CPB. The first arterial blood gas sample taken in the intensive care unit showed relapse of the acidosis and we administered an infusion of 150 mg dantrolene over 3 hours. The patient gradually recovered without sequel and MH was verified by muscle biopsy testing.     

Malignant hyperthermia susceptibility diagnosed with a family-specific ryanodine receptor gene type 1 mutation

Malignant hyperthermia (MH) is an autosomal dominant disorder of skeletal muscle calcium regulation, and the rate of calcium-induced calcium release (CICR), determined by using skinned fibers of skeletal muscle, has been employed as a diagnostic test for MH susceptibility in Japan. The ryanodine receptor (RYR1), encoding the major calcium-release channel in skeletal muscle sarcoplasmic reticulum, has been shown to be mutated in a number of MH pedigrees. We experienced the detection of accelerated CICR and/or an RYR1 mutation in a patient with an MH episode and his family. Accelerated CICR and an RYR1 mutation (c.14512C>G, p.L4838V) were found in the patient and his father. The MH-causative mutation (c.14512C>G, p.L4838V) was also found in his brother and his son (resulting in the diagnosis of MH without the CICR test), but the mutation was not found in his mother or two daughters. With the detection of the family-specific mutation in other family members, the diagnosis of MH was made without the invasive CICR test.