Association between known or strongly suspected malignant hyperthermia susceptibility and postoperative outcomes: an observational population-based study.

PURPOSE: Whether current standards of care management for malignant hyperthermia (MH)-susceptible patients result in acceptable postoperative clinical outcomes at a population level is not known. Our objective was to determine if patients with susceptibility to MH experienced similar outcomes as patients without MH susceptibility after surgery under general anesthesia. METHODS: This was a retrospective, population-based cohort study from 1 April 2009 until 31 March 2016 in the Canadian province of Ontario. Participants were adults who underwent common in- or outpatient surgeries under general anesthesia. The exposure studied was either known or strongly suspected MH susceptibility as determined by usage of a specific physician billing code. The primary outcome was a composite of all-cause death, hospital readmission, or major postoperative complications, all within 30 postoperative days. Separate analyses were employed, based on whether a patient had in- or outpatient surgery. Inverse probability of exposure weighting based on the propensity score was used to estimate adjusted exposure effects. RESULTS: The cohort included 957,876 patients (583,254 in- and 374,622 outpatients). There were 2,900 (0.3%) patients with a known or strong suspicion of MH susceptibility. For inpatients, the primary outcome occurred in 146,192 (25.1%) of the non-MH-susceptible group and in 337 (20.1%) of the MH-susceptible group (unadjusted risk difference [RD], -5.0%; 95% confidence interval [CI], -6.9 to -3.1%; P < 0.001). In outpatients, the primary outcome occurred in 9,146 (2.4%) of the non-MH-susceptible group and in 32 (2.6%) of the MH-susceptible group (RD, 0.2%; 95% CI, -0.7 to 1.1%; P = 0.72). After adjustment, MH susceptibility was not associated with the primary outcome in either the inpatients (adjusted risk difference [aRD], 1.2%; 95% CI, -1.3 to 3.6%; P = 0.35) or outpatients (aRD, -0.1%; 95% CI -1.0 to 0.9%; P = 0.90). CONCLUSIONS: Among adults in Ontario who underwent common surgeries under general anesthesia from 2009 to 2016, known or strongly suspected MH was not associated with a higher risk of adverse postoperative outcomes. These findings support the current standard of care management for MH-susceptible patients.

RéSUMé: OBJECTIF: Nous ignorons si les normes actuelles de gestion des soins de patients susceptibles d'hyperthermie maligne (HM) aboutissent à des résultats cliniques postopératoires acceptables à l'échelle d'une population. Notre objectif a été de déterminer si des patients présentant une susceptibilité à l'HM présentaient une évolution comparable à celle des patients non connus susceptibles après chirurgie sous anesthésie générale. MéTHODES: Il s'agissait d'une étude de cohorte rétrospective, basée sur une population de la province canadienne de l'Ontario allant du 1er avril 2009 au 31 mars 2016. Les participants étaient des adultes, hospitalisés ou ambulatoires, ayant subi des interventions sous anesthésie générale. L'exposition étudiée était une susceptibilité à l'HM connue ou fortement suspectée, déterminée par l'utilisation d'un code de facturation spécifique des médecins. Le critère d'évaluation principal était un critère composite incluant les décès toutes causes confondues, les réadmissions hospitalières ou les complications postopératoires majeures qui étaient survenus dans un délai de 30 jours postopératoires. Des analyses séparées ont été utilisées, selon que les patients avaient été hospitalisés ou opérés en chirurgie d'un jour. La probabilité inverse de la pondération de l'exposition basée sur le score pour la propension a servi à estimer les effets ajustés de l'exposition. RéSULTATS: La cohorte a inclus 957 876 patients (583 254 patients hospitalisés et 374 622 patients ambulatoires). Parmi eux, 2 900 patients (0,3 %) avaient une susceptibilité à l'HM connue ou fortement suspectée. Pour les patients hospitalisés, le critère d'évaluation principal est survenu chez 146 192 (25,1 %) des patients du groupe non susceptible d'HM et chez 337 (20,1 %) patients du groupe susceptible d'HM (différence de risques [DR] non ajustée : −5,0 %; intervalle de confiance [IC] à 95 % : −6,9 % à −3,1 %; P < 0,001). Pour les patients ambulatoires, le critère d'évaluation principal est survenu chez 9 146 (2,4 %) des patients du groupe non susceptible d'HM et chez 32 (2,6 %) patients du groupe susceptible d'HM (différence de risques [DR] non ajustée : 0,2 %; IC à 95 % : −0,7 % à 1,1 %; P = 0,72). Après ajustement, la susceptibilité à l'HM ne s'est pas avérée associée au critère d'évaluation principal dans le groupe de patients hospitalisés (différence de risques ajustée [DRa], 1,2 %; IC à 95 % : −1,3 % à 3,6 %; P = 0,35) ou dans le groupe de patients ambulatoires (DRa : −0,1 %; IC à 95 % : −1,0 % à 0,9 %; P = 0,90). CONCLUSIONS: Parmi les adultes de la province de l'Ontario ayant subi des interventions chirurgicales usuelles sous anesthésie générale entre 2009 et 2016, l'HM connue ou fortement suspectée n'a pas été associée à un plus grand risque d'évolution postopératoire défavorable. Ces constatations sont en faveur du maintien des normes des soins actuels pour la gestion des patients susceptibles d'HM.

Succinylcholine for Emergency Airway Rescue in Class B Ambulatory Facilities: The Society for Ambulatory Anesthesia Position Statement.

Procedures in class B ambulatory facilities are performed exclusively with oral or IV sedative-hypnotics and/or analgesics. These facilities typically do not stock dantrolene because no known triggers of malignant hyperthermia (ie, inhaled anesthetics and succinylcholine) are available. This article argues that, in the absence of succinylcholine, the morbidity and mortality from laryngospasm can be significant, indeed, higher than the unlikely scenario of succinylcholine-triggered malignant hyperthermia. The Society for Ambulatory Anesthesia (SAMBA) position statement for the use of succinylcholine for emergency airway management is presented.

Do we foresee new emerging drugs to treat malignant hyperthermia?

Malignant hyperthermia (MH) is a life-threatening genetic sensitivity of skeletal muscles to volatile anesthetics and depolarizing neuromuscular blocking drugs occurring during or after anesthesia. Mortality of MH has been significantly reduced by using the skeletal muscle relaxant dantrolene. However, pharmacological disadvantages are known. By approval of a nanocrystalline dantrolene sodium suspension (DSS), a new product enters the market. DSS is a promising substance, but clinical data are lacking up to now. Especially with regard to newer knowledge on MH and its associated clinical presentations, there might be an increasing interest on DSS.

Malignant hyperthermia in children: an analysis of the North American malignant hyperthermia registry.

BACKGROUND: Clinical characteristics of malignant hyperthermia (MH) in pediatric patients have not been elucidated. In this study, we used the North American Malignant Hyperthermia Registry to determine differences in clinical characteristics of acute MH across pediatric age groups. We hypothesized that there are differences in clinical presentation, clinical course, and outcomes, which correlate with age. A secondary aim was to determine the types of preexisting medical conditions associated with pediatric MH. METHODS: We performed a retrospective review of the North American Malignant Hyperthermia Registry to identify pediatric subjects (up to and including 18 years) with an MH clinical grading score at or above 35 indicating "very likely" or "almost certain" MH. Preoperative patient characteristics, perianesthetic factors, and outcome data were compared for 3 cohorts based on age: 0 to 24 months, 25 months to 12 years, and 13 to 18 years. We used statistical analysis to determine differences among the groups. RESULTS: We analyzed 264 records: 35 in the youngest age group, 163 in the middle age group, and 66 in the oldest group. There was no indication of any predisposing risk factors for MH based on family history or physical examination. Sinus tachycardia, hypercarbia, and rapid temperature increase were the most common signs of acute MH (observed in 73.1%, 68.6%, and 48.5%, respectively) and were more common in the oldest age cohort. Higher maximum temperatures and higher peak potassium values were seen in the oldest age cohort. Masseter spasm was more common in the middle age cohort. The youngest age cohort was more likely to develop skin mottling and was approximately half as likely to develop muscle rigidity. The youngest age group also demonstrated significantly higher peak lactic acid levels and lower peak creatine kinase values. Treatments were similar across age cohorts. There were 10 MH-associated deaths, 6 in the middle age group and 4 in the oldest age group. Recrudescence of symptoms after initial treatment occurred in 14.4% of subjects, with no difference across age cohorts. Two of these subjects, 1 in the middle age group and 1 in the oldest age group, died after the recrudescence event. CONCLUSIONS: There are differences in clinical characteristics of acute MH among different age cohorts in childhood. Older subjects demonstrated higher body temperatures and higher potassium levels, and the youngest subjects had greater levels of metabolic acidosis. Most children in each age group were phenotypically normal before developing MH.

Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.

BACKGROUND: AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. METHODS: We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. RESULTS: Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 ± 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). CONCLUSIONS: Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.

Pediatric malignant hyperthermia: risk factors, morbidity, and mortality identified from the Nationwide Inpatient Sample and Kids' Inpatient Database.

BACKGROUND: Malignant Hyperthermia (MH) is a potentially fatal metabolic disorder. Due to its rarity, limited evidence exists about risk factors, morbidity, and mortality especially in children. METHODS: Using the Nationwide Inpatient Sample and the Kid's Inpatient Database (KID), admissions with the ICD-9 code for MH (995.86) were extracted for patients 0-17 years of age. Demographic characteristics were analyzed. Logistic regression was performed to identify patient and hospital characteristics associated with mortality. A subset of patients with a surgical ICD-9 code in the KID was studied to calculate the prevalence of MH in the dataset. RESULTS: A total of 310 pediatric admissions were seen in 13 nonoverlapping years of data. Patients had a mortality of 2.9%. Male sex was predominant (64.8%), and 40.5% of the admissions were treated at centers not identified as children's hospitals. The most common associated diagnosis was rhabdomyolysis, which was present in 26 cases. Regression with the outcome of mortality did not yield significant differences between demographic factors, age, sex race, or hospital type, pediatric vs nonpediatric. Within a surgical subset of 530,449 admissions, MH was coded in 55, giving a rate of 1.04 cases per 10,000 cases. CONCLUSIONS: This study is the first to combine two large databases to study MH in the pediatric population. The analysis provides an insight into the risk factors, comorbidities, mortality, and prevalence of MH in the United States population. Until more methodologically rigorous, large-scale studies are done, the use of databases will continue to be the optimal method to study rare diseases.

CHRNG genotype-phenotype correlations in the multiple pterygium syndromes.

BACKGROUND: Germline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia. METHODS: In order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS. RESULTS: CHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies. DISCUSSION: The mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.

Unexpected MH deaths without exposure to inhalation anesthetics in pediatric patients.

Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist.

The severity of sevoflurane-induced malignant hyperthermia.

BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal complication of general anesthesia triggered by volatile anesthetics. In animal studies, sevoflurane has been reported to be a weak triggering agent. The aim of this study was to evaluate the clinical severity of sevoflurane-induced MH compared to isoflurane. METHODS: From the Japanese MH database containing information for 520 MH cases since 1961, we analyzed 147 cases classified by the MH Clinical Grading Scale (CGS) as 'very likely' or 'almost certain', accumulated from 1990 to 2009. Sevoflurane without succinylcholine (S-SCh (-) group) was given to 48 cases, and isoflurane without succinylcholine (I-SCh (-) group) was given to 30. Variables studied were outcome, CGS score, CGS rank, the first MH sign, and time from induction to onset of MH (occurrence time). Clinical signs and maximum laboratory data from six processes of the CGS were also analyzed. Each of the Mann-Whitney U-test or the unpaired t-test was used for group comparisons. RESULTS: Mortality was 8.3% in the S-SCh (-) group and 10.0% in the I-SCh (-) group (P = 0.803). The CGS scores were 53.4 (SD, 12.2) and 52.3 (11.7) (P = 0.691), respectively. The five processes of the CGS did not differ between groups. Median occurrence times were 72.5 minutes (range, 36.3-127.5) and 65.0 minutes (30.0-131.3), respectively (P = 0.890). CONCLUSION: There were no clinically apparent differences between MH triggered by sevoflurane and isoflurane, and thus no evidence to support the postulate that sevoflurane is a weak or weaker MH triggering agent.

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States.

BACKGROUND: The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes. METHODS: The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple comparisons. RESULTS: Of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death. The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr). Associated factors were muscular build (odds ratio, 18.7; P = 0.0016) and disseminated intravascular coagulation (odds ratio, 49.7; P < 0.0001). Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide (216 vs. 87 min; P = 0.003). Unrelated factors included patient or family history, anesthetic management, and the MH episode. CONCLUSIONS: Modern US anesthetic practice did not prevent MH-associated cardiac arrest and death in predominantly young, healthy patients undergoing low- to intermediate-risk surgical procedures.

[Severe dehydration and August 2003 heat wave in a cohort of adults with cystic fibrosis]. / Déshydratation sévère, conséquence de la canicule d'août 2003 sur une cohorte d'adultes atteints de mucoviscidose.

OBJECTIVE: To study dehydration related to the August 2003 heat wave in France in a cohort of adults with cystic fibrosis. Method Retrospective study of the telephone calls received from and hospital admissions of all adult cystic fibrosis patients (n=245) regularly followed in our specialized clinic. RESULTS: Six patients developed extracellular dehydration with functional kidney failure concomitant to intracellular dehydration with hypokalemia and hypochloremia. Rehydration measures normalized the blood chemistry measures within 48 hours for all patients except one, who died of malignant hyperthermia. CONCLUSION: In hot weather, it is essential for patients with cystic fibrosis to take measures (hydration, salt supplementation) to prevent severe dehydration.

Malignant hyperthermia in the head and neck surgery patient: an update and review.

Malignant hyperthermia, a disorder often initiated by exposure to a variety of anesthetic agents, continues to be of major importance to the head and neck surgeon because: 1. approximately 40% of all reported reactions have occurred during anesthesia for head and neck surgery; 2. the possibility of mortality still exists despite the use of new pharmacologic agents, such as dantrolene; and, 3. subtle variations in the intraoperative and postoperative presentation of malignant hyperthermia are being increasingly recognized and treated. The authors briefly tabulate the 280 cases--which have occurred worldwide during otolaryngologic, dental, facial plastic, ophthalmologic and neurosurgical procedures--that are registered with the Department of Anaesthesia, University of Toronto, Canada. A case report depicting a less-than-typical reaction is presented. The authors emphasize that early recognition of the clinical features of an ongoing reaction, whether mild or severe, is by far the most important factor in reducing morbidity and mortality of patients who suffer hyperthermic crises while undergoing head and neck surgery.

Halothane testing for malignant hyperthermia in swine: dose-response effects.

Purebred Pietrain malignant hyperthermia (MH)-susceptible pigs (n = 102) were subjected to halothane (0%, 1%, 2%, 3%, 4%, and 5%) in oxygen. The number of pigs in each group exhibiting muscle rigidity (MH(+) reaction) and the reaction times were recorded, as were the number of deaths resulting from MH. Mortality was not affected by the halothane concentration. However, halothane concentration did markedly affect the number of MH(+) reactions and the reaction times. False-negative reactions were apparent in the pigs at halothane concentrations less than 3%. Increasing the halothane concentration incrementally to 5% (from 0%) significantly (P less than 0.05) decreased reaction times between treatment groups. The reductions in reaction times which occurred in the pigs given the 3%, 4%, and 5% halothane concentrations (62.1, 56.2, and 50.05)--although significant (P less than 0.05)--would indicate that 3% halothane would generally be sufficient for MH testing.

Noneffectiveness of verapamil in preventing halothane-induced malignant hyperthermia in susceptible swine.

Pietrain pigs susceptible to malignant hyperthermia (MH; porcine stress syndrome) were treated with the slow-channel calcium blocker verapamil and then subjected to halothane testing. There was no significant delay in the onset of MH among pigs (3 groups) given different doses of verapamil (1, 5, and 10 mg/kg) and saline control Pietrain pigs. The mortality due to MH (83.3%) was significantly higher among the pigs given the largest dose (10 mg/kg) than in the other groups. Verapamil was not effective in preventing or delaying a MH reaction. This antiarrhythmic drug should be used cautiously during a MH reaction in susceptible individuals.

[Malignant hyperthermia]. / Maligne Hyperthermie.

Malignant hyperthermia is an autosomal dominant disorder of the skeletal muscle that predisposes affected individuals to a life-threatening hypermetabolic reaction in response to volatile anaesthetics and depolarizing muscle relaxants. The underlying heterogeneous genetic defects are mainly point mutations within the ryanodine receptor gene of the sarcoplasmic reticulum. Following the introduction of efficient diagnostic and therapeutic tools--the in vitro contracture test and intravenous treatment with dantrolene--a dramatic decline in mortality rates has been observed. The association of malignant hyperthermia-like reactions with other neuromuscular disorders requires the collaboration of several clinical disciplines to achieve a timely recognition of this still life-threatening disorder.

[Malignant hyperthermia and appendicular sepsis. Can they be differentiated during surgical procedure?]. / Hyperthermie maligne et état infectieux d'origine appendiculaire. Peut-on les différencier en cours d'intervention?

OBJECTIVE: To assess the possibility to differentiate clinically intraoperative malignant hyperthermia (MH) and sepsis. STUDY DESIGN: Comparative retrospective study of clinical cases. PATIENTS: Sixteen patients operated on for acute appendicitis and developing clinical signs of MH confirmed or not by in vitro caffeine halothane contracture tests (IVCT). METHOD: To isolate the patients' characteristics with regard to the diagnosis of sepsis and MH crisis. To compare both groups of clinical features with results of IVCT. RESULTS: The diagnosis of MH sensitivity has been excluded in ten hyperthermic patients and confirmed in four others with IVCT. No correlation was existing between the importance of perioperative sepsis, MH features and IVTC results. CONCLUSIONS: This study confirmed the difficulty to differentiate clinically MH and sepsis during surgery. Considering the severe outcome of MH crisis, it is recommended to start the specific therapy even in case of appendicular sepsis.