Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

Intravenous dantrolene in hypermetabolic syndromes: a survey of the U.S. Veterans Health Administration database.

BACKGROUND: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings. METHODS: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons. RESULTS: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene. CONCLUSIONS: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.

PURPOSE: As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH). METHODS: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. RESULTS: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance. CONCLUSION: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.

Genomic Screening for Malignant Hyperthermia Susceptibility.

It is timely to consider the utility and practicability of screening for malignant hyperthermia susceptibility using genomic testing. Here the authors pose a simple, but bold question: what would it take to end deaths from malignant hyperthermia? The authors review recent advances and propose a scientific and clinical pathway toward this audacious goal to provoke discussion in the field.

Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014.

BACKGROUND: The cost-benefit of stocking dantrolene in maternity units for treating malignant hyperthermia (MH) has been recently questioned because of the low incidence of MH crisis in the general population and the low utilization of general anesthesia in obstetrics. However, no study has examined the prevalence of MH susceptibility in obstetrics. This study aimed to assess the prevalence of MH diagnosis and associated factors in obstetric patients. METHODS: Data for this study came from the National Inpatient Sample from 2003 to 2014, a 20% nationally representative sample of discharge records from community hospitals. A diagnosis of MH due to anesthesia was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was estimated according to the delivery mode and patient and hospital characteristics. RESULTS: During the 12-year study period, 47,178,322 delivery-related discharges [including 15,175,127 (32.2%) cesarean deliveries] were identified. Of them, 215 recorded a diagnosis of MH, yielding a prevalence of 0.46 per 100,000 [95% confidence interval (CI), 0.40 to 0.52]. The prevalence of MH diagnosis in cesarean deliveries was 0.81 per 100,000 (95% CI, 0.67 to 0.97), compared with 0.29 per 100,000 (95% CI, 0.23 to 0.35) in vaginal deliveries (P <  0.001). Multivariable logistic regression revealed that cesarean delivery was associated with a significantly increased risk of MH diagnosis [adjusted rate ratio (aOR) 2.88; 95% CI, 2.19 to 3.80]. Prevalence of MH diagnosis was lower in Hispanics than in non-Hispanic whites (aOR 0.47; 95% CI, 0.29 to 0.76) and higher in the South than in the Northeast census regions (aOR 2.44; 95% CI, 1.50 to 3.96). CONCLUSION: The prevalence of MH-susceptibility is about 1 in 125,000 in cesarean deliveries, similar to the prevalence reported in non-obstetrical surgery inpatients. The findings of this study suggest that stocking dantrolene in maternity units is justified.

Early Development, Identification of Mode of Action, and Use of Dantrolene Sodium: The Role of Keith Ellis, Ph.D.

Dantrolene-a nitrofurantoin derivative-was developed by Snyder et al. in 1967. After initial discovery of its muscle relaxation potential, investigations in a number of species demonstrated dose-dependent reductions in skeletal muscle tone that were long lasting, relatively nontoxic, and free of adverse effects such as respiratory impairment. Ellis et al. then published a number of papers investigating the means by which dantrolene produced these effects. Using a series of classic physiologic models, Ellis investigated potential sites of action for the new drug, eventually narrowing this down to the intracellular calcium-release mechanism. Ellis went on to play a pivotal role in the discovery of dantrolene's effectiveness for the treatment of malignant hyperthermia, after reading a scientific bulletin about muscle rigidity in pigs affected by porcine stress syndrome, contacting Gaisford Harrison and sending dantrolene to him for trial.

Prevalence of Malignant Hyperthermia Diagnosis in New York State Ambulatory Surgery Center Discharge Records 2002 to 2011.

BACKGROUND: Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhaled anesthetics and the depolarizing neuromuscular blocking drug succinylcholine. Epidemiologic research on MH is largely limited to inpatients. In this study, we examined the prevalence of recorded MH diagnosis in patients discharged from ambulatory surgery centers (ASCs). METHODS: We analyzed the New York State Ambulatory Surgery Dataset for the years 2002 to 2011 and identified patients with a discharge diagnosis of MH due to anesthesia by using the International Classification of Disease, Ninth Revision, Clinical Modification code 995.86. MH prevalence was assessed by demographic, clinical, and ASC characteristics. RESULTS: During the study period, 31 of 17,092,765 discharges from ASCs had a recorded diagnosis of MH, yielding a prevalence of 0.18 per 100,000 discharges (95% confidence interval, 0.12-0.25). The prevalence of recorded MH diagnosis per discharge differed significantly across age groups and surgical procedure categories. All patients with a recorded diagnosis of MH were from hospital-based ASCs and were discharged alive from ASCs. CONCLUSIONS: The prevalence of recorded MH diagnosis in ASC patients is approximately 1 per 500,000 and varies considerably with surgical procedures.

Diversity and Similarity of Anesthesia Procedures in the United States During and Among Regular Work Hours, Evenings, and Weekends.

BACKGROUND: Anesthesiologists providing care during off hours (ie, weekends or holidays, or cases started during the evening or late afternoon) are more likely to care for patients at greater risk of sustaining major adverse events than when they work during regular hours (eg, Monday through Friday, from 7:00 AM to 2:59 PM). We consider the logical inconsistency of using subspecialty teams during regular hours but not during weekends or evenings. METHODS: We analyzed data from the Anesthesia Quality Institute's National Anesthesia Clinical Outcomes Registry (NACOR). Among the hospitals in the United States, we estimated the average number of common types of anesthesia procedures (ie, diversity measured as inverse of Herfindahl index), and the average difference in the number of common procedures between 2 off-hours periods (regular hours versus weekends, and regular hours versus evenings). We also used NACOR data to estimate the average similarity in the distributions of procedures between regular hours and weekends and between regular hours and evenings in US facilities. Results are reported as mean ± standard error of the mean among 399 facilities nationwide with weekend cases. RESULTS: The distributions of common procedures were moderately similar (ie, not large, <.8) between regular hours and evenings (similarity index .59 ± .01) and between regular hours and weekends (similarity index, .55 ± .02). For most facilities, the number of common procedures differed by <5 procedures between regular hours and evenings (74.4% of facilities, P < .0001) and between regular hours and weekends (64.7% of facilities, P < .0001). The average number of common procedures was 13.59 ± .12 for regular hours, 13.12 ± .13 for evenings, and 9.43 ± .13 for weekends. The pairwise differences by facility were .13 ± .07 procedures (P = .090) between regular hours and evenings and 3.37 ± .12 procedures (P < .0001) between regular hours and weekends. In contrast, the differences were -5.18 ± .12 and 7.59 ± .13, respectively, when calculated using nationally pooled data. This was because the numbers of common procedures were 32.23 ± .05, 37.41 ± .11, and 24.64 ± .12 for regular hours, evenings, and weekends, respectively (ie, >2x the number of common procedures calculated by facility). CONCLUSIONS: The numbers of procedures commonly performed at most facilities are fewer in number than those that are commonly performed nationally. Thus, decisions on anesthesia specialization should be based on quantitative analysis of local data rather than national recommendations using pooled data. By facility, the number of different procedures that take place during regular hours and off hours (diversity) is essentially the same, but there is only moderate similarity in the procedures performed. Thus, at many facilities, anesthesiologists who work principally within a single specialty during regular work hours will likely not have substantial contemporary experience with many procedures performed during off hours.

Malignant hyperthermia testing in probands without adverse anesthetic reaction.

BACKGROUND: Malignant hyperthermia (MH) is triggered by reactions to anesthetics. Reports link nonanesthetic-induced MH-like reactions to a variety of disorders. The objective of the authors was to retrospectively investigate the reasons for referrals for MH testing in nonanesthetic cases and assess their phenotype. In addition, the response to the administration of oral dantrolene in nonanesthetic probands with positive caffeine-halothane contracture test (CHCT) was investigated. METHODS: Following institutional research ethics board approval, probands without reaction to anesthesia, who underwent CHCT, were selected. Clinical details and response to dantrolene were analyzed. RESULTS: In total, 87 of 136 (64%) patients referred for nonanesthetic indications tested positive to the CHCT. Of these, 47 with a high creatine kinase (CK), 9 with exercise-induced rhabdomyolysis and/or exercise intolerance, 2 with high CK and exercise-induced rhabdomyolysis and/or exercise intolerance, 15 with postviral chronic fatigue, and 14 with muscle weakness of unknown etiology had a positive CHCT. These patients had a higher CK compared with those with negative CHCT. Oral dantrolene improved the musculoskeletal symptoms in 28 of 34 (82%) CHCT-positive patients. Response to treatment was associated with a significantly higher pretreatment CK and a greater posttreatment CK reduction. CONCLUSIONS: A positive CHCT may represent more than simply an anesthetic-related disorder. Individuals with positive CHCTs may exhibit muscle symptoms without exposure to MH-triggering anesthetics. Oral dantrolene may be useful in alleviating these symptoms.

Accuracy of malignant hyperthermia diagnoses in hospital discharge records.

BACKGROUND: In 1997, the International Classification of Diseases (ICD), 9th Revision Clinical Modification (ICD-9) coding system introduced the code for malignant hyperthermia (MH) (995.86). The aim of this study was to estimate the accuracy of coding for MH in hospital discharge records. METHODS: An expert panel of anesthesiologists reviewed medical records for patients with a discharge diagnosis of MH based on ICD-9 or ICD-10 codes from January 1, 2006 to December 31, 2008 at six tertiary care medical centers in North America. All cases were categorized as possible, probable, or fulminant MH, history of MH (family or personal) or other. RESULTS: A total of 47 medical records with MH diagnoses were reviewed; 68.1% had a documented surgical procedure and general anesthesia, and 23.4% (95% CI, 12.3-38.0%) had a possible, probable, or fulminant MH event. Dantrolene was given in 81% of the MH events. All patients judged to have an incident MH event survived to discharge. Family and personal history of MH accounted for 46.8% of cases. High fever without evidence of MH during admission accounted for 23.4%, and the reason for MH coding was unclear in 6.4% of cases. CONCLUSIONS: Approximately one quarter of ICD-9 or ICD-10 coded MH diagnoses in hospital discharge records refer to incident MH episodes and an additional 47% to MH susceptibility (including personal history or family history). Information such as surgical procedure, anesthesia billing data, and dantrolene administration may aid in identifying incident MH cases among those with an ICD-9 or ICD-10 coded MH diagnosis in their hospital discharge records.

Cost-effectiveness analysis of stocking dantrolene in ambulatory surgery centers for the treatment of malignant hyperthermia.

BACKGROUND: Malignant hyperthermia (MH) is a rare hypermetabolic syndrome of the skeletal muscle and a potentially fatal complication of general anesthesia. Dantrolene is currently the only specific treatment for MH. The Malignant Hyperthermia Association of the United States has issued guidelines recommending that 36 vials (20 mg per vial) of dantrolene remain in stock at every surgery center. However, the cost of stocking dantrolene in ambulatory surgery centers has been a concern. The purpose of this analysis is to assess the cost-effectiveness of stocking dantrolene in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States. METHODS: A decision tree model was used to compare treatment with dantrolene to a supportive care-only strategy. Model assumptions include the incidence of MH, MH case fatality with dantrolene treatment and with supportive care-only. Sensitivity analyses were performed to assess the robustness of the estimated cost-effectiveness. RESULTS: The estimated annual number of MH events in ambulatory surgery centers in the United States was 47. The incremental effectiveness of dantrolene compared with supportive care was 33 more lives saved per year. The incremental cost-effectiveness ratio was $196,320 (in 2010 dollars) per life saved compared with a supportive care strategy. Sensitivity analysis showed that the results were robust for the plausible range of all variables and assumptions tested. CONCLUSION: The results of this analysis suggest that stocking dantrolene for the treatment of MH in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States is cost-effective when compared with the estimated values of statistical life used by U.S. regulatory agencies.

Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

The Malignant Hyperthermia Association of the United States and the Department of Anesthesia at the University of Toronto sponsored a Scientific Conference on November 1-2, 2013 in Toronto, ON, Canada. The multidisciplinary group of experts, including clinicians, geneticists, and physiologists involved in research related to malignant hyperthermia (MH), shared new insights into the pathophysiology of diseases linked to the type-1 ryanodine receptor gene (RYR1) as well as the relationship between MH and "awake MH" conditions, such as exertional rhabdomyolysis and exertional heat illness. In addition, the molecular genetics of MH and clinical issues related to the diagnosis and management of disorders linked to RYR1 were presented. The conference also honoured Dr. David H. MacLennan for his contributions to our understanding of the genetics, pathogenesis, and treatment of MH and other RYR1-related myopathies. This report represents a summary of the proceedings of this conference.

Estimate of the relative risk of succinylcholine for triggering malignant hyperthermia.

BACKGROUND: Facilities with volatile anesthetic agents stock dantrolene for the treatment of malignant hyperthermia (MH). The availability of dantrolene at these facilities satisfies cost-utility norms even for sites with as few as 1 anesthetic per workday, based on the overall incidence of MH per anesthetic. We considered the stocking of dantrolene at facilities with succinylcholine alone (i.e., where volatile anesthetics are not available), by using registry data and estimates of the frequency of administration of succinylcholine during anesthesia. We determine the magnitude of the relative risk of the administration of succinylcholine for triggering MH. METHODS: The relative risk of triggering MH by succinylcholine versus volatile agents was calculated using data from 2 sources. The ratio of the number of cases of MH among patients receiving succinylcholine to number among patients not receiving succinylcholine was estimated from the previously published cohort of 284 cases of MH from the North American MH Registry of the MH Association of the United States (MHAUS). The percentage of anesthetics with succinylcholine was estimated using anesthesia information management system data from a typical North American hospital comprising tertiary operating rooms, obstetrics unit, ambulatory surgical center, and endoscopy and radiological suites. RESULTS: The relative risk of MH with versus without succinylcholine was 19.6 (lower 95% confidence limit > 16.1). Limiting to cases with volatile anesthetics, the relative risk was 9.1 (>7.5). Both relative risks exceed 1.0 (P < 0.0001). Because more than half of the reported cases of MH included the use of succinylcholine, the relative risk exceeded 1.0 provided fewer than half of anesthetics in North America included the use of succinylcholine. The incidences of succinylcholine use at the hospital were 5.8% and 11.6% for all anesthetics and for anesthetics with volatile agents, respectively. CONCLUSIONS: Our results provide no insight into the triggering mechanism for MH (i.e., succinylcholine could in isolation have an extremely low incidence of inducing MH, yet markedly increase the risk when administered in combination with volatile anesthetics). Until more epidemiologic data are collected and analyzed, having dantrolene available, where succinylcholine may be used, is reasonable, and this practice should be maintained.

Special article: Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities.

CLINICAL PROBLEM: Volatile anesthetics and/or succinylcholine may trigger a potentially lethal malignant hyperthermia (MH) event requiring critical care crisis management. If the MH triggering anesthetic is given in an ambulatory surgical center (ASC), then the patient will need to be transferred to a receiving hospital. Before May 2010, there was no clinical guide regarding the development of a specific transfer plan for MH patients in an ASC. MECHANISM BY WHICH THE STATEMENT WAS GENERATED: A consensual process lasting 18 months among 13 representatives of the Malignant Hyperthermia Association of the United States, the Ambulatory Surgery Foundation, the Society for Ambulatory Anesthesia, the Society for Academic Emergency Medicine, and the National Association of Emergency Medical Technicians led to the creation of this guide. EVIDENCE FOR THE STATEMENT: Most of the guide is based on the clinical experience and scientific expertise of the 13 representatives. The list of representatives appears in Appendix 1. The recommendation that IV dantrolene should be initiated pending transfer is also supported by clinical research demonstrating that the likelihood of significant MH complications doubles for every 30-minute delay in dantrolene administration (Anesth Analg 2010;110:498-507). STATEMENT: This guide includes a list of potential clinical problems and therapeutic interventions to assist each ASC in the development of its own unique MH transfer plan. Points to consider include receiving health care facility capabilities, indicators of patient stability and necessary report data, transport team considerations and capabilities, implementation of transfer decisions, and coordination of communication among the ASC, the receiving hospital, and the transport team. See Appendix 2 for the guide.

Special article: Future directions in malignant hyperthermia research and patient care.

Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States (MHAUS) recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care.

Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records.

BACKGROUND: Case reports have linked malignant hyperthermia (MH) to several genetic diseases. OBJECTIVE/AIM: The objective of this study was to quantitatively assess excess comorbidities associated with MH diagnosis in pediatric hospital discharge records. PATIENTS AND METHODS: Data for this study came from the Kids' Inpatient Database (KID) for the years 2000, 2003, and 2006. The KID contains an 80% random sample of patients under the age of 21 discharged from short-term, non-Federal hospitals in the United States, with up to 19 diagnoses recorded for each patient. Using all pediatric inpatients as the reference, we calculated the standardized morbidity ratios (SMRs) and 95% confidence intervals (CIs) for children with MH diagnosis according to major disease groups and specific medical conditions. RESULTS: Of the 5,916,989 nonbirth-related hospital discharges studied, 175 had a recorded diagnosis of MH. Compared with the general pediatric inpatient population, children with MH diagnosis were significantly more likely to be diagnosed with diseases of the musculoskeletal system and connective tissue (SMR 5.7; 95% CI: 3.9-7.9), diseases of the circulatory system (SMR 3.3; 95% CI: 2.1-4.8), and congenital anomalies (SMR 3.2; 95% CI: 2.3-4.4). The specific diagnosis that was most strongly associated with MH was muscular dystrophies (SMR 31.3; 95% CI 12.6-64.6). CONCLUSIONS: Diseases of the musculoskeletal system and connective tissue are significantly associated with MH diagnosis in children. Further research is warranted to determine the clinical utility of these comorbidities in assessing MH susceptibility in children.

Drug-induced Hyperthermic Syndromes in Psychiatry.

Hyperthermia, or extreme elevations in body temperature, can be life-threatening and may be caused by prescription drugs or illegal substances acting at a number of different levels of the neuraxis. Several psychotropic drug classes and combinations have been associated with a classic clinical syndrome of hyperthermia, skeletal muscle hyper-metabolism, rigidity or rhabdomyolysis, autonomic dysfunction and altered mental status ranging from catatonic stupor to coma. It is critical for clinicians to have a high index of suspicion for these relatively uncommon drug-induced adverse effects and to become familiar with their management to prevent serious morbidity and mortality. Although these syndromes look alike, they are triggered by quite different mechanisms, and apart from the need to withdraw or restore potential triggering drugs and provide intensive medical care, specific treatments may vary. Clinical similarities have led to theoretical speculations about common mechanisms and shared genetic predispositions underlying these syndromes, suggesting that there may be a common "thermic stress syndrome" triggered in humans and animal models by a variety of pharmacological or environmental challenges.