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.

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.

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.

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.

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.

Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin.

STUDY OBJECTIVE: Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhalational anesthetics and the depolarizing neuromuscular blocking agent succinylcholine. Epidemiologic data on the geographic variation in MH prevalence is scant. The objective of this study is to examine the prevalence of recorded MH diagnosis in patients discharged from hospitals in four states in the United States. DESIGN: Observational study. SETTING: Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) for California (2011), Florida (2011), New York (2012) and Wisconsin (2012). PATIENTS: A total of 164 hospital discharges that had a recorded diagnosis of MH using the International Classification of Disease, 9th Revision, Clinical Modification code 995.86. METHODS: MH prevalence was assessed by patient demographic and clinical characteristics. MAIN RESULTS: The prevalence of MH per 100,000 hospital discharges ranged from 1.23 (95% Confidence Interval [CI], 0.80-1.66) in New York to 1.91 (95% CI, 1.48-2.34) in California, and the prevalence of MH per 100,000 surgical discharges ranged from 1.47 (95% CI, 0.93-2.02) in New York to 2.86 (95% CI, 2.00-3.71) in Florida. The prevalence of MH in male patients was more than twice the prevalence in female patients. Of the 164 patients with MH diagnosis, 11% were dead on discharge. CONCLUSIONS: There exists a modest variation in the prevalence of recorded MH diagnosis in hospital discharges in California, Florida, New York and Wisconsin. Epidemiologic patterns of MH diagnosis in hospital discharges appear to be similar across the four states. Further research is needed to better understand the geographic variation and contributing factors of MH in different populations.

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings.

CONTEXT: Recent case reports on malignant hyperthermia (MH)-like syndrome in physically active populations indicate potential associations among MH, exertional heat stroke (EHS), and exertional rhabdomyolysis (ER). However, an expert consensus for clinicians working with these populations is lacking. OBJECTIVE: To provide current expert consensus on the (1) definition of MH; (2) history, etiology, and pathophysiology of MH; (3) epidemiology of MH; (4) association of MH with EHS and ER; (5) identification of an MH-like syndrome; (6) recommendations for acute management of an MH-like syndrome; (7) special considerations for physically active populations; and (8) future directions for research. SETTING: An interassociation task force was formed by experts in athletic training, exercise science, anesthesiology, and emergency medicine. The "Round Table on Malignant Hyperthermia in Physically Active Populations" was convened at the University of Connecticut, Storrs, September 17-18, 2015. CONCLUSIONS: Clinicians should consider an MH-like syndrome when a diagnosis of EHS or ER cannot be fully explained by clinical signs and symptoms presented by a patient or when recurrent episodes of EHS or ER (or both) are unexplained. Further research is required to elucidate the genetic and pathophysiological links among MH, EHS, and ER.

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.

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.

A rare genetic variant of the ryanodine receptor in a suspected malignant hyperthermia susceptible patient.

Malignant hyperthermia (MH) remains a diagnostic challenge. This case report describes the anesthetic management of a suspected intraoperative MH episode and the subsequent, genetic sequence analysis of 3 genes associated with MH. The results of the molecular genetic testing revealed heterozygosity for a rare variant, c.12553G>A (p.Ala4185Thr), in the RYR1 gene encoding the ryanodine receptor. Although the RYR1 gene has previously been implicated in the pathogenesis of MH, (1) this particular variant has only been reported in one other case of MH; (2) the role for diagnostic genetic testing in the diagnosis of MH will be examined.

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.

Malignant hyperthermia: a review.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to <5 % in 2006.

Implications of National Anesthesia Workload on the Staffing of a Call Center: The Malignant Hyperthermia Consultant Hotline.

Recently, we analyzed data from the American Society of Anesthesiologist's (ASA) Anesthesia Quality Institute (AQI) to report the United States (U.S.) anesthesia workload by time of day and day of the week. The AQI data were reported using the Central Time zone. Times for the N = 613 calls to the Malignant Hyperthermia Association of the United States (MHAUS) Malignant Hyperthermia (MH) Hotline from August 1, 2012, through March 7, 2014, were adjusted similarly. The MH Hotline effectively provides at all times to each anesthesia group an additional board-certified anesthesiologist who has expertise in managing, diagnosing, and/or preventing MH crises. We compared the timing of calls with the MH Hotline consultants relative to times of most anesthesia workload nationally. The interval 6:30 AM to 6:30 PM Central Time on regular workdays accounted for most (P < 0.0001) calls to the MH Hotline (62.5% ± 2.0% [mean ± standard error]). However, the interval accounted for significantly less than the 82.2% of anesthesia minutes and 84.5% of general anesthesia minutes during that interval nationally (both P < 0.0001). Thus, most calls to the MH Hotline occurred when anesthesia groups nationwide were the busiest. Weekends accounted for 15.3% ± 1.5% of MH Hotline calls, significantly greater than the rates of 5.2% of anesthesia minutes and 4.3% of general anesthesia minutes during weekends nationally (both P < 0.0001). Thus, the MH Hotline was used proportionately more often when anesthesia providers have fewer colleagues present and available for consultation (all P < 0.0001). These findings may be expected of other (future) national support centers for anesthesia.

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.