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Pediatric Anesthesiology: Research Report

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

Larach, Marilyn Green MD, FAAP*; Brandom, Barbara W. MD*†; Allen, Gregory C. MD, FRCPC; Gronert, Gerald A. MD§; Lehman, Erik B. MS

Author Information
doi: 10.1213/ANE.0000000000000421

Malignant hyperthermia (MH) is an autosomal dominant myopathy (MIM No. 145600)a manifested by sustained skeletal muscle hypermetabolism related to altered calcium homeostasis. In human susceptible individuals, MH is usually triggered by exposure to volatile anesthetic drugs and/or the depolarizing muscle relaxant, succinylcholine. MH has been associated with abnormalities in the RYR1 (ryanodine receptor type 1 gene), encoding the skeletal muscle isoform of the calcium release channel of the sarcoplasmic reticulum,1 and CACNA1S, encoding the α1 subunit of the L-type calcium channel isoform of the sarcolemma (dihydropyridine receptor).2 In the United States, clinical testing for RYR1 MH-associated mutations began in 2005. Thirty-one MH-causative mutations have been described in RYR1.b

MH mortality has been estimated as 0.0082 per 100,000 U.S. surgical inpatients, constituting 1% of all anesthesia-related deaths for the years 1999 to 2005.3 We have previously reported our findings on MH events voluntarily submitted to The North American Malignant Hyperthermia Registry (Registry) of the Malignant Hyperthermia Association of the United States (MHAUS) from 1987 through 2006. This study found a 2.7% cardiac arrest rate and a 1.4% mortality rate for 291 MH events. In this early cohort, cardiac arrest and death were associated with muscular build, the complication of disseminated intravascular coagulation, and a longer time period between anesthetic induction and maximal end-tidal carbon dioxide (CO2).4 Also, temperature abnormalities were the first to third MH sign in 63.5% of patients with a median temperature maximum of 39.1°C. As would be expected, there was an association between peak temperature and risk of disseminated intravascular coagulation.5

The MHAUS Hotline continues to receive reports of MH events complicated by cardiac arrest and death. We therefore evaluated reports received by the Registry from 2007 through 2012 (recent cohort) to update MH cardiac arrest and death rates, summarized the 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 support the hypothesis that the risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring.


The University of Pittsburgh IRB deemed this study exempt.c The study cohort was identified as shown in Figure 1. We examined AMRA (adverse metabolic or muscular reaction to anesthesia) reports received by the Registry from January 1, 2007, through December 31, 2012. The AMRA report is a standardized form including relevant medical and anesthetic history that clinicians complete and voluntarily submit to the Registry after a suspected MH incident.d As shown in Figure 1, we included AMRA reports documenting episodes that occurred in the United States or Canada, involved at least 1 anesthetic drug or neuromuscular blocker given before the event, and ranked as a “very likely” or “almost certain” MH event on the MH clinical grading scale (CGS).e,6

Figure 1
Figure 1:
Flow sheet to identify the cohort of patients included in this analysis.

We excluded 3 AMRA reports that described events before January 1, 2005. We also excluded 5 AMRA reports when all authors agreed that the underlying pathologic condition was not MH (e.g., aspiration, asthma, systemic absorption of insufflated CO2 during laparoscopic surgery, myopathies other than central core disease, seizure, sepsis, surgical complication). For in-depth analysis, reviewers were not blinded to outcome and studied the entire case report complete with molecular genetic analysis and free text added by reporting health care professionals.f

The dataset included demographic data (age, gender, muscular body build), family MH history, previous anesthetic history of unusual metabolic responses, adverse anesthetic response (anesthetic drugs, ventilation mode, monitor type including specific temperature monitor site), location in which the suspected MH episode was first recognized (operating room, postanesthesia care area, intensive care area), and clinical signs of MH (masseter spasm, generalized muscular rigidity, hypercarbia, hypertension). The dataset also included the time intervals from anesthetic induction to documentation of the first sign of an adverse anesthetic reaction, the maximal end-tidal partial pressure of CO2 (PCO2), maximal temperature, discontinuation of volatile anesthetic drugs, and first dantrolene dose. The dataset also included the maximal temperature, maximal serum potassium, maximal end-tidal PCO2, maximal arterial PCO2, lowest pH, maximal base deficit,g initial dantrolene dose (mg/kg), need for cardiopulmonary resuscitation, and survival to hospital discharge. Also included were results of molecular genetic DNA analysis of RYR1 and CACNA1S when these were available.h

Statistical Analysis

Mean and standard deviations are reported unless otherwise noted. Wilcoxon rank sum tests were used to compare the medians of time intervals.

The relationship between the likelihood of dying from an MH episode and the mode of temperature monitoring (no temperature monitoring, skin temperature monitoring only, and core temperature monitoring [1 or more of the following: pulmonary artery, nasopharyngeal, esophageal, and/or tympanic]) was evaluated. The primary hypothesis of an association between mode of monitoring versus mortality after an MH episode was assessed by the Cochran-Armitage test for proportions, with the hypothesis that the proportional mortality would be no probe > skin probe > core probe.7,8 The relative risk of dying with no probe versus core probe and skin probe versus core probe was assessed using the method of Miettinen and Nurminen.9 The relative risk was adjusted for 2 comparisons by setting α to 0.05/2 and then adjusting for a single-sided test (decreasing risk with increased monitoring). Because a single-sided test was assumed for both the Cochran-Armitage test and the calculation of the confidence interval, only the lower bound of the confidence interval is reported.

We evaluated the secondary hypothesis that peak temperature was correlated with the duration of anesthetic exposure before dantrolene administration (time to dantrolene). The P value of the slope of the relationship between time to dantrolene and peak temperature was evaluated using the Fisher exact test adjusted for 3 comparisons.

We examined the ability of 6 physiologic measurements (temperature, potassium, pH, base deficit, arterial CO2, and end-tidal CO2) to distinguish between patients who died from MH and patients who survived an MH event. For each physiologic measurement, we calculated the P value and confidence interval of the difference in the measurement between patients who lived and died. The P value was used to rank order the measurements from best (the measurement differed in the patients who died) to worst (the measurement was not different in patients who lived and died). The confidence interval was used to graphically display the data by (1) taking the mean of both groups (patients who died and patients who lived), (2) subtracting the mean of the 2 subgroup means from all data points, and (3) dividing the result by the confidence interval, yielding an estimate of effect size.

We tested the relative risk of death in this cohort versus our previous cohort, using the Fisher exact test, adjusted for 4 comparisons. Exact χ2 tests were used to compare other characteristics of the earlier and recent cohorts.


Figure 1 shows the process of identifying the study cohort. One hundred eighty-nine reports were received by the Registry between January 1, 2007 through December 31, 2012. Eighty-four (44.4%) met entry criteria and constitute the recent cohort. Of these 84 patients, 8 died of MH. (The data for the 84 patients may be found in Supplements 1–3, Supplemental Digital Content 1,; Supplemental Digital Content 2,; Supplemental Digital Content 3,

Temperature Monitoring

Figure 2 shows the relationship among MH deaths, peak temperature, and temperature monitoring. The x-axis is the peak temperature reported to the Registry. The y-axis is the cumulative number of deaths. The type of monitoring probe is indicated by color. Patients who died are indicated by an open circle with a “+” in the center.

Figure 2
Figure 2:
The relationship among peak temperature, malignant hyperthermia death, and method of temperature monitoring. The risk of death increases with increasing temperature.

All deaths occurred in patients whose peak temperature was 38.9°C or higher (mean temperature of 41.6 ± 1.7°C). Most patients with high temperatures had either no temperature probe or only a skin temperature probe. Only 3 of 9 patients whose temperature exceeded 41°C survived. Of the 9 patients whose temperature exceeded 41°C, only 2 had core temperature monitoring. Both survived.

Table 1 shows the mortality from an MH event as a function of temperature monitoring: 30%, 21%, and 2% for no monitoring, skin temperature monitoring only, and core temperature monitoring, respectively (P = 0.0012). The relative risk (lower bound) for no probe versus core probe was 13.8 (2.1). The relative risk (lower bound) for skin probe versus core probe was 9.7 (1.5).

Table 1
Table 1:
Mortality Associated with Type of Temperature Monitoring: Relative Risk for None and Skin Temperature Versus Core Temperature Monitoring

Figure 3 shows the difference in peak temperature, potassium, pH, base deficit, arterial CO2, and end-tidal CO2 in patients who lived and died. The y-axis is the effect size, calculated as described in Methods. The P value is used to rank order the measurements but not for statistical inference. In this dataset, temperature difference best distinguished patients who lived from those who died. Had we used the P values for statistical inference, the P value of 0.0022 for peak temperature would have been significant, even after adjusting for multiple comparisons. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died.

Figure 3
Figure 3:
The difference in physiologic parameters between patients who died (mean = gray line) and patients who lived (mean = black line). Red = no probe, blue = skin probe, green = core probe, yellow = other probe. Patients who lived appear as solid circles. Patients who died appear as an open circle with a “+” in the center. Peak Temp = peak temperature. pH is arterial pH. Base deficit is arterial base deficit. Peak K = peak serum potassium; EtCO2 = peak end-tidal partial pressure of carbon dioxide. The number in parentheses is the P value, used to help identify the physiologic measure that best identifies patients at risk of death.

Figure 4 shows the relationship between the time from anesthetic induction to dantrolene administration (x-axis) and peak temperature (y-axis). Longer anesthetic exposures before dantrolene are associated with higher peak temperatures (P = 0.00014 without correction, P = 0.00042 corrected for 3 comparisons).

Figure 4
Figure 4:
The relationship between peak temperature and the time from anesthetic induction to first dantrolene dose (induction to dantrolene). TheP value is adjusted for 3 comparisons. Three of 8 patients suffering malignant hyperthermia death are not shown because the time at which they received dantrolene was not reported.

Additional Patient and Event Characteristics

Nineteen (23%) patients developed signs of MH after the procedure was completed. Twelve were still in the operating room, and 7 (8.3%) were in either the postanesthesia care or intensive care units. No patient developed MH after discharge from the postanesthesia care unit. The time between anesthetic induction and the first adverse sign was longer in those who presented after a surgical procedure with a median of 145 (103 first quartile, 199 third quartile, range 23–480) minutes vs 90 (27 first quartile, 135 third quartile, range 0–600) minutes; P = 0.02. For the 82 patients in whom volatile anesthetics were reported, all had received either isoflurane, sevoflurane, or desflurane, and 6 received succinylcholine.

After their MH events, 8 of 84 (9.5%) patients were discovered to have a family anesthetic history consistent with possible MH.i Because the abnormal family anesthetic history was not revealed preoperatively, 5 of these patients (including 3 who died) received both a volatile anesthetic drug and succinylcholine, and 3 received a volatile anesthetic drug without succinylcholine.

Patient and Event Characteristics for Those Who Died

Of 84 MH patients, there were 7 cardiac arrests during the initial MH event and 8 (9.5%) deaths before discharge from the hospital. One 21-year-old patient was declared brain dead on postoperative day 8. All patients who suffered a cardiac arrest died despite resuscitation efforts. Four patients were Caucasian, 2 were Hispanic, 1 was Native American, and 1 was of undocumented race. Seven of the 8 who died were anesthetized for elective low- or intermediate-risk surgery, and 5 of 8 were healthy preoperatively.j Those who died were 31.4 ± 16.9 (range 18–67) years old.

Diagnoses of thyroid storm and airway obstruction were pursued before the administration of dantrolene in 2 cases. Four of 8 (50%) fatal anesthetics were administered in free-standing facilities. All fatal anesthetics lasted longer than 30 minutes. Time between anesthetic induction to first adverse sign of a fatal anesthetic reaction was 131.4 ± 60.5 (range 60–199) minutes. Seven of 8 fatal MH events were diagnosed in the operating room, with 2 of these detected after surgery had been completed. One event was recognized in the postanesthesia care unit.

Six of 8 patients had postmortem genetic studies, with the findings of 3 MH–causative RYR1 mutationsk and 3 RYR1 variants of uncertain significance. Two of these variants have been found in other well-studied MH-susceptible subjects1 (Table 2).

Table 2
Table 2:
Selected Characteristics of Each Malignant Hyperthermia Event in Subjects with Molecular Genetic Findings

Differences Between Early and Recent MH Cohort Survival

In our earlier MH cohort, there were 4 deaths in 291 events, for a death rate of 1.4%.4 The death rate of 9.5% in this cohort is significantly higher than our previous cohort (relative risk = 6.9; 95% confidence interval, 1.7–28; P = 0.0043, adjusted for 4 comparisons). There was low power to detect other differences between cohorts (34% for cardiac arrest mortality, 34% for operating facility location, 65% for muscular build, 39% for temperature probe site).


MH associated with general anesthesia continues to be lethal. Nearly 10% of MH episodes in this most recent cohort resulted in death, higher than the risk of death from MH in our earlier cohort reported 6 years ago. How can MH continue to be so lethal when there is a specific and effective antidote and when nearly all anesthesia providers are taught how to recognize and treat MH?

These data suggest the answer is the failure to adopt uniform temperature monitoring standards. In this study, 30% of the subjects died from an MH episode if their temperatures were not monitored, 21% died if only their skin temperature was monitored, but only 2% (1 subject) died when core temperature was monitored. The difference was highly statistically significant. No temperature monitoring at least doubles the risk of death compared to core temperature monitoring. Skin temperature monitoring in lieu of core temperature monitoring increases the risk of mortality by at least 50%.

Perhaps the consistent lack of monitoring is driven by a belief that change in temperature is a late sign of MH. We have previously shown that temperature abnormalities are an early MH sign in the majority of events.5 Now, as shown in Figure 3, we demonstrate that deranged temperature better identifies patients who will die from an MH episode than potassium, pH, arterial CO2, base deficit, or end-tidal CO2.

Relative to the early cohort, the recent MH event mortality rate has increased from 1.4% to 9.5%, although no other significant differences were detected between the 2 cohorts.4 Our power to detect other differences was limited by the small numbers of patients who had suffered cardiac arrest or death in each cohort.

The mean temperature of those who died in the recent cohort was 41.6°C. In a 1978 study, Bynum et al.10 suggested that temperatures of 41.6°C to 42°C for 45 minutes to an hour constitute a critical thermal maximum in humans. Once the critical thermal maximum is reached, the high temperatures cause irreversible tissue damage due to apoptosis, making it difficult for patients to recover.11 Our study is limited by the lack of data regarding the length of time each patient spent at his or her maximal temperature. Going forward, the Registry will query maximal temperature duration.

American Society of Anesthesiologists monitoring standards state that “every patient receiving anesthesia shall have temperature monitored when clinically significant changes in body temperature are intended, anticipated or suspected.”l This is in contrast to the MHAUS recommendation that “all patients undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe.”m The guidance on monitoring after 30 minutes reflects the difficulty of interpreting core temperature changes during this initial anesthetic period.12 In the 2007–2012 cohort, the first sign of fatal MH events occurred >30 minutes after anesthetic induction.

The MH deaths associated with inadequate temperature monitoring documented in this study should prompt re-examination of current American Society of Anesthesiologists and MHAUS temperature monitoring standards. Our data demonstrate that without continuous core temperature monitoring, clinicians are unable to “anticipate or suspect” what is going to happen in time to intervene in fatal MH events. Continuous and reliable monitoring of core temperature could have allowed rescue before patients’ temperatures became critical. Revision of temperature monitoring standards should alert clinicians regarding life-threatening nonspecific MH-presenting signs such as inappropriate tachycardia and hypercarbia.5

In 23% of all cases in this report, the first MH sign was noted after the surgical procedure was complete, with 8.3% identified in either the postanesthesia or intensive care units. This is higher than the 1.9% observed by Litman et al.13 in an earlier Registry cohort. The reasons for this difference are unclear. Our findings emphasize the value of continued vigilance for MH, including accurate temperature monitoring even after surgery has been completed.

Our study is limited by incomplete patient data, underreporting, and/or biased reports inherent in a fragmented medical system and a Registry dependent on voluntary reporting of an infrequent event. The small number of cases reduced power. These limitations may impact our findings. Nevertheless, we report 8 lethal events.

When death highly suspicious for MH occurs, the anesthesia care team should take responsibility for ensuring that blood or muscle is collected for postmortem RYR1 analysis.n When an MH-causative mutation is found, familial mutation analysis may serve as the first step in identifying surviving relatives who now require non-MH-triggering anesthetics.14 There should be a low threshold for initiating the MH treatment protocol in susceptible individuals even in the absence of anesthetic drugs.15

We report 3 individuals in whom a possible familial MH history was discovered only after death. This underscores the importance of identifying those who are susceptible to this potentially lethal disorder and disseminating this information appropriately to family members and health care providers. Patients undergoing general anesthetics should be encouraged to ask all family members about adverse anesthetic events, including perioperative deaths, before they meet their anesthetic providers for evaluation.

Muscle contracture testing remains a valuable method for documenting pathogenicity when a genetic variant of uncertain significance is found. Muscle contracture testing remains the only validated method for demonstrating that an individual does not have an increased risk of MH.16

Finally, to prevent MH deaths, clinicians should monitor core temperatures intraoperatively whenever their patients undergo general anesthesia for at least 30 minutes.


Name: Marilyn Green Larach, MD, FAAP.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Marilyn Green Larach has seen the original study data, has reviewed the analysis of the data, has approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Barbara W. Brandom, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Barbara W. Brandom has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Barbara W. Brandom received research support from the Malignant Hyperthermia Association of the United States, which is a not-for-profit group. She is the current director of The North American MH Registry, which is a subsidiary of MHAUS.

Name: Gregory C. Allen, MD, FRCPC.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Gregory C. Allen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Gerald A. Gronert, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Gerald A. Gronert has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Erik B. Lehman, MS.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Erik B. Lehman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

This manuscript was handled by: Steven L. Shafer, MD.


We express our sympathy to the families whose relatives died during MH events and our gratitude to anesthesiologists, intensive care physicians, surgeons, nurse anesthetists, other health care professionals, and MHAUS MH Hotline Consultants who anonymously submitted AMRA report forms. This project would not have been possible without the financial support of MHAUS for The North American Malignant Hyperthermia Registry during the study period. We acknowledge the support of John Williams, MD, Peter and Eva Safar Professor of Anesthesiology, University of Pittsburgh Medical Center, who allowed the Safar Fund to support The North American Malignant Hyperthermia Registry of MHAUS so that this work could be continued. We thank Kristee Adams, BA, The North American Malignant Hyperthermia Registry of MHAUS administrative assistant, and Michael Young, MS, The North American Malignant Hyperthermia Registry of MHAUS technical database manager, for their assistance in preparing and disseminating data. The authors thank Steven L. Shafer, MD, Editor-in-Chief of Anesthesia & Analgesia, for assistance with the statistical analysis.


a Accessed September 21, 2013.
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b Accessed July 4, 2014.
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c University of Pittsburgh IRB# PRO12070525.
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d Accessed September 21, 2013.
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e Due to unreliability of reported myoglobin units in the AMRA forms, myoglobinuria and myoglobinemia were excluded from the muscle breakdown category of the clinical grading scale calculation. Also, points for rapid reversal of metabolic and/or respiratory acidosis with IV dantrolene were awarded if these conditions “existed,” dantrolene was given, and a decrease in end-tidal PCO2 or arterial PCO2 was reported.
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f For cardiac arrest/death cases, reviewers were MGL, BWB, GCA, GAG. For non-cardiac arrest/death cases, reviewers were MGL, BWB, GCA.
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g If unreported, base deficit was calculated using calculator found at this website and accessed during the months of August through October 2013:
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h Reports of RYR1 screening were available from a few survivors. RYR1 clinical screening results were available in 5 of those who died. These clinical tests were limited to sequence analysis of the hotspots of RYR1 where all the proven MH-causative mutations are located. The family of another subject who died consented to a research protocol with screening of all 106 exons in RYR1 and all 44 exons in CACNA1S.1
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i Examples include patients with a family history of a possible MH death; a mother who experienced heat stroke and was intolerant to anesthetic gases and a brother who may have had King-Denborough syndrome; 2 paternal great uncles who died on the operating table; a sister who had an intraoperative hyperthermic episode; and a paternal grandfather who had 2 cardiac arrests during separate general anesthetics.
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j Underlying conditions in 3 of those who died included insulin-dependent diabetes mellitus in a 22-year-old male undergoing a urologic procedure; cardiac ablation performed for recurrent vasovagal bradycardia in a 28-year-old male with a recent crush injury and abdominal free air for an emergent exploratory laparotomy; and diabetes mellitus type 2, coronary artery disease, hypercholesterolemia, and hypertension in a 67-year-old male undergoing repeat back surgery for single level fusion.
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k Accessed October 6, 2013.
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l Standards for basic anesthetic monitoring. Approved by the ASA House of Delegates on October 21, 1986, and last amended on October 20, 2010, with an effective date of July 1, 2011. Accessed October 3, 2013.
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m Accessed October 3, 2013.
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n Accessed September 25, 2013. Both addresses of clinical laboratories where RYR1 screening is performed and those of MH Diagnostic Muscle Biopsy Centers are listed at this website.
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