North American Malignant Hyperthermia Research Articles

Postoperative malignant hyperthermia confirmed by calcium-induced calcium release rate after breast cancer surgery, in which prompt recognition and immediate dantrolene administration were life-saving: a case report

BackgroundMalignant hyperthermia (MH) is a rare genetic disease characterized by the development of very serious symptoms, and hence prompt and appropriate treatment is required. However, postoperative MH is very rare, representing only 1.9% of cases as reported in the North American Malignant Hyperthermia Registry (NAMHR). We report a rare case of a patient who developed sudden postoperative hyperthermia after mastectomy, which was definitively diagnosed as MH by the calcium-induced calcium release rate (CICR) measurement test.Case presentationA 61-year-old Japanese woman with a history of stroke was hospitalized for breast cancer surgery. General anesthesia was introduced by propofol, remifentanil, and rocuronium. After intubation, anesthesia was maintained using propofol and remifentanil, and mastectomy and muscle flap reconstruction surgery was performed and completed without any major problems. After confirming her spontaneous breathing, sugammadex was administered and she was extubated. Thereafter, systemic shivering and masseter spasm appeared, and a rapid increase in body temperature (maximum: 38.9 °C) and end-tidal carbon dioxide (ETCO2) (maximum: 59 mmHg) was noted. We suspected MH and started cooling the body surface of the axilla, cervix, and body trunk, and administered chilled potassium-free fluid and dantrolene. After her body temperature dropped and her shivering improved, dantrolene administration was ended, and finally she was taken to the intensive care unit (ICU). Body cooling was continued within the target range of 36–37 °C in the ICU. No consciousness disorder, hypotension, increased serum potassium level, metabolic acidosis, or cola-colored urine was observed during her ICU stay. Subsequently, her general condition improved and she was discharged on day 12. Muscle biopsy after discharge was performed and provided a definitive diagnosis of MH.ConclusionsThe occurrence of MH can be life-threatening, but its frequency is very low, and genetic testing and muscle biopsy are required to confirm the diagnosis. On retrospective evaluation using the malignant hyperthermia scale, the present case was almost certainly that of a patient with MH. Prompt recognition and immediate treatment with dantrolene administration and body cooling effectively reversed a potentially fatal syndrome. This was hence a valuable case of a patient with postoperative MH that led to a confirmed diagnosis by CICR.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility.

Malignant hyperthermia susceptibility (MHS) is a disorder of the regulation of calcium in skeletal muscle. Muscular individuals have been shown to have a 13.6-fold increased risk of death during malignant hyperthermia (MH) episodes and are more likely to experience a recurrence after initial treatment. Twenty-five percent of severe MH episodes have occurred in elite athletes. This study investigated the association between MHS and muscular body build. Data were obtained from existing reports in the North American Malignant Hyperthermia Registry, including the Report of Muscle Biopsy and Contracture Testing (caffeine-halothane contracture test [CHCT]) as well as Adverse Metabolic or Muscular Reaction to Anesthesia (AMRA) reports. Malignant hyperthermia susceptible individuals were compared with MH negative individuals with regard to body build and reason for testing. Males were also compared with females. Both the CHCT and the AMRA forms were reviewed for comments. Of the 1,292 individuals diagnosedwith MHS by CHCT, males were more likely to be diagnosed with the disorder than females (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.99 to 2.7; P < 0.001). Muscular individuals were more likely to be diagnosed with MHS than non-muscular individuals (OR, 1.94; 95% CI, 1.51 to 2.49; P < 0.001). Males were more likely to be tested after having a possible MH episode (OR, 2.33; 95% CI, 1.45 to 2.1; P < 0.001). Logistic regression showed that male sex (OR, 2.28; 95% CI, 1.93 to 2.7; P < 0.001) and muscular body build (OR, 2.17; 95% CI, 1.21 to 3.9; P = 0.01) were independently predictive of MHS. The interaction between muscular body build and male sex was not significant (P = 0.13). Indications for testing, MH episode vs family history of MH, did not differ between muscular and non-muscular individuals (P = 0.44). Eight of 839 AMRAs and two reports of CHCT had comments describing athletic abilities. Ryanodine receptor type 1 (RYR1) gene mutations were found in five of these athletes. Muscular body build and male sex are strongly associated with MHS.

Survey of Long-Term Sequelae in Survivors of a Malignant Hyperthermia Reaction

BACKGROUND: Malignant Hyperthermia (MH) is a potentially fatal, autosomal dominant disorder associated with administration of volatile anesthetics and/or the depolarizing paralytic succinylcholine. Symptoms include muscle rigidity, tachycardia, elevated body temperature, and metabolic acidosis, which are secondary to accelerated skeletal muscle metabolism. MH susceptibility can be a chronic condition, and some MH susceptible patients may develop symptoms subsequent to anesthetic exposure. OBJECTIVE: This is the first study examining the sequelae of an MH event after hospital discharge. METHODS: A survey was sent to patients who voluntarily registered with the North American Malignant Hyperthermia Registry, which included questions on severity of symptoms predominating prior to the MH event, one month after the MH event, and presently on a scale of 1 - 10 with a free text option to expound further. Participants were also asked about their opinions on causality between MH and these symptoms. RESULTS: Twenty-three responses were analyzed (34.8% response rate). Participants were categorized by their age at the time of the MH event and years since the event. Most (83%) stayed in the ICU between 1 - 4 days, and 39% experienced the event over 25 years ago. While 43% did not attribute any long-term symptoms to their MH event, all others believed that certain symptoms were linked, including muscle pain (90%), muscle cramps (75%), muscle weakness (100%), back/joint pain (36%) and depression/anxiety (42%). CONCLUSIONS: Our study concluded that long-lasting morbidities may be attributed to an MH event. Chronic musculoskeletal symptoms are experienced by the majority of patients who experience acute MH.

Using a Vulnerability Theoretical Model to Assess the Malignant Hyperthermia Susceptible Population: Implications for Advanced Practice Emergency Nurses.

Malignant hyperthermia (MH) is a high-risk, low-occurrence medical emergency with symptoms that include a severe increased rate of metabolic activity and rigid skeletal muscles. Clinicians should be knowledgeable and prepared for an MH event because it can occur in areas outside the operating room and without anesthetic triggers. Patients who have this rare genetic condition may come to the emergency department (ED) presenting with symptoms of heat stroke. However, the incidence of suspected MH in the ED or other critical care areas is not easily quantifiable because clinicians may not report cases to a centralized registry. The purpose of this article is to describe the MH-susceptible vulnerable population, to apply a vulnerability theoretical model to assess patients and families, to identify strategies for health promotion to reduce vulnerability, and to discuss how advanced practice nurses who specialize in emergency care can help decrease the vulnerability of MH-susceptible patients and families. By using a vulnerability model to assess the MH-susceptible population, nurses can effectively sort out strategies to prevent poor patient outcomes related to MH and promote health for this high-risk population. Measuring accurate core temperatures, applying effective cooling methods, and administering dantrolene are key concepts in caring for a patient who is experiencing an MH event. Advanced practice emergency nurses can participate in reducing vulnerability for this population by applying the Emergency Nurses Association Clinical Nurse Specialist competencies to MH-related vulnerabilities. Enhancing preparedness, evaluating and coordinating education programs, advocating for report submissions to the North American Malignant Hyperthermia Registry, and assessing opportunities for community collaboration are among the strategies discussed for reducing vulnerability for the MH-susceptible population.

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.

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. 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. 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). 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.

Malignant Hyperthermia in Children

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. 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. 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. 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.

Anesthetic Drugs and Onset of Malignant Hyperthermia

The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.

Difficult diagnosis of malignant hyperthermia during laparoscopic surgery

Difficult diagnosis of malignant hyperthermia during laparoscopic surgery

Estimate of the Relative Risk of Succinylcholine for Triggering Malignant Hyperthermia

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. 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. 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. 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.

Confirmation of Nonanesthetic-induced Malignant Hyperthermia

To the Editor: We read with interest the important study by Groom et al. , Identical de novo Mutation in the type 1 Ryanodine Receptor Gene Associated with Fatal, Stress-induced Malignant Hyperthermia in Two Unrelated Families.1Although we are pleased that this article merited an editorial, Nonanesthetic Malignant Hyperthermia by Lehmann-Horn et al. ,2we have several concerns about its content.First, we question the editorial's statement, “The in vitro contracture test performed on a muscle biopsy of the boy reported in this article would be considered by Europeans as malignant hyperthermia (MH) equivocal.”2As reported by Groom et al. , case 1 had a mean response of 8.5 g (9.3, 9.0, 7.1 g) contracture in the presence of 3% halothane (less than 0.7 g contracture is designated non-MH susceptible) and a mean 2.4 g (1.9, 2.9 g, insufficient muscle to permit testing in triplicate) contracture in the presence of 2 mM caffeine (less than 0.3 g is non-MH susceptible)1(Sheila M. Muldoon, M.D., Professor of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, written communication, December 6, 2011). This MH contracture test was conducted according to the standards of the North American Malignant Hyperthermia Group3with clearly positive responses in all five muscle strips to both the halothane and the caffeine portions of this test.4The North American and European MH biopsy methods are similar but not identical. The most important differences are bolus versus incremental halothane exposure and the European designation of an equivocal research diagnostic category for subjects demonstrating positive contracture responses only to halothane or only to caffeine exposures.3,5Islander and Twetman have studied the concordance of the North American and European biopsy protocols. Although Islander and Twetman's excellent study found an accordance in diagnostic outcome between the European and North American protocols of 87%, they noted a 100% accordance for individuals with contractures exceeding thresholds in at least five of six tested muscle strips. They observed diverging outcomes in subjects with less reproducible test results near the cutoff limits of their respective protocols.6Because case 1's results markedly exceeded North American diagnostic thresholds by an order of magnitude in five of five tested muscle strips to both halothane and caffeine exposures, we contend that this patient should be designated by both North Americans and Europeans to be MH susceptible and not equivocal and thus, a suitable genetic research subject.Second, although we are aware of individual case reports, there have been no large-scale human studies that support the statement of Lehmann-Horn et al. that MH-susceptible individuals presenting with ophthalmoplegia and muscle hypotonia, hypertrophy, or spasms will be at risk for nonanesthetic MH. We believe that the authors should have clearly noted that this was only their opinion.Finally, despite diligent parental care and aggressive medical interventions, children such as the one described in case 1 are at risk of death from this poorly understood condition. In such situations, blaming the parents helps no one.

Complications Associated with the Administration of Dantrolene 1987 to 2006

Dantrolene is the only specific treatment for malignant hyperthermia (MH), a genetic disorder in which life-threatening temperature increase has been induced by inhalation anesthetics and succinylcholine. Because MH presents with nonspecific signs and delay of treatment can be fatal, dantrolene may be given as soon as MH is suspected. We report the complications associated with dantrolene administration as documented in AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports submitted to the North American Malignant Hyperthermia Registry. AMRA reports were analyzed for differences between subjects with and without complications attributed to dantrolene. Documentation of dantrolene dose and subject weight were inclusion criteria. Because some reported complications were likely due to factors other than dantrolene, a reduced set of cases was also defined. We used χ(2) and Mann-Whitney tests. Logistic regression was applied to describe factors associated with increased risk of complications. In the full dataset of 368 subjects, the most frequent complications associated with dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), and respiratory failure (3.8%). Logistic regression described a 29% increase in risk of any complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid administration was part of treatment, an 83% decrease in risk in the presence of neurosurgery, and a 74% decrease in risk in the presence of oral surgery. In the dataset reduced by removal of some serious complications that were judged likely to have been due to preexisting disease or the MH event, there were 349 subjects. The most frequent complications associated with dantrolene were muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). In this reduced dataset, logistic regression described a 25% increase in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in the presence of obstetric or gynecologic surgery, a 56% decrease in risk if furosemide was given, and no relationship with fluid administration or other types of surgery. Complications after dantrolene are common, but rarely life threatening. Unidentified factors in the surgical environment are associated with changes in the risk of complications. Fluid management, as part of the treatment of MH, has an important association with the risk of complications after dantrolene administration and should be monitored closely.

In Response

Dr. Setzer-Saade1 questions a malignant hyperthermia (MH) episode in a child without exposure to volatile anesthetics or succinylcholine. We now have the patient data reported to the North American Malignant Hyperthermia Registry of MHAUS via the AMRA (adverse metabolic/musculoskeletal to anesthesia) from 2004 and new information from the patient’s anesthesiologist, whose contact information was still accurate. This 2-year-old, 12.7-kg girl with a lean build presented for elective dental restorations due to dental caries (without known abscesses). She had a positive family history of MH but no personal history of muscle weakness, cramps, cola-colored urine, heat stroke or intolerance to heat, unexplained fevers, generalized infection, or exercise intolerance due to muscle pain, weakness, or fever. She did not have increased or decreased muscle tone, generalized muscle weakness, myopathy, ptosis, strabismus, hernia, clubbed foot, joint hypermobility, kyphosis, pectus carinatum, winged scapulae, skeletal fractures, or laryngeal papillomas. Her preoperative vital signs were arterial blood pressure 90/50 mm Hg, PR 115 beats per minute (bpm), respiratory rate 20 per minute, and oral temperature 98.2°F. This was her first anesthetic and the Ohmeda Excel 210 machine (not a workstation) was prepared by removing all anesthetic vaporizers, changing the soda lime in the carbon dioxide absorber, and flushing overnight with oxygen at 10 L/min. Monitoring included blood pressure, electrocardiograph, stethoscope, end-tidal PCO2, pulse oximeter, and both a skin liquid crystal temperature probe and an esophageal temperature probe. No forced air or IV warming device was used. She was well sedated with oral midazolam and accepted IV cannulation while breathing 30% nitrous oxide and 70% oxygen. Anesthetic drugs included IV propofol, IV morphine, nitrous oxide, and IV glycopyrrolate. Her trachea was intubated before the development of her adverse reaction. Fifteen minutes after induction, she developed an inappropriate rapidly increasing temperature with a maximum temperature of 41.6°C observed 25 minutes after induction. Thirty minutes after induction, her maximum expired CO2 was considered by the reporting anesthesiologist to be inappropriately increased to 52 mm Hg, despite assisted manual ventilation. Twenty-eight minutes after induction (13 minutes after her first adverse sign), she was given a dantrolene dose of 2.5 mg/kg and received a total of 3.9 mg/kg before her transfer to a children’s hospital. Other treatment included hyperventilation with 100% oxygen, active cooling, fluid loading, and IV sodium bicarbonate. Less than 5 minutes after dantrolene, her temperature began to decrease. After the adverse reaction, she had received midazolam and rocuronium, but her trachea was extubated with stable vital signs before transport. Forty-two minutes after induction, breathing 100% oxygen, arterial blood gas was pH 7.18, PCO2 52 mm Hg, PO2 515 mm Hg, BE −8.4 mEq/L, bicarbonate 19 mEq/L, and potassium 3.9 mEq/L. There was no bleeding tendency. Creatine kinase values were not reported because they were obtained at the facility to which she was transferred. Scheduled dental restorations were not completed. Additional adverse signs associated with MH did not recur. Sepsis workup was negative, and she was discharged the next day with an MH diagnosis. Diagnostic muscle biopsy and molecular genetic analysis were not performed. The clinical grading scale ranking for this patient’s event was “almost certain” MH.2 Did she really have MH instead of iatrogenic warming or sepsis? She had a brief anesthetic without external warming, her teeth were not abscessed, her sepsis workup was negative, and she was discharged on postoperative day 1. We judge that the most likely diagnosis was MH. If it was MH, what triggered this episode? Given the preparation of the anesthesia machine preoperatively, it is unlikely due to trace volatile anesthetics. Most likely, this episode was triggered by unknown factors. This has happened in known MH-susceptible individuals who receive “non-MH triggering” anesthetics.3,4 “Until we understand the mechanism of human MH triggering, no anesthetic regimen can guarantee safety”5 underscoring the need for vigilance. Marilyn Green Larach, MD, FAAP The North American Malignant Hyperthermia Registry of MHAUS and Penn State College of Medicine Hershey, Pennsylvania [email protected] Gerald A. Gronert, MD The North American Malignant Hyperthermia Registry of MHAUS and University of California at Davis Davis, California Gregory C. Allen, MD, FRCPC The North American Malignant Hyperthermia Registry of MHAUS and Olympia Anesthesia Associates Olympia, Washington Barbara W. Brandom, MD The North American Malignant Hyperthermia Registry of MHAUS and Children's Hospital and the University of Pittsburgh Pittsburgh, Pennsylvania Erik B. Lehman, MS Penn State College of Medicine Hershey, Pennsylvania

Clinical Presentation, Treatment, and Complications of Malignant Hyperthermia in North America from 1987 to 2006

We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.

Administrative Databases: Are They Useful for Clinical Analyses?

To the Editor:— We are pleased that Rosero et al. 1pursued a study of the epidemiology of malignant hyperthermia (MH). We agree with Rosero et al. that reporting to the North American Malignant Hyperthermia Registry may underestimate MH mortality. From the Malignant Hyperthermia Association of the United States Hotline and the American Society of Anesthesiologists Closed Claims Project database we are aware of deaths clearly due to MH that were not reported to the Registry. Reports to the North American Malignant Hyperthermia Registry are voluntary, but provide key details that administrative databases cannot.2†We encourage readers to report suspected MH episodes to the Registry, using forms that are available online at www.mhreg.org.Rosero et al. define MH cases by the hospital discharge diagnosis code of malignant hyperthermia as a result of anesthetics, after excluding other conditions associated with hyperthermia. Did the authors attempt to confirm that the 2,312 MH cases not admitted from another health facility had been exposed to an anesthetic, for example by linking them to surgical or procedural International Classification of Disease, ninth revision (ICD-9) codes? The diagnosis of MH would be more certain if there was some evidence of anesthetic exposure, not just a code.Like any database, the “output” depends on the accuracy of the data entered. The Nationwide Inpatient Sample depends on accurate coding by medical records departments, which in turn are dependent on clinical documentation. The diagnosis of MH requires no supporting evidence to be coded as such. Other studies have shown that incorrect coding and diagnostic inaccuracy can undermine calculations derived from administrative databases.3,4Rosero et al. conclude that the incidence of MH increased from 2000 to 2005. An equally plausible explanation is reporting bias: As coders became aware of the new ICD-9 code for MH, they used it more often. This code (995.86) was approved in 1997, thanks to the efforts of the Malignant Hyperthermia Association of the United States and American Society of Anesthesiologists, and coders may have been unaware of its existence, given the rarity of MH.Finally, we point out an error in Rosero et al. 's paper. The 2007 review by Rosenberg et al. 5did not consider our 2008 report of an MH-associated mortality rate of 1.4% to be “controversial.”2Their review was published almost a year before our paper, making it impossible to cite.*The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States, and Penn State College of Medicine, Hershey, Pennsylvania. mlarach@gmail.com

Postoperative Malignant Hyperthermia

The initial presentation of malignant hyperthermia (MH) may begin in the postoperative period. However, the maximal latency period between the end of anesthesia care and the onset of postoperative MH is unknown. The authors hypothesized that this latency period is short and is not manifested by hyperthermia as the initial presenting sign. The authors sought to test this hypothesis and to describe the clinical characteristics of postoperative MH by analysis of suspected cases in the North American Malignant Hyperthermia Registry. Of 528 possible or suspected cases of MH in the North American Malignant Hyperthermia Registry, the authors identified 64 possible reports of postoperative MH. The records were reviewed in detail by the authors, each of whom assigned a qualitative score of "likely," "not likely," "not enough information available," or "not applicable" (where MH was not the final definitive diagnosis). Postoperative MH was confirmed after a consensus meeting of the three senior authors who reviewed in detail all possible "likely" cases. The authors identified postoperative MH in 10 subjects. All received volatile agents and 5 also received succinylcholine. All demonstrated signs characteristic of acute MH, including generalized rigidity, hypercapnia and/or tachypnea, tachycardia, and hyperthermia. No subject demonstrated hyperthermia as the presenting sign. The latency period between the anesthesia finish time and the onset of a sign indicative of acute MH ranged from 0 to 40 min. Postoperative MH is uncommon, occurring in 10 of 528 suspected MH cases (1.9%) reported to the North American Malignant Hyperthermia Registry. Postoperative MH began shortly after completion of the anesthetic care. Hyperthermia was not a presenting sign of MH.

Cardiac Arrests and Deaths Associated with Malignant Hyperthermia in North America from 1987 to 2006

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. 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. 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. 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.

Analysis of the Clinical Variables Associated with Recrudescence after Malignant Hyperthermia Reactions

Some patients develop recrudescence after a malignant hyperthermia (MH) reaction, but it is not clear which patients are at risk. The authors analyzed clinical variables associated with recrudescence after a clinical MH episode. Data were obtained from Adverse Metabolic Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Patients who underwent general anesthesia and with an MH clinical grading score of 20 or greater, indicating a likely MH reaction, were included in this analysis. Patient characteristics, anesthetic agents, MH reaction clinical details, and postoperative outcomes were compared in the recrudescence and no recrudescence groups using chi-square tests and Z tests for categorical variables and the Student t test for continuous variables. Associations of clinical variables with recrudescence were assessed with univariate and multivariate logistic regression. Of 308 patients, 63 (20%) had recrudescence. The mean time from initial reaction to recrudescence was 13 h (SD = 13 h). Patients with recrudescence were more likely to have a muscular body type (P < 0.01), malignant hyperthermia score of 35 or greater (P < 0.01), a temperature increase (P < 0.01), and more than 150 min from induction to adverse reaction (P < 0.05). Muscular body type, a temperature increase, and a longer time from induction to initial malignant hyperthermia reaction were associated with recrudescence on multivariate logistic regression analysis. Recrudescence occurred in 20% of patients. Muscular body types had a higher rate of recrudescence, perhaps associated with increased muscle mass. The risk of recrudescence increased as time from induction to the initial MH reaction increased, perhaps as a result of greater muscle exposure to triggering agents.

Malignant hyperthermia genetic testing in North America Working Group Meeting. Bethesda, Maryland. September 4-5, 2002.

Malignant hyperthermia genetic testing in North America Working Group Meeting. Bethesda, Maryland. September 4-5, 2002.

Genetic Mutation Characterized in Malignant Hyperthermia Canine Population

Genetic Mutation Characterized in Malignant Hyperthermia Canine Population. Roberts et al. (page 716)In pigs and in up to 50% of humans who experience malignant hyperthermia (MH) events, the disorder has been linked to mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor 1 (RyR1). To determine the molecular basis of canine MH, Roberts et al. established a breeding colony by mating a male mixed-breed dog that was MH-susceptible (MHS) and had survived an in vivo halothane–succinylcholine challenge to three unaffected females, producing four litters. Two additional litters were produced by back-crossing to an unaffected daughter and by mating an MHS son to an unaffected female. Of the total of 47 dogs produced from this breeding program, 31 were subjected to a halothane–succinylcholine challenge in an effort to trigger an MH event. The researchers also biopsied specimens of gracilis muscle obtained from all 47 dogs to determine whether they were MHS or MH normal (MHN) according to the North American Malignant Hyperthermia Group’s test protocol for establishing MH (the in vitro contracture test with halothane and caffeine).During the in vivo challenge, tachycardia, hyperthermia, and hypercapnia developed in 24 dogs, establishing them as MHS. (In contrast to pigs and humans with MH, dogs do not exhibit lactic acidemia, metabolic acidosis, or extensor rigidity.) With the in vitro contracture test, 23 dogs were MHS, 19 were MHN, and 5 were indeterminate. Animals were then tested for linkage to the MHS phenotype. Results of the mutational analysis showed that MH susceptibility in this study colony was transmitted as an autosomal dominant trait. All MHS dogs were heterozygous for the new T1640C mutation found on chromosome 1. None of the MHN dogs carried this mutation. Detection of this mutant allele by clinical challenge and in vitro contracture testing suggests that a dog model may be useful for developing improved phenotypic detection of heterozygotes needed for human diagnosis and genetic investigations.