Malignant hyperthermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle in response to administration of volatile anesthetic drugs and/or depolarizing muscle relaxants.1,2 An MH reaction is characterized by dysregulation of cytoplasmic calcium homeostasis and, consequently, excessive anaerobic and oxidative metabolism in skeletal muscle tissue.3–5 This accelerated rate of metabolism may rapidly overwhelm the body’s capacity to compensate resulting in typical clinical signs including hyperthermia, hypercarbia, muscle rigidity, tachycardia, acidosis, and rhabdomyolysis.
Due to genetic diversity, MH incidence and prevalence vary greatly among different populations. The dramatic reduction in MH mortality since the 1970s has been attributed to increased MH awareness, increased use of nontriggering anesthetics, improved monitoring standards allowing early detection, and availability of dantrolene sodium.6
However, studies on the incidence of adverse MH reactions in North American clinical institutions revealed an MH morbidity rate of 35%7 and an MH mortality rate as high as 12%.8 Therefore, MH remains a serious life-threatening condition and early detection is invaluable in minimizing mortality and MH-related complications.7
Clinical diagnosis of MH is initially made in the operating room, which can be difficult due to the nonspecific nature of MH clinical signs and symptoms. Larach et al.9 devised a set of clinical diagnostic criteria for MH research in the development of the Clinical Grading Scale (CGS), a standardized scale that serves to approximate the qualitative likelihood of an MH event. However, an assigned MH rank may underestimate the likelihood of an MH event if important monitors were not used or if relevant blood tests were not obtained. In addition, the likelihood of an individual’s MH susceptibility may be difficult to estimate if MH-triggering anesthetic drugs were withdrawn early in the reaction.
Many North American MH experts recommend that after an adverse anesthetic reaction that may have been MH, the index case (proband) undergoes a caffeine-halothane contracture test (CHCT). The CHCT is the current “gold standard” diagnostic test for MH susceptibility in North America. It measures the degree of contracture of in vitro muscle samples to caffeine and halothane.10 For research purposes, where maximizing specificity is desirable, CHCT has a sensitivity of 88% and a specificity of 81% based on testing results from 10 MH diagnostic centers, submitted to the North American Malignant Hyperthermia Registry (NAMHR). When used clinically where maximizing sensitivity is desirable, the diagnostic cutpoints are changed to yield a sensitivity of 97% and a specificity of 78%.11 It remains the most reliable North American procedure to diagnose MH susceptibility. A similar test, the in vitro contracture test, is the gold standard diagnostic test for countries outside of North America with a sensitivity of 99% and a specificity of 94%.12
Although there have been several studies conducted around the globe on the epidemiology of MH,7,13–18 to our knowledge, there has not been any comprehensive study on the characteristics of the index adverse anesthetics in CHCT-confirmed MH susceptible (MHS) probands. Therefore, we examined available descriptive and demographic data on index adverse anesthetics reported to the Toronto Malignant Hyperthermia Investigation Unit (MHIU) between 1992 and 2011. We also evaluated associations between complications, clinical signs, and dantrolene treatment to further facilitate timely clinical diagnosis and treatment of MH.
After receiving IRB approval, probands referred to the MHIU at Toronto General Hospital from 1992 to 2011 were identified. Probands with an index adverse anesthetic reaction (documented by the original anesthetic record), who survived the MH reaction and were diagnosed as MHS by CHCT,11 were included in this study. These individuals were not captured by the NAMHR, because the MHIU was not participating in the Registry from 1992 to 2011. Due to the retrospective nature of the study, written informed consent was waived by the IRB. Genetic screening was offered to all the MHS probands referred from 1994 to 2011 and performed on the consenting individuals only.
All episodes were characterized with regard to the following features from the review of hospital records: (1) demographics (gender, age, and race); (2) evidence of musculoskeletal comorbidities before reaction and prior unremarkable anesthetics; (3) type of anesthetic triggers (volatile anesthetics and/or succinylcholine), duration of anesthetic from induction to last drug administered and time of reaction onset (intraoperative or postoperative); (4) clinical signs of adverse anesthetic reactions, CGS score, dantrolene use (based on review of anesthetic and postanesthetic records up to 72 hours; dose could not be analyzed due to inadequate documentation), and dantrolene administration time (defined as minutes between first clinical sign and first dantrolene dose); (5) laboratory findings (creatine kinase, pH, myoglobinuria, and coagulation profile, where available); (6) complications; (7) as per North American MH group standards for genetic studies contracture of ≥0.7 g to 3% halothane or contracture of ≥0.3 g to 2.0 mmol/L caffeine in at least 1 muscle fascicle was considered to be a positive CHCT;11 and (8) ryanodine receptor 1 (RYR1) gene screening was performed on all consenting individuals, according to previous published methods19 and considered positive if an MH-causative mutation was found.a
Complications due to MH included disseminated intravascular coagulation (defined as International Normalized Ratio > 2, partial thromboplastic time > 40 seconds, platelets < 100,000 per microliter of blood, and fibrinogen < 1.0 g/L); renal (creatinine > 150 µmol/L), cardiac (ejection fraction < 40% by echocardiography), coma, compartment syndrome (requiring fasciotomy), and pulmonary edema (as documented by chest radiograph evidence). There were insufficient data on bilirubin values to analyze hepatic dysfunction since increased transaminase levels may be secondary to rhabdomyolysis alone, and there were no preoperative values for comparison. All the complications, as a group, were analyzed for association with the interval between onset of clinical signs and dantrolene administration. The CGS score was also calculated for each adverse anesthetic reaction as an indicator of how closely it approached the clinical case definition of an MH event. CGS scores of 35 to 49 are ranked as “very likely” MH events, and scores of ≥50 are “almost certain” MH events.9
Continuous variables were described using medians, ranges, and interquartile ranges (IQRs). Categorical variables were described using frequencies and percentages. Confidence intervals for percentages were calculated using exact binomial methods. A distribution-free method was used to calculate a confidence limit for median time to dantrolene with the CIQUANTDF option in SAS’s PROC UNIVARIATE (SAS Institute Inc, Cary, NC). To test for significant associations between binary variables, Fisher exact test was applied; for associations between 1 binary variable and a variable with >2 categories Pearson χ2 test was applied; the nonparametric Kruskal-Wallis test was applied when comparing >2 groups on continuous variables, and the Wilcoxon rank-sum test was used to compare 2 groups; the Cochran-Armitage trend test was used to test for a trend in percentages across ordered categories. Pairwise comparisons were performed to investigate significant associations when comparing 2 groups. All statistical analyses were performed using SAS 9.3 TS Level 1M1 (SAS Institute Inc). A 2-tailed P < 0.05 was used to define statistical significance of all hypotheses tests.
Between 1992 and 2011, 373 probands with adverse anesthetic reactions were referred to MHIU. Fifty-one probands refused CHCT, and of the remaining 322 probands, 201 were diagnosed by CHCT as MHS. Of these, 72 patients with incomplete medical records (i.e., absence of anesthetic record) were excluded. Therefore, 129 MHS probands with adverse anesthesia reactions were included in our study. Patient demographics, selected medical history, characteristics of index adverse anesthetics, and the details of CHCT results are summarized in Table 1. Patients were predominately male, Caucasian, with median age at the time of the index anesthetic of 23 years.
Index adverse anesthetic reactions were triggered by either succinylcholine or volatile anesthetics or both. There were no adverse anesthetic reactions in the absence of these triggers. Volatile anesthetics included enflurane, halothane, isoflurane, sevoflurane, and desflurane. There was no significant difference in duration of anesthetic between the volatile-only group, succinylcholine-only group, and volatile and succinylcholine group (P = 0.53; Table 1).
First signs of adverse anesthetic reactions occurred in the postanesthesia care unit in 8 extubated patients. However, there was not a single case after discharge from the postanesthesia care unit.
The frequency of clinical signs and laboratory findings are compiled in Table 2. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). The most common initial signs were masseter muscle rigidity (29.5%), sinus tachycardia (27.9%), and hypercarbia (15.0%).
The characteristics of the 20 index anesthetic reactions triggered by succinylcholine without volatile anesthetics are enumerated in Table 3 (also Appendix). Thirty-five percent of these reactions were classified as “very likely” or “almost certain” MH using the CGS. Also, 35% of the individuals experiencing these reactions triggered by succinylcholine without volatile anesthetics were found to have RYR1 MH-causative mutations.
A total of 26 patients (20.1%) suffered complications (Table 4). The most common complications were renal dysfunction and cardiac dysfunction.
Fifty-seven (44.2%) patients received dantrolene treatment after an adverse anesthetic reaction. The median time between onset of the first clinical sign and dantrolene administration was 20 minutes (IQR, 15–20), with a range of 12 to 70 minutes (IQR, 15–25). As shown in Table 5, the proportion of patients who received dantrolene was significantly larger among patients who received volatile anesthetics without succinylcholine as compared with those who received succinylcholine without volatile anesthetics (P = 0.007). The proportion of patients who received dantrolene was also significantly larger with CGS values of ≥35 (71% vs 10.5%, P < 0.001). When the time between onset of the first clinical sign and dantrolene administration was longer, the proportion of patients experiencing a complication was also larger (23.5 vs 15.0 minutes, P = 0.005). As shown in Table 6, there were no significant differences between the group that received and the group that did not receive dantrolene as regards to duration of anesthetic, CHCT, or genetic results.
Figure 1 shows that for each 10-minute delay in administration of dantrolene, complications increased substantially (the exact Cochran-Armitage trend test shows that complication rate increased with increasing minutes to dantrolene use, P < 0.001).
As shown in Table 7, complications occurred more frequently in the group of probands with the CGS values ≥35 (30.6%) in comparison with the probands whose CGS values were <35 (7.0%). However, there were no significant differences in type of anesthetic triggers or duration of anesthetic in probands with higher CGS values, compared with those with CGS values of <35.
This is the first study of nationwide Canadian epidemiologic data on MH accumulated over the past 3 decades (1992–2011). Our study of 129 index adverse anesthetic events suggestive of possible MH susceptibility, showed that they occurred predominantly in younger male patients and that the most common signs were hyperthermia, tachycardia, and hypercarbia. These results are consistent with those reported in 286 MH cases from the NAMHR database7 and in 383 MH cases from Japan.13
When dantrolene was given, we observed a higher complication rate when the time between the first clinical sign and dantrolene use was longer. This finding, also made in the previous studies in other populations,7,13 indicates that early dantrolene administration reduces the incidence of complications. Surprisingly, in our study less than half of the patients (44.2%) received dantrolene likely due to the abortive nature of the index anesthetic reaction, or less typical presentation of MH, with the percentage increasing to 71% in those experiencing a “very likely” or “almost certain” MH event as measured by the CGS. The importance of early administration of dantrolene in reducing morbidity is further underlined by our findings that when dantrolene administration was delayed beyond 50 minutes, complication rates increased to 100%.
There were several observations in our study that differed from previous reports.7,13–15 First, our study revealed a higher than previously reported percentage of events triggered by succinylcholine alone (15.5%) demonstrating that this drug given without concomitant volatile anesthetics can trigger adverse events in MHS patients. Seven of these patients experienced an event graded as “very likely” or “almost certain” MH, and 7 had a causative RYR1 mutation. All 20 patients whose events were triggered by succinylcholine without volatile anesthetics were found to be MHS when biopsied. Four of these patients had their reaction while undergoing electroconvulsive therapy. To our knowledge, this is the first report of such a large series of patients who had experienced an adverse MH event triggered by succinylcholine without volatile anesthetics. Therefore, we concur with Dexter et al.21 about the necessity of stocking dantrolene. Our findings underscore the necessity of investigating adverse reactions triggered by succinylcholine without volatile anesthetics and the need to stock dantrolene in any facility that uses succinylcholine even if only for airway rescue.
Second, our report shows a lower (20.1%) than previously reported (34.8%)7 complication rate along with a lower rate of dantrolene administration (44.2%). The most common complication in our study was renal dysfunction (14.7%). Larach et al.7 reported level of consciousness change and cardiac dysfunction as the most common MH-related complications; renal dysfunction comprised only 7% in their study group.
The lower complication rate could have been due to our laboratory criteria for diagnosing some of the complications but could also have been due to the differences in the study inclusion criteria. In contrast to the previous studies, which used the CGS rankings of “very likely” or “almost certain” as measures for likelihood of MH events,7,13 in our retrospective study positive CHCT results were used as a part of the inclusion criteria to confirm MHS status of selected patients. Currently, the gold standard method of MH diagnosis in North America is the CHCT.11 Due to the stringent inclusion criteria, only 129 MH patients of 373 cases were included in the study. Of the selected patients, 44.2% did not show typical MH presentation and were ranked by the CGS as “less than likely” or “unlikely” of having MH. They were, however, confirmed MHS and were included in this study, emphasizing the limitations of using CGS as the sole basis for MH susceptibility diagnosis. Interestingly, the complication rate for the subset of patients with “very likely” or “almost certain” MH events in this report (30.6%) was comparable with the previous NAMHR study rate of 34.8%.7
There are several limitations associated with our study. As a retrospective study, our findings were limited by data availability; for example, in the majority of anesthetic records the dantrolene dosing and type of temperature monitoring route were lacking. In addition, our study was limited to the MH patients who survived the reaction and were referred to us for CHCT.
Other limitations also included lack of universal surveillance for outcomes, variability in treatment, diagnostic, and management protocols, and a long timeframe during which general medical care as a whole would have changed. In addition, we did not correct for multiple statistical comparisons. Nonetheless, correction techniques such as the Bonferroni method are inappropriately conservative for a study such as ours. Specifically, these methods incorrectly assume that all our comparisons were independent of each other and have also been criticized for testing an irrelevant null hypothesis.22 Furthermore, due to the limited number of cases, we did not analyze the succinylcholine without volatile anesthetic trigger event subgroup for recrudescence, reaction duration, or complication rate.
In conclusion, this is the first study summarizing nationwide data on MH reactions in Canada for the past 3 decades. We report 20 index adverse anesthetic reactions triggered by succinylcholine without concomitant administration of volatile anesthetics in probands who were subsequently confirmed as MHS. Seven of these reactions were “very likely” or “almost certain” MH events. We concur with previous studies that early diagnosis and rapid dantrolene treatment reduce MH-associated complications.
APPENDIX: SELECTED INDEX ANESTHETICS TRIGGERED BY SUCCINYLCHOLINE WITHOUT VOLATILE ANESTHETIC AGENTS Cited Here
Case A—Appendectomy in the Operating Room (Year—2008)
A 15-year-old (67 kg) male was admitted for appendectomy. He had no previous surgery and no family history of anesthetic problems. Anesthesia was induced with midazolam (2 mg), fentanyl (150 mcg), propofol (200 mg), and succinylcholine (120 mg). He developed masseter muscle rigidity (MMR) after succinylcholine. Although the anesthesiologist was able to intubate, he noticed that the end-tidal carbon dioxide was 55 mm Hg despite a high minute ventilation (8–9 L/min). He developed a sinus tachycardia of 120. His temperature peaked at 36.8°C. The case was cancelled (but performed 2 days later), and anesthesia was maintained with propofol and remifentanil. The first arterial blood gas results were pH of 7.26, PCO2 of 48 mm Hg, a PO2 of 402 mm Hg, and base excess of −3.7 mEq/L. Dantrolene (220 mg) was given almost 1 hour after the first sign. In about 2 hours, his urine became positive for myoglobin. He was transferred to the intensive care unit (ICU), and 4 hours after the first adverse anesthetic sign his creatine kinase (CK) peaked at 26,979 IU/L. In the ICU, he was kept on a labetalol drip to treat his hypertension. A CHCT, 18 months later, showed an abnormal contractures to halothane (2.4 g contracture). A causative MH mutation (p.Arg2435His) in RYR1 was found.
Case B—Airway Rescue in the Emergency Department (Year—1993)
A 22-year-old (60 kg) man was admitted to the emergency department following a motor vehicle accident. There was no crush injury. While there, his Glasgow Coma Score decreased and a decision was made to intubate him. After the administration of succinylcholine (60 mg), he developed MMR. A second dose of succinylcholine (50 mg) was given and the rigidity increased, and became widespread involving all 4 extremities. His temperature was 35.7°C, and no rise of temperature was noted. His arterial blood gas showed a pH of 7.2, a PCO2 of 67 mm Hg, a PO2 of 160 mm Hg, and base excess of −2.3 mEq/L. He was given fentanyl, diazepam, and dantrolene (160 mg), kept intubated and admitted to ICU. The next day his CK rose to 35,173 IU/L, and his urine became positive for myoglobin. One year later he underwent CHCT, and he was reactive to both halothane (7.6 g contracture) and caffeine (1.8 g contracture). Several years later he underwent genetic testing, and he was found to have a known causative MH mutation in RYR1 (p.Gly2434Arg).
Case C—Tonsillectomy in the Operating Room (Year—1992)
A 3-year-old (12 kg) female received sodium pentothal and succinylcholine (20 mg). Following muscular fasciculations, she developed MMR and generalized rigidity; however intubation was accomplished, and surgery was continued with total IV anesthesia (TIVA). Her temperature rose from 36.4°C to 38.1°C (attributed by the anesthesiologist to atropine which she got an hour earlier). No tachycardia was noted. There was no observed myoglobinuria, and a CK 12 hours after the event was normal. Dantrolene was not given. CHCT was done 12 years later, which was reactive to both halothane (4.0 g contracture) and caffeine (0.5 g contracture). No genetic testing was done.
Case D—Electroconvulsive Therapy in Treatment Suite (Year—2011)
A 43-year-old (90 kg) man, who other than medically resistant depression was healthy. He was being treated with electroconvulsive therapy (ECT). On his first ECT session, after receiving 80 mg methohexital and 70 mg succinylcholine, and before the induction of a convulsion, he developed generalized rigidity. ECT was aborted, and he was intubated, ventilated, and transferred to the ICU. Approximately 20 minutes later, on arrival at the ICU, initial blood work, including arterial blood gas was performed, and then he was treated with dantrolene (total dose: 300 mg). His arterial blood gas showed a pH of 7.32, a PCO2 of 62 mm Hg, a PO2 of 310 mm Hg, and base excess of −1 mEq/L. His CK peaked at 35,333 IU/L. He remained afebrile. His CHCT was reactive to caffeine (3 g contracture) and halothane (11.2 g contracture). On genetic testing, he was found to have a known causative MH mutation in RYR1 (p.Gly2434Arg).
Name: Sheila Riazi, MSc, MD.
Contribution: This author participated in study design, data collection, analysis, and manuscript preparation.
Attestation: Sheila Riazi approved the final manuscript. Sheila Riazi attests to the integrity of the original data and the analysis reported in this manuscript. Sheila Riazi is the archival author.
Name: Marilyn Green Larach, MD, FAAP.
Contribution: This author participated in study design and manuscript preparation.
Attestation: Marilyn Green Larach approved the final manuscript.
Name: Charles Hu, BSc.
Contribution: This author participated in conduct of the study, data collection, analysis, and manuscript preparation.
Attestation: Charles Hu approved the final manuscript. Charles Hu attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Duminda Wijeysundera, MD, PhD.
Contribution: This author participated in study design and manuscript preparation.
Attestation: Duminda Wijeysundera approved the final manuscript.
Name: Christine Massey, BSc.
Contribution: This author participated in data analysis.
Attestation: Christine Massey approved the final manuscript.
Name: Natalia Kraeva, PhD.
Contribution: This author participated in genetic testing and manuscript preparation.
Attestation: Natalia Kraeva approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
The authors would like to thank the previous MHIU directors, Drs. Beverly Britt and Julian Loke, for their contributions to patient selection and supervising the CHCT. The authors also thank Mrs. Wanda Frodis for performing the CHCT.
a European Malignant Hyperthermia Group. Available at: http://www.emhg.org/. Accessed March 30, 2012.
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