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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© 2014 International Anesthesia Research Society
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