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Anesthetic Drugs and Onset of Malignant Hyperthermia

Visoiu, Mihaela MD*; Young, Michael C. MS*; Wieland, Keith CRNA; Brandom, Barbara W. MD*

doi: 10.1213/ANE.0000000000000062
Pediatric Anesthesiology: Research Report
Free

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

From the *Department of Anesthesiology, and Nurse Anesthesia Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Michael C. Young, MS, is currently affiliated with NAMHR of MHAUS, University of Pittsburgh, Pittsburgh, Pennsylvania.

Accepted for publication November 1, 2013.

Funding: Not funded.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will be available from the authors.

Address correspondence to Barbara W. Brandom, MD, Department of Anesthesiology, University of Pittsburgh Medical Center, NAMHR-UPMC Mercy Hospital, 1400 Locust St., 8th Floor Rm8522, Ermire Building (B), Pittsburgh, PA 15219. Address e-mail to brandombw@anes.upmc.edu.

Malignant hyperthermia (MH) can be a devastating, potentially lethal response during or after anesthetic administration.1–7 The incidence of suspected MH is more frequent when inhaled anesthetics and succinylcholine are administered together.8 MH-like reactions have been reported in the absence of anesthetics.9,10 We hypothesized that the time between the beginning of anesthetic administration and the recognition of the first sign of MH (MH onset time) is dependent on the inhaled anesthetic administered. Potential confounding factors could be the administration of succinylcholine, the nature, number of the first MH signs, severity of the MH episode, age and gender of the patient, and the year of the MH incident. Over several decades, many anesthetic practices have changed. The duration of anesthetic exposure before the first sign of MH is recognized may have changed as well. Because MH can progress rapidly, it is important for anesthesia providers to diagnose an MH episode as early as possible. Awareness of the factors associated with the onset of MH might facilitate early diagnosis.

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METHODS

The University of Pittsburgh IRB deemed this study exempt from full committee review. Seven hundred twelve Adverse Metabolic/Musculoskeletal Reactions to Anesthesia reports (AMRAs) received at the North American Malignant Hyperthermia Registry after January 1, 1987, and before January 1, 2010, were reviewed. The AMRA reports contain de-identified medical and anesthetic data that clinicians recorded after an adverse metabolic and/or musculoskeletal reaction to anesthesia occurred. Only reports from the United States and Canada were included. The inhaled anesthetics administered, the presence or absence of succinylcholine, the clinical grading scale (CGS),11 gender and age of the subject in years at the time of the MH event, and the details of the MH event were obtained from the AMRA reports.

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Data Inclusion and Exclusion Criteria

Case inclusion criteria were documentation of the time when anesthetic administration began, the time when the first MH sign was noted, and a judgment regarding the likelihood that MH occurred. Only cases judged possible or fulminant MH by the clinician on the scene were included. If the clinician submitting the AMRA report did not clearly indicate that the case was possible MH, fulminant MH, or not MH, the case was independently reviewed in detail by the authors with medical expertise (BWB, MV). The case was defined as “possible MH” only for the purpose of this study, if the clinician submitting the AMRA report wrote that MH was possible, referred the patient to an MH diagnostic center, or administered dantrolene. The case was defined as “not MH” if the underlying medical or surgical condition was a likely cause of the adverse reaction. One patient classified as possible MH by the clinician submitting the AMRA report was excluded due to documentation of muscular disease (merosin deficiency). Another case was excluded because the patient received dantrolene premedication.

Cases were included if data such as age, nature of the first MH sign, or year of the anesthetic event were missing. Cases were included if the inhaled anesthetic administered was not noted, but there was documentation that inhaled induction was used and/or that inhaled anesthetics were discontinued. Four hundred seventy-seven AMRA reports met these inclusion criteria. MH onset time was defined as the time between the beginning of anesthetic administration and documentation of the first sign of MH.

The MH onset times were documented for 4 groups defined by the type of drug exposure that is likely to elicit MH. These groups were inhaled anesthetic and succinylcholine given, (Inh/Sux); inhaled anesthetic but no succinylcholine given, (Inh/No Sux); no inhaled anesthetic, but succinylcholine was administered, (No Inh/Sux); and neither inhaled anesthetic nor succinylcholine were given, (No Inh/No Sux). Cases were excluded from further analysis of the difference between inhaled anesthetics, if >1 inhaled anesthetic was administered. In addition, the MH onset times were compared with patients who received 1 of 4 frequently given inhaled anesthetics (halothane, sevoflurane, desflurane, and isoflurane) in the presence and absence of succinylcholine.

An AMRA report could record 1 first MH sign or a number of first MH signs that were reported to have occurred simultaneously. These signs included hypercarbia, sinus tachycardia, masseter muscle spasm, generalized muscle rigidity, tachypnea, cyanosis, skin mottling, rapidly increasing temperature, sweating, hyperkalemia, ventricular tachycardia, ventricular fibrillation, cola-colored urine, and excessive bleeding.1 Four hundred seventy-seven cases were analyzed to compare MH onset times between cases with different first signs of MH, and between those cases in which 1 unique sign of MH was noted, and those in which >1 simultaneous first sign of MH were noted. In these 477 reports, MH onset times were compared between cases with or without masseter spasm and with or without exposure to succinylcholine. When the effect of age was examined, only 456 cases contributed to the analysis.

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Statistical Analysis

Descriptive statistics for continuous data are summarized as mean, standard deviation (SD), median, first and third quartile, minimum and maximum. Mann-Whitney test or Kruskal-Wallis test was performed to determine differences between 2 or more groups, respectively, for nonnormally distributed continuous data. When an overall difference was found with the Kruskal-Wallis test, post hoc comparisons were performed using the Mann-Whitney test, and adjustment for multiple comparisons was performed using the Dunn-Sidak adjustment method.12 Adjusted P values for post hoc comparisons are presented. When no statistically significant difference was found between the groups, the Wilcoxon Mann-Whitney odds measure (WMWodds) and the corresponding confidence interval (CI) were computed using a Bonferroni correction when appropriate. All statistical analyses were 2 sided, and the significance level was set at 0.05.

χ2 was used to compare the frequency of a binary variable in females versus males. Spearman correlation coefficient was calculated to evaluate the relationship of MH onset time with the year of event, the CGS (also known as Larach Score) of the event, and the age of the subject. Regression analysis was applied to examine factors associated with the log of MH onset time. Data were analyzed using PASW statistics 18.0.0 (released July 30, 2009; SPSS Inc., Chicago, IL). The WMWodds measure and corresponding CIs were calculated using SAS (version 9.3; SAS Institute, Cary, NC) to execute the program provided at (http://links.lww.com/AA/A565.).13,14 Corrections were made in these CIs for multiple comparisons.

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RESULTS

Descriptive Statistics

In the 477 AMRAs examined, age was reported in 456. The mean age was 23.7 years, median 19 years (SD = 19.5) (first quartile 7 years, third quartile 35 years, minimum 0 years; maximum 90 years). Three hundred thirty-four patients (70%) were men and 139 (29.1%) were women. Gender was unknown in 4 (0.8%). Gender distribution did not vary with age or type of inhaled anesthetic exposure (P = 0.329), but more women than men (64.7% vs 53.9%, P = 0.032) were exposed to succinylcholine. The median CGS in 477 reports was 48, which is in the “very likely MH” category. The first quartile CGS was 33, which is in the “somewhat more than likely” category, and the third quartile CGS was 58, which is in the “almost certain MH” category.11 The median year of occurrence of the MH event was 1997 (first quartile 1993, third quartile 2001) in 475 reports (Fig. 1).

Figure 1

Figure 1

The anesthetic exposures reported in 477 cases are presented in Figure 2. In 257 cases (53.9%), a combination of inhaled anesthetic and succinylcholine was reported. One hundred ninety-nine patients (41.7%) received only inhaled anesthetics. In 14 cases (2.9 %), succinylcholine was reported with no exposure to inhaled anesthetics. Seven patients were not exposed to inhaled anesthetic or succinylcholine.

Figure 2

Figure 2

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MH Onset Times in the Presence of Different Inhaled Anesthetics

In 394 cases, MH onset time in the presence of only 1 of the 4 inhaled anesthetics (halothane, sevoflurane, isoflurane, and desflurane) was documented (Table 1). There was a statistically significant difference (P < 0.0001) in the MH onset time among the 4 inhaled anesthetics without regard for potential differences in age and succinylcholine administration among these groups. However, administration of succinylcholine was associated with shorter MH onset time (Table 1; P < 0.0001) in the presence of every anesthetic.

Table 1

Table 1

In the presence of succinylcholine, MH onset time during halothane anesthesia was shorter than sevoflurane anesthesia (P = 0.041), desflurane anesthesia (P = 0.014), and isoflurane anesthesia (P < 0.001) (Table 1). There was no statistically significant difference in MH onset time during sevoflurane vs desflurane anesthesia (P = 1.000; The WMWodds is 1.12 with 99.2% CI, 0.51–2.57). There was no statistically significant difference in MH onset time during sevoflurane vs isoflurane anesthesia (P = 0.97; The WMWodds is 1.34 with 99.2% CI, 0.74–2.56) or desflurane vs isoflurane anesthesia (P = 1.00; The WMWodds is 1.18 with 99.2% CI, 0.61–2.37) when succinylcholine was administered.

In the absence of succinylcholine, MH onset time during halothane anesthesia was shorter than during desflurane anesthesia (P = 0.001) and isoflurane anesthesia (P < 0.0001) but no different during sevoflurane anesthesia (P = 0.261; The WMWodds is 1.94 with 99.2% CI, 0.92–5.25) (Table 1). In addition, MH onset time during sevoflurane anesthesia was shorter than desflurane anesthesia (P = 0.047) and isoflurane anesthesia (P = 0.001). There was no statistically significant difference in MH onset time during desflurane vs isoflurane anesthesia (P = 1.000; The WMWodds is 1.05 with 99.2% CI, 0.46–2.47) when succinylcholine was not administered.

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The Nature of First MH Signs

For the 322 cases with 1 unique first sign of MH, the most often encountered first MH signs were hypercarbia (30.7%), masseter muscle spasm (24.8%), and sinus tachycardia (21.1%). In the 4 categories of drug exposure (Inh/Sux; Inh/No Sux; No Inh/Sux; No Inh/No Sux), there was a significant difference in the frequency of masseter spasm (P < 0.0005), hypercarbia (P = 0.004), and sinus tachycardia (P = 0. 046) (Fig. 3) as the first sign of MH. There is no difference in median age among the above 4 groups (P = 0.576).

Figure 3

Figure 3

When only 1 first sign of MH was recorded, there were differences in the first sign of MH among the 4 inhaled anesthetics (P < 0.0005). Masseter muscle spasm as the first MH sign was most often reported in those who received halothane (60.8%) followed by isoflurane (15.3%), desflurane (13.5%), and sevoflurane (12.9%) (P < 0.0005). Masseter spasm was more often reported in females (42.1 %) than in males (17.9%) (P < 0.0005).

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MH Onset Time and First MH Signs

The variable of interest, MH onset time, differed with the first sign of MH (Table 2). In the 322 cases with 1 unique first MH sign documented, the median MH onset time was 45 (first quartile 10, third quartile 115) minutes. In the 155 cases with multiple first MH signs documented, median MH onset time was 55 (first quartile 30, third quartile 165) minutes, which was not significantly different from the onset time of MH when 1 unique first sign was reported (P = 0.144; The WMWodds is 1.18 with 95% CI, 0.94–1.49). When only patients who received succinylcholine were considered (N = 271), there was no difference in median MH onset time (median of 25 minutes), between those with 1 (N = 187) or multiple first MH signs (N = 84) (P = 0.335; The WMWodds is 1.16 with 95% CI, 0.86–1.57).

Table 2

Table 2

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MH Onset Times and Masseter Muscle Spasm

Masseter spasm was noted, as a first or later sign of MH, in 138 cases and was more frequent in the presence of succinylcholine (P < 0.0005). Masseter spasm was also noted in 20 cases in which succinylcholine was not administered (Table 3). In the 322 cases with 1 unique first MH sign, masseter spasm (N = 80) was the earliest sign of MH (P < 0.0005), with median 5 (first quartile 2, third quartile 10) minutes. When succinylcholine was administered, masseter spasm was more common during exposure to halothane than during other general anesthetics (P < 0.0005).

Table 3

Table 3

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MH Onset Time without Masseter Muscle Spasm

Because the effect of masseter spasm on MH onset time was so strong, the cases with masseter spasm were removed, and analysis was repeated. For the 339 cases without masseter spasm, there was no significant difference in MH onset time between those with 1 unique first MH sign and those with multiple first MH signs (P = 0.091; The WMWodds is 1.25 with 95% CI, 0.95–1.67).

In the 281 cases exposed to 1 volatile anesthetic but with no reported masseter spasm, MH onset time was different between subjects exposed to halothane, sevoflurane, desflurane, or isoflurane anesthesia (Table 4; P < 0.0005). In these 281 cases, MH onset time during halothane anesthesia was not significantly shorter than during sevoflurane anesthesia (P = 1.000; The WMWodds is 1.32 with 99.2% CI, 0.68–2.78) nor during desflurane anesthesia (P = 0.184; The WMWodds is 1.86 with 99.2% CI, 0.87–5.09), but it was significantly shorter in the presence of halothane than in the presence of isoflurane anesthesia (P = 0.001). MH onset time was also significantly shorter in the presence of sevoflurane compared with isoflurane anesthesia (P = 0.001) (Table 4). There was no statistically significant difference in MH onset time during sevoflurane vs desflurane anesthesia (P = 1.000; The WMWodds is 1.35 with 99.2% CI, 0.75–2.60) or desflurane vs isoflurane anesthesia (P = 0.650; The WMWodds is 1.38 with 99.2% CI, 0.80–2.54) in these cases.

Table 4

Table 4

For 339 cases with no reported masseter spasm, there was no statistically significant difference in MH onset time in the presence (N = 153) or the absence (N = 186) of succinylcholine, median 80 (first quartile 28, third quartile 141) minutes vs median 82.5 (first quartile 10, third quartile 115) minutes (P = 0.619; The WMWodds is 1.06 with 95% CI, 0.83–1.37). In the absence of masseter spasm and presence of succinylcholine (N = 135), there was no statistically significant difference in MH onset time among 4 major volatile anesthetics given (P = 0.180). The comparison of MH onset time between halothane and sevoflurane had WMWodds of 1.3 with 99.2% CI, 0.39–5.58. The comparison of MH onset time between halothane and desflurane had WMWodds of 1.07 with 99.2% CI, 0.34–3.57. The comparison of MH onset time between halothane and isoflurane had WMWodds of 1.89 with 99.2% CI, 0.69–8.95. The comparison of MH onset time between sevoflurane and desflurane had WMWodds of 1.09 with 99.2% CI, 0.41–2.99. The comparison of MH onset time between sevoflurane and isoflurane had WMWodds of 1.43 with 99.2% CI, 0.68–3.37. The comparison of MH onset time between desflurane and isoflurane had WMWodds of 1.47 with 99.2% CI, 0.68–3.67.

There was a statistically significant difference (P < 0.0001) in MH onset time between the inhaled anesthetics when masseter spasm had not been reported and succinylcholine was not given (N = 146). In these 146 cases, MH onset time during halothane anesthesia (median 25, first quartile 15, third quartile 53.75 minutes) was shorter than during desflurane anesthesia (median 92, first quartile 59, third quartile 206.5 minutes) (P = 0.039) and isoflurane anesthesia (median 135, first quartile 68.75, third quartile 224 minutes)(P = 0.002). In addition, MH onset time during sevoflurane anesthesia (median 45, first quartile 11, third quartile 120 minutes) was shorter than during isoflurane anesthesia (P = 0.001). There was no statistically significant difference in MH onset time during halothane vs sevoflurane (P = 0.997; The WMWodds is 1.50 with 99.2% CI, 0.67–4.01) or between desflurane and sevoflurane (P = 0.228; The WMWodds is 2.10 with 99.2% CI, 0.99–5.99) or desflurane and isoflurane anesthesia (P = 1.000; The WMWodds is 1.22 with 99.2% CI, 0.51–3.20).

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Interaction of Age with Anesthetic Exposure

In this cohort, halothane was administered only to patients younger than 20 years old (the oldest being 17 years old), and desflurane was administered primarily to patients older than 20 years old (only 8 patients who received desflurane were younger than 20 years of age, with the youngest being 13 years old). The unequal exposure of subjects of different ages to these inhaled anesthetics made it difficult to examine the effects of the type of inhaled anesthetic independently from the age of the subject. Several approaches were used to examine the effect of age and inhaled anesthetics on MH onset time. Regression analysis was used to examine the significance of factors associated with the log of the MH onset time in 377 cases. However, a stable model could not be constructed.

The data were divided in 2 groups determined by the age of the subject at the time of the MH episode so that those older or younger than 20 years were examined separately (Table 5). There was no statistically significant difference in succinylcholine exposure, but in those who received 1 of the 4 inhaled anesthetics, median MH onset time was shorter in those younger than 20 years (P < 0.001) (Table 5). Of the 178 subjects in the group younger than 20 years old, 76 (42.7%) had received halothane (Table 6).

Table 5

Table 5

Table 6

Table 6

When this analysis was repeated with the 199 subjects >20 years old, MH onset time was shorter (P < 0.0005) in those who received succinylcholine. The type of inhaled anesthetics and age were not statistically significant (P = 0.08 and P = 0.11, respectively) (Table 6).

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MH Onset Time in the Presence of Succinylcholine without Inhaled Anesthetics

In 14 cases, succinylcholine was administered without inhaled anesthetic. Eleven of these subjects (78.57%) experienced possible MH, and 3 (21.42%) experienced fulminant MH. When compared with other drug exposures, this group had the shortest MH onset time 7.5 (first quartile 1, third quartile 29.5) minutes (P = 0.018) (Table 7), and the median age of subjects in this group was 26 (first quartile 15, third quartile 38) years. The most frequent initial signs of MH in these patients were masseter spasm and tachycardia, each in 7 patients (50%), followed by hypercarbia in 5 patients (35.7%), elevated temperature in 4 patients (28.6%), and rapidly increasing temperature in 4 patients (28.6%). Ten of these 14 subjects had 1 unique first MH sign, masseter spasm in 6 cases (60%), hypercarbia in 2 cases (20%) (Fig. 3), cyanosis and hyperkalemia in 1 case each. The median CGS in these cases was 30.5 (first quartile 15, third quartile 40).

Table 7

Table 7

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MH Onset Time and the Type of MH Episode

When cases with masseter spasm were included, the MH onset time was shorter in those cases judged as possible MH than in those judged fulminant MH, median 45 (first quartile 8, third quartile 115) minutes and median 65 (first quartile 18.8, third quartile 136.3) minutes (P = 0.006), respectively (Table 8). Masseter spasm as the first and only MH sign was most often encountered in the possible MH cases.

Table 8

Table 8

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Correlation Between Year of MH Event, MH Onset Time, and Anesthetic Exposure

Considering all cases with 1 unique first or multiple first MH signs, MH onset time was significantly shorter (P < 0.0005) before than after 1997. There was a statistically significant difference in the frequency of exposure to the 4 inhaled anesthetics and succinylcholine before and after 1997 (Table 9; P < 0.0005). Masseter spasm was more often encountered in the cases reported from 1997 or earlier, 35.4% vs. 11.5% (P < 0.0005). When the cases with masseter spasm were removed, there was no significant correlation between the MH onset time and the year of the MH event (P = 0.379).

Table 9

Table 9

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MH Onset Time in the Absence of Drugs Expected to Cause MH

In 7 cases reported as possible MH, neither inhaled anesthetics nor succinylcholine were administered. These were patients thought to be MH susceptible (MHS) after preoperative evaluation. Therefore, the anesthetic plan did not include inhaled anesthetics or succinylcholine. When compared with other groups of drug exposure, this was the youngest group, with median age 15 (first quartile 2, third quartile 39) years and had the longest MH onset time, 155 (first quartile 30, third quartile 330) minutes (Table 7). The most frequent initial sign of MH in this group was rapidly increasing temperature in 6 cases (86%), followed by tachycardia or elevated temperature, each in 3 cases (57%), hypercarbia in 2 cases (29%) and masseter spasm or generalized rigidity each in 1 case (14%). Only 2 of these cases had 1 unique first MH sign (Fig. 3), masseter spasm, or rapidly increasing temperature. The median CGS in these cases was 25 (first quartile 18, third quartile 55).

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DISCUSSION

The clinical presentation of MH was recently described in detail using AMRAs from the North American Malignant Hyperthermia Registry.1 However, the factors that may be related to the time from the beginning of anesthetic administration to the observation of the first sign of MH were not explored in that study. Previous studies in animals suggested that there is a difference in potency of inhaled anesthetics15 regarding triggering of MH. Halothane exposure resulted in significantly more rapid onset of MH than did isoflurane and desflurane in MHS pigs. In the same study, succinylcholine administration in the absence of inhaled anesthetic triggered MH in 9 of the 10 animals tested,15 but it has been questioned whether or not these events were MH episodes.16 Our results, restricted to subjects who did not receive succinylcholine and in whom masseter spasm was not reported, are consistent with this study in pigs. Sevoflurane was not examined in that animal model. In our study, sevoflurane exposure resulted in faster MH onset time than did isoflurane for the subjects with no masseter spasm and no exposure to succinylcholine.

Hopkins16 presented an analysis of the time from induction of anesthesia until clinical features of MH were observed for 75 MH cases in the United Kingdom. He reported a significantly faster onset of the MH reaction in the presence of halothane (median 20 minutes, range 5–45 minutes) compared with enflurane (55, 20–480 minutes) and sevoflurane (60, 10–210 minutes) but not isoflurane (30, 5–210 minutes). No analysis of potential confounding factors such as succinylcholine administration or subject age at the time of the MH event was presented.16 Migita et al.17 reported MH onset time after exposure to sevoflurane without succinylcholine in 48 cases and isoflurane without succinylcholine in 30 cases. Median MH onset times were 72.5 minutes (range 36.3–127.5) in the presence of sevoflurane, and 65 minutes (range 30–131.3) in the presence of isoflurane.17 Migita et al.17 tried to address age as a factor that could alter onset time of MH, but only 1 subject younger than 10 years old received isoflurane. In his patients who received sevoflurane, MH onset time was shorter in children (younger than 10 years) only when compared with adolescents and young adults (10–29 years).

Our analysis, restricted to subjects who did not receive succinylcholine and in whom masseter spasm was not reported, is not consistent with previous results reported by Hopkins16 and Migita et al.17 We examined the onset of MH during exposure to halothane but not enflurane. Halothane exposure did not result in faster MH onset time than did sevoflurane, but it did in comparison with isoflurane. Sevoflurane exposure resulted in faster MH onset time than did isoflurane. The median MH onset time during isoflurane anesthesia in this study is 4.5 times longer than that reported by Hopkins16 and 2.1 times longer than that reported by Migita et al.17

In the human cohort of MH cases presented here, there is evidence that the administration of succinylcholine was associated with earlier onset of MH signs only when masseter spasm was the first sign of MH. Migita et al.17 did not report masseter spasm as being one of the most common first MH signs. Previous studies in animals demonstrated that succinylcholine can increase resting tension of the masseter muscle, which may be interpreted as masseter spasm.18,19 It could be that after administering succinylcholine and detecting resistance to mouth opening, many of the anesthesiologists in North America elected to diagnose MH and initiate therapy.

This cohort includes cases in which succinylcholine was the only MH “trigger” to which patients were exposed. In addition, there are subjects in this cohort who experienced signs of MH without exposure to either succinylcholine or inhaled anesthetics. We cannot prove that the patients reported in these AMRAs truly experienced an MH event because there are no diagnostic results attached to these de-identified AMRA reports. However, the clinical judgment of the anesthesia team was that MH was occurring. These cases suggest that there is no guarantee that any anesthetic regimen can entirely remove the possibility that an MH episode may occur.

We chose to examine differences in MH onset time between different initial signs of MH because the clinician might notice 1 MH sign faster than another. For example, masseter muscle spasm was reported earlier than were other MH signs after administration of succinylcholine (118 cases), during exposure to only inhaled anesthetics (19 cases) or during IV anesthesia (1 case). In this cohort, the occurrence of masseter spasm defined the shortest MH onset time in all types of anesthetics examined. This is not surprising because one of the earliest and most important tasks that the anesthesiologist must perform after induction of anesthesia is management of the airway. If it is difficult to open the mouth because of the presence of masseter muscle spasm, this is very likely to be noticed early during the process of airway management.

Of what importance are these observations to current anesthesia practice? MH signs should be expected to occur later during general anesthesia than reported previously.

In part, this is because halothane is no longer in use, but the same trend was observed during administration of isoflurane or sevoflurane. Likely this is due to decreasing administration of succinylcholine during potent inhaled anesthesia in the past decade. The increasing age of the surgical population may also contribute to delayed appearance of MH signs.

MH onset time was longer in those cases classified as fulminant MH. It is possible some of initial first MH signs were missed. Perhaps, when the nonspecific signs of MH were not recognized early, there was more exposure to inhaled anesthetic and more difficulty in removing anesthetic from the muscle. Thus, delay in recognition of MH could be expected to result in fulminant MH episodes. In pigs, MH episodes did not appear to be more difficult to treat when the initial signs were delayed, but a longer exposure to inhaled anesthetic resulted in more phenylephrine administration. In this study of porcine MH, PaCO2 increase was chosen to define MH onset time.15 In the human cohort presented here, a longer time between the beginning of exposure to anesthetic and the appearance of the first sign of MH was associated with more fulminant episodes. Similarly, Migita et al.7 reported 4 fatal cases in the sevoflurane-no succinylcholine group, with a median MH onset time of 170 minutes (minimum 100–maximum 210), a longer interval than in the rest of that cohort.

The MH onset times reported in 7 MH cases in the absence of succinylcholine or volatile anesthetics were very long. MH episodes in the absence of a causative drug have been reported.9,10,20 The 7 cases in this cohort were reported as being possible MH episodes. Because MH is a potentially fatal condition that may progress rapidly, the anesthesia provider may diagnose and treat an episode of MH earlier with fewer signs when there is a family history of MH, and the patient presents with increased temperature. One may argue that elevated core temperature alone is not enough to precipitate treatment of MH. However, elevated environmental temperature, without exposure to inhaled anesthetics, can be followed by lethal MH in MHS animals.21 Thus, it is important to evaluate the MHS patient with increasing core temperature for other signs of MH.

In summary, the combination of inhaled anesthetic and succinylcholine was associated with the fastest MH onset time. The MH onset time can be very rapid when masseter muscle spasm is the first MH sign recognized after administration of succinylcholine. When not controlled for age, halothane exposure resulted in significantly more rapid onset of MH than did isoflurane and desflurane in the subjects with no masseter spasm and no exposure to succinylcholine. Under the same conditions, MH onset time was faster during sevoflurane than isoflurane anesthesia. The onset of MH was faster in younger subjects. The first signs of MH have occurred later in the course of anesthesia after 1998, when administration of halothane and succinylcholine was reported less often.

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DISCLOSURES

Name: Mihaela Visoiu, MD.

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

Attestation: Mihaela Visoiu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: I have received research support from the Malignant Hyperthermia Association of the United States (MHAUS) that is a not for profit group.

Name: Michael C. Young, MS.

Contribution: This author helped design the study and analyze the data.

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

Conflicts of Interest: My position is funded by the MHAUS.

Name: Keith Wieland, CRNA.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Keith Wieland 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: Barbara W. Brandom, MD.

Contribution: This author helped design the study and write the manuscript.

Attestation: Barbara W. Brandom has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: I have received research support from the MHAUS that is a not for profit group. I am the current Director of the North American MH Registry that is a subsidiary of MHAUS.

This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).

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ACKNOWLEDGMENTS

The authors express their gratitude to the anesthesiologists, intensive care physicians, nurse anesthetists, and other health care providers who submitted Adverse Metabolic/musculoskeletal Reaction to Anesthesia (AMRA) reports to the North American Malignant Hyperthermia Registry (NAMHR). These data are available because of >20 years of support from the Malignant Hyperthermia Association of the United States (MHAUS) to the NAMHR. The project described was supported by the National Institutes of Health through Grant Number UL1TR000005. We thank the statistician B. Rosario, PhD, from the University of Pittsburgh. Her work was instrumental for our response to the statistical critique of review of the manuscript. We also acknowledge E. Jane McCarthy, PhD (Phys), CRNA, FAAN, and Maria Cicerone, CRNA, MSN, who did the pilot study on this topic using the NAMHR database years ago.

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