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Anesth Analg 2001;93:683-689
© 2001 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

A Noninvasive Investigation of Muscle Energetics Supports Similarities Between Exertional Heat Stroke and Malignant Hyperthermia

David Bendahan, PhD*, Geneviève Kozak-Ribbens, MD, PhD*, Sylviane Confort-Gouny, PhD*, Badih Ghattas, PhD{dagger}, Dominique Figarella-Branger, MD, PhD{ddagger}, Michel Aubert, MD§, and Patrick J. Cozzone, PhD*

*Centre de Résonance Magnétique Biologique et Médicale and {ddagger}Service d’Anatomie Pathologique, Faculté de Médecine de Marseille, Marseille, France; {dagger}Groupement de Recherche en Econométrie Quantitative d’Aix-Marseille, Centre de la Vieille Charité, Marseille, France; and §Service d’Anesthésie-Réanimation, Hôpital d’Instruction des Armées de Laveran, Marseille, France

Address correspondence and reprint requests to Professor Patrick J. Cozzone, Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS n° 6612, Faculté de Médecine de Marseille, 27, Bd J. Moulin 13005, Marseille, France. Address e-mail to patrick .cozzone{at}medecine.univ-mrs.fr


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Exertional heat stroke (EHS) is usually triggered by strenuous exercise performed under hot and humid environmental conditions. Although the pathogenesis of an EHS episode differs from that of a clinical malignant hyperthermia (MH) crisis, both conditions share some similarities in symptoms, such as the abnormal increase in core temperature. By use of 31P magnetic resonance spectroscopy, we analyzed the muscle energetics of 26 post-EHS subjects for whom in vitro halothane/caffeine contracture tests were abnormal and investigated possible similarities with subjects susceptible to MH. An early decrease of pH was noted during the first minute of exercise in EHS subjects as compared with controls. EHS subjects were divided into two subgroups according to the diagnostic score previously developed for MH subjects. The 19 subjects (73%) with a score higher than 2 displayed significantly larger caffeine-induced and earlier ryanodine-induced contractures on muscle biopsies as compared with the rest of the group (7 subjects). The results demonstrate that muscle energetics are abnormal in subjects who have experienced EHS and suggest a possible link between MH and EH, although all EHS cannot be considered as MH.

IMPLICATIONS: 31P magnetic resonance spectroscopy of forearm muscles in subjects having developed exertional heat stroke shows a failure in muscle energetics and suggests a possible link with malignant hyperthermia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Exertional heat stroke (EHS) is caused by an imbalance between internal heat production and heat loss and is generally exacerbated by several factors, such as inadequate fluid, caloric, or electrolyte intake. It is associated with a classical symptomatology, i.e., increased body temperature (higher than 40°C) and neurologic impairment that could lead to coma, with the addition of rhabdomyolysis-induced myoglobinuria and acute renal failure (1). EHS generally occurs during strenuous activity under hot and humid environmental conditions. Subjects are often healthy young adults with no apparent clinical or biological deficits. The pathogenesis of EHS differs from a malignant hyperthermia (MH) crisis. First, the triggering agent is different. MH is a disorder of skeletal muscle in which volatile anesthetics and depolarizing muscle relaxants trigger a sustained increase in myoplasmic calcium concentration, thereby producing hypermetabolic and contractile activities. An MH crisis occurs in predisposed subjects and leads to a dramatic increase in core temperature. In addition, neurologic signs are rarely recorded during an MH crisis, and dantrolene is used to prevent a fatal issue, whereas cooling is largely used as therapy during EHS. DNA mutations involved in the susceptibility to MH have been reported for only 50% of subjects susceptible to MH, and for the remaining 50% this information is still not available (2). With respect to EHS subjects, no information regarding MH mutations has been reported.

Because of some similarities between MH and EHS, it could be hypothesized that EHS, in the same way as MH, is associated with the existence of an infraclinical myopathy. In this respect, electromyographic (3), histologic, and metabolic studies have provided conflicting and scanty results. In this study, we analyzed the physiologic (by using in vitro contracture tests) and metabolic (by using 31P magnetic resonance spectroscopy [MRS]) bases of EHS. We addressed the issue of possible etiologic similarity between the group of EHS subjects and MH susceptible (MHS) subjects for whom a noninvasive diagnostic strategy has been reported (4).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by the ethics committee at Timone Hospital in Marseille, France. The 52 subjects were chosen retrospectively on the basis of in vitro halothane/caffeine contracture tests (IVCT). All of them were healthy subjects referred to the laboratory for MH diagnosis. Twenty-six were members of MH families for whom IVCTs were normal (MH negative; MHN). The other 26 subjects, all military commandos who had experienced EHS, displayed abnormal IVCT and were investigated at least 6 mo after a well-documented EHS episode. They constituted the EHS group and are part of the 250 subjects investigated in Marseille after an EHS episode. Most of the EHS subjects collapsed after 8 km of alternate marching and running with full battle dress, including 15 kg of equipment with rifle, boots, and combat jacket. None of them had taken drugs or alcohol before the EHS episode. EHS subjects ranged in age between 20 and 40 yr and were compared with 26 age- and sex-matched MHN subjects. The 31P MRS tests were usually performed the day before muscle biopsy was performed for IVCT. At the time of examination, no muscular symptoms were reported by the EHS subjects. Informed consent was provided by all subjects before MRS examination.

IVCTs were performed on muscle biopsies as previously described and in accordance with the protocol recommended by the European Malignant Hyperpyrexia Group (EMHG) (4,5). Subjects were recognized as MHS if the results of both contracture tests (halothane and caffeine) were positive. In addition, and according to the recommendations of the EMHG, a ryanodine contracture test was performed by using 1 µM of high-purity ryanodine as previously described (6).

Muscle samples for morphological analyses were 1) snap-frozen in isopentane precooled in liquid nitrogen and stored at -80°C until use; 2) placed in formaldehyde fixative and paraffin-embedded for routine histology; and 3) fixed in 2.5% glutaraldehyde in 0.1 M phosphate-buffered saline, postfixed with 1% osmic acid, and embedded in araldite for conventional transmission electron microscopy. Ultrathin sections were double-stained with uranyl and lead citrate. Histoenzymology was performed on serial transverse cryostat sections (6 µm thick) and stained by routine histochemical methods as previously described (7). Paraffin sections were stained with hematoxylin-phloxine-saffron and Masson trichrome. Ultra-thin sections were examined with a Jeol 100 C electron microscope (Jeol Co., Tokyo, Japan).

Magnetic resonance spectra of forearm flexor muscles were recorded at 4.7 teslas (Bruker Biospec System, Karlsruhe, Germany) throughout rest-exercise (finger flexions)-recovery protocols, as previously reported (4,8,9). Spectra were time-averaged over 1 min (32 scans) and sequentially recorded during 3 min of rest, 3 min of exercise, and 20 min of recovery. Exercise was successively performed under aerobic and ischemic conditions. A resting period of at least 2 h was allowed between the two exercise periods. All subjects performed both protocols in the same order. The protocol under ischemia involved the application of a sphygmomanometer over the upper arm; this was inflated, just before the start of exercise, above the maximum arterial pressure to achieve circulatory occlusion during the exercise period. At the end of exercise, the pressure was quickly released.

Metabolite concentrations were obtained from peak areas of phosphorus metabolite signals, including creatine phosphate (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP), and phosphomonoesters (PME, mainly corresponding to glucose 6-phosphate and fructose 6-phosphate), as previously described (10). Relative concentrations of phosphorus metabolites were expressed with respect to [PCr] measured at rest (100%). Intracellular pH was calculated from the chemical shift of Pi relative to PCr at -2.45 ppm with respect to 85% H3PO4 (11). [PCr] recovery was fitted to an exponential function as follows (12):

equation


where t is time in minutes and [PCr] refers to PCr relative concentration. "Rest" and "cons" subscripts denote, respectively, level at rest and level at the end of exercise minus level at rest (percentage of [PCr] content at rest). The kinetic constant (k) is expressed per minute. Also, the initial rate of postexercise [PCr] recovery (Vi) was calculated from the time-zero derivative of the previous equation as follows:

equation


To provide quantitative information about the distribution of each variable, values in tables and figures are presented as mean ± SD. Analyses of variance (ANOVAs) with general linear models have been performed to analyze the metabolic changes recorded in each group during the transitions from rest to exercise and from exercise to rest and to compare these changes between the two groups. The general linear models procedure of the SAS software (SAS Institute, Cary, NC) options REPEATED, LSMEANS, and CONTRAST were used. Each test was performed for [PCr], [PME], and pH during both protocols.

For each group, one-way ANOVA with repeated measures (the repeated factor being time) was used to analyze the metabolic changes during exercise. The F test was performed to determine the overall effect of time on metabolite concentrations and pH throughout exercise. Then, multiple comparisons procedures (Scheffé contrasts) were used to compare each value of pH, [PCr], or [PME] recorded throughout the exercise period with its respective basal value measured at rest. The same procedure was applied for the analysis of [PCr], [PME], and pH during the postexercise recovery period.

Between-groups (MHN versus EHS) comparative analyses of metabolite concentrations and pH time-dependent changes during exercise and recovery were performed by using two-way ANOVAs with repeated measures (the repeated variable being time). Wilks’ {lambda} tests were performed to analyze the effects of time and the interaction between time and groups. Post hoc repeated comparisons (Scheffé contrasts) were performed to analyze the between-group differences for the averaged values of pH and metabolite concentrations. The significance level for testing hypotheses was set at 0.05.

On the basis of the selection of 19 MRS variables recorded or calculated during both protocols, we previously formulated a diagnostic test with 100% specificity and sensitivity for subjects unequivocally diagnosed as MHS from in vitro contracture tests (4). Briefly, this test involves counting the number of abnormal values (MRS score) recorded among the 19 variables. A subject was classified as MHS when he or she displayed more than two abnormalities. This classification was also used for EHS subjects.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Results of in vitro contracture tests are displayed in Figure 1 as box plots. For the EHS group, contractures recorded with both halothane and caffeine were significantly larger than 0.2 g (with the threshold defined according to the EMHG protocol) (5). For the sake of comparison, results from 13 MHS subjects are also displayed. Histologic analyses did not show any abnormalities except for one patient with signs of rhabdomyolysis.



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  		Figure 1. Results of in vitro contracture tests expressed as contracture (g) for 2% halothane (A) and 2 mM caffeine (B). Tests have been performed on 26 subjects with exertional heat stroke (EHS) and 26 controls according to the European Malignant Hyperpyrexia Group guidelines (5). For the sake of comparison, results from 13 malignant hyperthermia-susceptible (MHS) subjects are displayed. Results are presented as means ± SE. MHN = malignant hyperthermia negative.

 
At the beginning of each protocol, under normoxia or ischemia, pH, [PCr]/[Pi], and [PCr]/[ATP] values were similar in both groups, indicating that full recovery was achieved between protocols. It is interesting to note that the PME signal, located in the 3- to 5-ppm region and mostly ascribed to glucose 6-phosphate (10), was significantly lower at rest in the EHS group.

The [PCr] and pH time-dependent changes recorded throughout both exercises (normoxic and ischemic) were qualitatively similar and illustrate the balance between ATP production from aerobic and anaerobic pathways (Fig. 2). The magnitude of these modifications was always larger under ischemic conditions because of reduced oxygen supply (13,14). During the first minute of exercise, no significant pH decrease was observed for MHN subjects (Table 1). Throughout the remainder of exercise, pH continuously decreased as a sign of anaerobic ATP production. The [PCr] decrease with respect to time evidenced ATP production from PCr hydrolysis, and the rate was minimal at the third minute of exercise. An accumulation of PME was noted as a result of the imbalance between glycogen phosphorylase and phosphofructokinase activities (10). ATP homeostasis was maintained during exercise.



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  		Figure 2. Metabolic changes (creatine phosphate [PCr] and pH) recorded through the aerobic (A, B) and ischemic (C, D) exercises. Results are presented as mean ± SD. {square} Malignant hyperthermia-negative (MHN) group; {blacksquare} exertional heat stroke (EHS) group. *Significant difference between MHN and EHS groups (P < 0.05). The first point corresponds to the value averaged at rest.

 

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  		Table 1. Values (Means ± sd) of Several Metabolic Variables Measured and Calculated Throughout the Rest-Exercise-Recovery Protocols
 
Under both conditions of exercise, time-dependent changes of [PCr] and [PME] were similar in the EHS group as compared with controls. On the contrary, under both conditions of oxygen availability, a significant pH decrease was measured at the onset of exercise in the EHS group (Table 1, Fig. 2). Regarding the raw values of pH, this difference remained for the second and third minute of exercise and was observed only in the normoxic protocol. However, considering the rates of pH changes calculated for each minute of exercise (after the first minute of exercise), no significant difference was reached between groups for both conditions of exercise. Finally, the extent of pH change measured at the end of the normoxic exercise was significantly larger in EHS subjects than in controls. This difference was not observed under ischemic conditions.

Recovery profiles of [PCr] and pH recorded under aerobic conditions after both types of exercise are displayed in Figure 3. The generation of protons coupled to aerobic PCr resynthesis accounted for the postexercise acidosis noted in the MHN group (Fig. 3). This additional acidosis was not statistically different between EHS and control subjects. The initial rate of [PCr] recovery, calculated from the monoexponential fit, did not reveal any differences between groups (Fig. 3). In both groups, the kinetics of recovery were faster for higher end-of-exercise pH values, as expected (9).



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  		Figure 3. Metabolic changes (creatine phosphate [PCr] and pH) recorded after the aerobic (A, B) and ischemic (C, D) exercises. Results are presented as mean ± SD. {square} Malignant hyperthermia-negative group; {blacksquare} exertional heat stroke group. The first point corresponds to the end-of-exercise value.

 
This analysis demonstrates that anomalies recorded in the EHS group were mainly associated with pH time-dependent changes at the onset of exercise, whereas no further significant differences were recorded for [PCr], [PME], or [ATP] profiles. Neither the rest nor the recovery periods evidenced abnormality, except for the lower [PME] measured at rest in the EHS group.

According to the diagnostic test of MHS subjects previously reported (4) and described in Methods, we have classified the EHS subjects. Nineteen subjects (73%) displayed a MRS score larger than 2 (averaging 6), suggesting that they may be MHS. They were referred to as EHS I. The remainder (seven subjects; EHS II) had MRS scores lower than 2, thereby excluding their susceptibility to MH. It is interesting to note that results of IVCT were significantly different between those two subgroups of EHS subjects (Table 2). Contracture developed upon exposure to halothane was similar in both groups, whereas the intensity of caffeine-induced contracture was twice as large in EHS I as compared with EHS II (Table 2). In addition, the onset of contracture upon exposure to ryanodine was also significantly earlier in EHS I.


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  		Table 2. Results of In Vitro Contracture Tests in the Two Exertional Heat Stroke Subgroups Separated According to the Metabolic Score Defined by Magnetic Resonance Spectroscopy
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This analysis was performed on subjects who experienced an EHS episode and for whom in vitro caffeine-, halothane-, and ryanodine-induced contracture tests were positive. In considering the six-month delay between the heat stroke episode and the MRS examination, reported metabolic abnormalities cannot be interpreted as mere consequences of the stroke but more likely existed before the episode.

Positivity of IVCT clearly confirmed a possible relationship of EHS in this group of subjects with a latent myopathy, as already shown for MH (4). Despite the positivity of IVCT, these EHS subjects are different from MHS subjects with a family history of MH. MHS subjects often display histologic abnormalities—from nonspecific, such as atrophy of type II fibers, vasculitis, or rhabdomyolysis, to a disorganization of the intermyofibrillar network mimicking multicore or multiminicore disease (7). None of our EHS subjects displayed such anomalies, and none of them reported any family history of MH. Genetic information that could clarify the status of EHS subjects with respect to MH is lacking. This information is also not available for 50% of the MH families.

We have demonstrated that these EHS subjects displayed an early intracellular acidosis at the onset of both normoxic and ischemic exercises. It is interesting to note that this abnormality has been reported in MHS subjects (4,15) as a sign of abnormal glycolytic activity. Also, Payen et al. (16) did report a pH decrease twice as large in EHS subjects as compared with controls. The pH changes in exercising muscle are modulated by glycogenolysis activity, the amount of PCr hydrolyzed, and the capacity of muscle cells to handle proton production and elimination (17–19). Proton efflux, calculated from pH and [PCr] changes during the postexercise recovery period according to Kemp et al. (20) was normal (results not shown). The alkalinizing effect of PCr hydrolysis was also similar between the groups. Therefore, the remaining cause accounting for the early pH decrease recorded upon exercise for the EHS subjects is an excessive contribution of glycogenolysis to meet energy demand. This mechanism could result from a direct hyperactivation of glycogenolysis caused by an abnormally large Ca2+ concentration in the cytosol. It could also be regarded as an adaptive mechanism aimed at compensating for a deficient aerobic energy production. However, abnormality of aerobic metabolism can be excluded because kinetics of [PCr] recovery, a largely recognized index of mitochondrial metabolism (9,21–23), were not altered in EHS subjects. This observation clearly confirms that the early metabolic changes affecting pH are linked to an abnormally high activation of glycogenolysis, as previously found in MHS subjects, and might account for the abnormal consequences of strenuous exercise in EHS subjects (4).

According to the classification based on the previously reported magnetic resonance score (4), 73% of the EHS subjects had an average of six metabolic abnormalities, indicating that they may be susceptible to MH. It is interesting to note that the onset of muscle contracture upon exposure to ryanodine occurred significantly earlier for these subjects. It is accepted that in more than 50% of the MH families, MH susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum. Thus, metabolic abnormalities in EHS subjects detected by 31P MRS may indicate a defect affecting the calcium release channel of the sarcoplasmic reticulum, which translates as a very abnormal ryanodine contracture test by IVCT.

Abnormal IVCT has been reported for subjects who displayed severe exercise-induced stroke (24–28). For some subjects, but not all, family members had abnormal IVCTs, suggesting, in agreement with these metabolic results, that MH is a more general stress-induced syndrome, of which heat stroke could be one manifestation. In agreement with this hypothesis and on the basis of results recorded in animals and humans (29–31), other factors, such as physical stress or heat, have been recognized to induce MH, in addition to volatile anesthetics and depolarizing muscle relaxants. EHS subjects might have an underlying skeletal muscle abnormality that is probably distinct from MH but involves a similar dysregulation of myoplasmic calcium cycling. This alteration of calcium regulation could explain in vitro abnormal contracture of muscle bundles exposed to anesthetics and in vivo heat stroke after strenuous exercise. We do not have any specific information about the possible inherited component of this muscle abnormality. Since 1988, 250 subjects who displayed EHS have been investigated in Marseille by use of IVCT and MRS. Among them, 32% have been diagnosed as MHS, demonstrating, in agreement with previous studies, that not all EHS subjects have muscle abnormality. Similarly, positive IVCT has been reported in other a priori unrelated myopathies, such as periodic paralysis and muscular dystrophies (32–38). However, for EHS subjects with abnormal IVCT, such as the 26 cases reported in this article, there is a frequent incidence of similarities between anomalies related to EHS and MH.

We conclude from our results that, similar to MH crisis, EHS is related to a failure of muscle energetics that may be associated with a latent myopathy that is readily identified by noninvasive 31P MRS.


   Acknowledgments
 
Supported, in part, by grants from AFM (Association Française contre les Myopathies), PHRC 1997 (Program Hospitalier de Recherche Clinique), and CNRS (Centre National de la Recherche Scientifique).


   References
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 Introduction
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 Discussion
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Accepted for publication May 4, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press