MALIGNANT hyperthermia (MH) is characterized by a hypermetabolic response to all commonly used inhalational anesthetics and depolarizing muscle relaxants leading to muscle rigidity, metabolic acidosis, hypercapnia, tachycardia, and fever. 1Furthermore, it is well known that in certain breeds of swine, MH can be easily triggered by environmental stress. In contrast, MH unrelated to anesthesia occurs rarely in humans. Several investigators have presented case reports of patients suffering from MH during strenuous exercise, excitement, and environmental heat, 2–7indicating the existence of a human stress syndrome. However, it is still a matter of debate whether stress-induced MH episodes are caused by an increased sympathoadrenergic activity, 1,8alterations in the serotonergic system, 9,10or genetic heterogeneity. 11
We investigated a young MH-susceptible (MHS) man with a history of MH-like episodes induced by mild physical stress to determine hemodynamic and metabolic responses after graded exercise.
A 34-yr-old man (height, 175 cm; weight, 80 kg) was admitted to our MH consultation clinic because of suspicion of a human stress syndrome. In response to mild exercise or emotional stress, he manifested recurrent elevations in body temperature up to 40°C and fatigue associated with muscle cramping and aching. These symptoms disappeared spontaneously after several hours of rest. The patient had noted first signs of a reduced stress tolerance 10 yr earlier. Since that time, the aforementioned stress-associated symptoms had increased in severity and occurred more frequently.
Prior examinations from internists, neurologists, psychiatrists, and dermatologists did not reveal pathologic findings. All blood parameters were within normal limits, and no signs of autoimmune diseases were found. Allergies and cardiac disorders were ruled out. There were no signs of chronic or acute infections. The patient did not take any medication, drugs, or alcohol on a regular basis. There was no history of muscle diseases or of anesthetic complications within the family of the patient. Three months after the patient was tested, his brother and sister were tested, also as MHS, with the in vitro contracture test (IVCT) 12; however, both had no stress intolerance. The patient himself had two uneventful regional anesthesia procedures before our investigations. Because his clinical episodes resembled stress-induced MH, a muscle biopsy specimen for IVCT and muscle histology was obtained, genetic mutation screening was performed, and, in addition to our usual practice, the patient underwent graded exercise on a bicycle ergometer.
IVCTs and Muscle Histology
The IVCTs with halothane and caffeine were performed according to the protocol of the European MH Group. 12Muscle bundles, excised from the vastus lateralis muscle, were dissected into eight strips. Only viable muscle samples (twitch response to supramaximal stimulation ≥ 10 mN) were used. Two samples were tested with each drug. The muscle specimens of this patient developed abnormal contracture responses to halothane 0.44 mM and caffeine 1.5 mM, indicating susceptibility to MH. In addition, a ryanodine contracture test with 1 μM ryanodine was performed twice as described previously. 13After administration of ryanodine, an accelerated and increased contracture development was observed, indicating MH susceptibility.
An additional muscle sample was excised for histologic examination. All investigations performed on this muscle specimen (morphometry, immunohistochemistry, fiber size and ratio analysis, etc. ) showed normal findings.
Preparation of DNA and oligonucleotides, genotyping, and detection of mutations in the ryanodine receptor gene were performed as described previously. 14Mutation screening led to the discovery of a substitution of A for G7297. The patient was heterozygous for this mutation. This nucleotide substitution results in the substitution of Arg for Gly2433, which was shown to be associated with MH. 14
The patient was investigated 4 months after the IVCT. A cannula was inserted during local anesthesia for intravenous infusion of 2 ml · kg−1· h−1Ringer’s solution. Furthermore, an arterial cannula was inserted into the left radial artery for pressure monitoring and blood sampling, and a Swan-Gantz catheter was inserted into the right cubital vein for measurement of hemodynamic parameters and to obtain blood samples. A standard 12-lead electrocardiogram was monitored continuously and recorded. Room temperature in the laboratory was 18°C, and the patient wore sportswear.
At the end of a 60-min resting period, baseline data were measured (table 1), and the patient started exercise on a bicycle ergometer at a workload of 50 W followed by continuous incremental workloads of 75, 100, and 125 W, with no break between each level. The period spent at each load was 3 min. Electrocardiogram was monitored continuously throughout the experiments. After each period, hemodynamic variables (heart rate, mean arterial pressure, central venous pressure, and mean pulmonary artery pressure), right atrial temperature (°C) via the Swan-Gantz catheter, mixed venous and arterial blood gases, lactate levels, and creatine kinase in serum were measured immediately before increasing the work load. After the exercise period, all variables were measured for 360 min. Furthermore, hormone levels such as adrenaline, noradrenaline, and serotonin were determined before and immediately after exercise, as well as 120 and 360 min after the experiments.
Most variables at rest were within normal limits, except blood pressure (mean arterial pressure, 110 mmHg) and creatine kinase with 91 U/l (normal, 30–80 U/l), which showed slight elevations. After starting exercise, heart rate increased from 97 beats/min to 177 beats/min (table 2), mean arterial pressure increased to 130 mmHg at 125 W workload, and mean pulmonary artery pressure increased from 8 mmHg to a maximum of 15 mmHg. Pulmonary capillary wedge pressure increased from 8 to 14 mmHg, whereas central venous pressure remained unchanged at 1 mmHg. Mixed venous oxygen saturation decreased concomitantly from 79% before exercise to a minimum of 49% at 125 W, resulting in an arteriovenous oxygen content difference of 3.2 ml · 100 ml−1before and 10.4 ml · 100 ml−1at the end of exercise (fig. 1A). These values normalized 5 min after the patient stopped exercising. Arterial and mixed venous carbon dioxide concentrations as well as p H were stable during the exercise; however, lactate concentration increased from 1 mM to a maximum of 9.9 mM (fig. 1B). Temperature increased from 36.9°C at rest up to 38.9°C at a workload of 125 W.
Serum potassium concentration increased from 3.8 U/l to 4.8 U/l after exercise. Catecholamine levels increased fourfold during the study, adrenaline from 65 ng/l (normal, <60 ng/l) to 233 ng/l, and noradrenaline from 253 ng/l (normal, <260 ng/l) to 930 ng/l, which normalized within 60 min after exercise. Serotonin levels did not change. Creatine kinase concentration reached a maximum of 453 U/l at the last measurement. All other parameters reached the level of the baseline values before this investigation.
Because of these findings and the patient’s clinical symptoms, we decided to attempt therapy with dantrolene. This treatment was started 2 weeks later with orally administered dantrolene at a dose of 0.25 mg/kg per day. After 7 days, the dose was increased to 0.5 mg/kg. However, the patient developed migraine, dizziness, and severe muscle weakness. Therefore, dantrolene administration was stopped, and therapy with a β-blocker was started. With this treatment symptoms became a little better, and the patient learned to reduce severity and frequency of such episodes by avoiding stress situations.
Physical and emotional stress are triggers of MH in susceptible swine. The role of stress for MH induction in humans is unclear. A large number of reports presented cases of individuals suffering from MH during stressful situations. 2–7These cases include patients with MH-like symptoms after a long-distance run, 2after extreme emotional 3and physical stress, 4,5,7,15or extended car trips. 6In most of these cases, susceptibility to MH was evaluated with an IVCT; however, the definite trigger mechanisms could not be detected, and exercise tests were not performed. In some patients, dantrolene was shown to be effective in the treatment 3or prevention 16of such symptoms. A possible explanation for the variation in clinical expression in stress-induced MH syndromes may be a result of the genetic heterogeneity that is present in humans compared with pigs.
Prior studies systematically investigated the effects of different forms and intensities of exercise in MHS patients compared with control individuals. 17–20The investigators found no significant differences between MHS and MH-normal patients in response to mild exercise. 17,19Thermoregulation, plasma catecholamine levels, and metabolic changes in the MHS individuals were comparable with the data from control individuals. In a later study, leg exchange of energy substrates was quantified by measuring leg blood flow and arterial-venous content differences at rest and during different levels of exercise. 20The results of that study indicated normal sympathetic activity and muscle metabolism in MHS patients during rest, as well as during moderate and severe exercise. In contrast to these findings, free fatty acids, cortisol, and blood lactate levels were significantly increased in MHS but not in MH-normal subjects, indicating an abnormality in the sympathetic activity. 18Regarding the results of these exercise studies, no differences in heart rate, 19creatine kinase, 17temperature, 18,19lactate 17,19and K+17were found between MHS subjects and controls. Compared with these data, our patient developed markedly higher values after exercise than controls or other MHS individuals. However, the fundamental problem with all studies is that the investigators used different experimental protocols (type and grade of exercise), study populations (i.e. , patients with and without stress syndromes), the condition of patients and control individuals was not proofed before the investigations, and the measurements during exercise were not identical. Therefore, it could be speculated that MHS subjects with a history of stress intolerance would present other reactions in response to exercise, as in our case report.
The sympathetic system has been proposed to play a major role in genesis of porcine stress syndrome. 1However, activation of the sympathetic nervous system seems to be a secondary response to stress, because it has been shown that total spinal anesthesia failed to attenuate the course of porcine MH, whereas the expected catecholamine increases were prevented. 21In a considerable number of case reports, the possibility of triggering MH-like episodes in humans by stress has been demonstrated 2–7; however, whether these responses were caused by an overactivity of the sympathetic nervous system remained unclear. Furthermore, in vitro studies on skeletal muscles from MHS patients showed no effect of adrenaline and noradrenaline on halothane-induced contractures. 22In our patient, catecholamine levels were increased fourfold during exercise, which is comparable to the changes during porcine MH, 8but this might be a physiologic response to the applied workloads.
Serotonin, which is also an important stress hormone, can be a trigger agent of MH in susceptible pigs. 9Furthermore, it has been shown that serotonin levels in plasma are significantly enhanced during halothane-induced MH. 23Under in vitro conditions, serotonin induced a marked contracture development in muscle specimens from MHS but only small contractures in control samples. 10Therefore, it could be hypothesized that serotonin might also trigger MH in humans. However, in this patient, serotonin levels in plasma remained stable at a normal level throughout our investigation.
It is well known that special breeding programs led to the genetic selection of swine with muscle hypertrophy and leanness but also to susceptibility for MH, associated with a reduced tolerance to stress. 1,11Genetic linkage studies showed that a single amino acid mutation (Arg615 to cysteine) in the porcine skeletal muscle ryanodine receptor gene on chromosome 6 is tightly linked to the MH phenotype. The corresponding mutation in the human ryanodine receptor gene is localized on the chromosome 19q13.1–13.2 region. 11At present, 17 different single-point mutations have been identified in the human ryanodine receptor gene in MH families. Furthermore, recent studies demonstrate linkage to DNA markers from chromosomes 1, 3, 5, 7, and 17 with the MHS phenotype. 11It can be hypothesized that these genetic differences in humans and swine are associated with diverging properties or sensitivities with respect to MH trigger. Furthermore, it is tempting to speculate that different genetic mutations in the human ryanodine receptor gene are responsible for an enhanced sensitivity to stress, explaining the existence of a human stress syndrome in some patients. Moreover, heterogeneity could be a satisfactory explanation for the complex pharmacology in MH as well as for different clinical MH presentations (i.e. , mild and fulminant forms, rhabdomyolysis).
Heterogeneity in humans may lead to different expressions of symptoms and probably sensitivity to MH trigger, including stress. It would therefore be desirable to standardize test protocols for exercise studies and to select MHS patients with a history of stress intolerance for these experiments. These attempts could be interesting contributions in our understanding of trigger mechanisms in MH. Although treatment with dantrolene failed in this case report because of severe side effects, this treatment was shown to be beneficial in other patients with stress symptoms 3,16; therefore, a therapy attempt with dantrolene should be recommended in patients with MH episodes unrelated to anesthesia.