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To the Editor: Malignant hyperthermia (MH) is an autosomal dominant condition in which certain anesthetics trigger calcium dysregulation in skeletal muscle, resulting in a catastrophic, life-threatening hypermetabolic syndrome.¹ More than 50% of families with MH have mutations in the gene encoding the ryanodine receptor (RYR1).² In a porcine model of MH, nonanesthetic, stress-induced deaths have been reported in pigs homozygous for the Arg614Cys mutation in the RYR1 gene,³ but this phenomenon has not been reported in humans with MH mutations. To our knowledge, we report the first case of nonanesthetic, stress-induced hyperpyrexic death in an individual with a history of MH.

Report of a Case
At age 12 years, the patient underwent general anesthesia with sevoflurane for reduction of a humerus fracture. Fifteen minutes after induction, he was found to have an abrupt increase in end tidal CO₂ (>70 mm Hg), heart rate (150/min), and temperature (36.7°C to 39.4°C). Diaphoresis, but not muscle rigidity, was observed, and he was later found to have a maximum blood creatine kinase level of 9049 U/L. A diagnosis of MH was made, and he was successfully treated with dantrolene sodium.⁴ He recovered without sequelae.

Eight months later, the patient participated in a football game when the ambient temperature was approximately 80°F (26°C). After the game, he showered and complained of ascending weakness and muscle stiffness. Prehospital personnel found him sitting, hot, diaphoretic, hyperventilating, and complaining of tingling in his extremities. Seizure activity and respiratory arrest ensued. Electrocardiographic monitoring revealed a sinus tachycardia of 136/min without ectopy, and assisted ventilation was begun with 100% oxygen. Endotracheal intubation was unsuccessful because of jaw clenching. Ventricular fibrillation developed and was treated with epinephrine and defibrillation per advanced cardiopulmonary life support. On arrival at the hospital, the patient's rectal temperature was higher than 108°F (>42.2°C). His electrocardiogram rhythm on arrival was a wide complex brachycardia that quickly degenerated again to ventricular fibrillation. The trachea was intubated (without neuromuscular relaxant) and resuscitation continued, including therapy for hyperkalemia (sodium bicarbonate, calcium chloride, glucose, and insulin) and administration of dantrolene for suspected MH. Results of arterial blood gas analysis revealed a pH of 6.76, PCO₂ of 115 mm Hg (15.3 kPa), and PO₂ of 22 mm Hg (2.9 kPa). Serum potassium concentration was 8.8 mEq/L (8.8 mmol/L) and rose to 14.5 mEq/L (14.5 mmol/L) despite improvement in blood gas concentrations. The resuscitation was discontinued after 1 hour.

Findings on postmortem examination included mild left ventricular hypertrophy and evidence of acute aspiration of gastric contents. Rigor was full in all extremities and the jaw. Internal organ examination revealed normal anatomic position of coronary ostia and widely patent coronary arteries with normal distribution. No evidence of cardiac trauma, obstructive pathological features, or ischemia was found. The musculoskeletal system and soft tissues did not show unusual features. Results of histopathologic examination of muscle tissue were unremarkable.

Analysis of DNA obtained from the patient and immediate family members revealed an altered RYR1 gene sequence, C487T, creating a substitution of arginine for 163 cysteine in the patient and in his father. Because of his premature death, the patient had not had a muscle biopsy contracture test performed.

Comment
Exercise-induced rhabdomyolysis has been associated with mutations of the RYR1 gene,⁵ and it has been suggested that stress might trigger MH; however, the exact nature of this association is unknown. To our knowledge, stress-induced hyperpyrexic death without anesthetic exposure in an individual with genetic predisposition and a previous clinical MH episode has not been reported previously. The clinical presentation of MH during prior anesthesa in this patient is associated with a clinical grading scale of 5 (very likely MH).⁶ Postmortem examination did not reveal any of the usual etiologic characteristics associated with sudden death in an adolescent. Histopathology demonstrated an athletic heart but not hypertrophic cardiomyopathy. No substance of abuse was found. Observers denied exposure to excessive environmental conditions or exertion by the patient.

This patient may have died of MH not associated with anesthetic agents. We speculate that other patients susceptible to MH may have died with an assumed diagnosis of heat stroke; however, their MH susceptibility may have been unknown or not considered. Death due to nonanesthetic MH may represent only a small percentage of patients who develop heat stroke; nonetheless, MH susceptibility should be considered as these patients may demonstrate an exaggerated response to stress. Dantrolene may be indicated, and familial testing should be pursued. We encourage consultation with the Malignant Hyperthermia Association of the United States following any catastrophic hyperpyrexic presentation (http://www.mhaus.org or 800-98-MHAUS).

Joseph R. Tobin, MD
Department of Anesthesiology

Donald R. Jason, MD; Venkata R. Challa
Department of Pathology

Thomas E. Nelson, PhD
Department of Anesthesiology
Wake Forest University School of Medicine
Winston-Salem, NC

Nyamkhishig Sambuughin, PhD
Barrow Neurological Institute
Phoenix, Ariz

1. Nelson TE, Flewellen EH. The malignant hyperthermia syndrome. N Engl J Med. 1983;309:416-418. ISI | PUBMED 2. Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve. 2000;23:4-17. FULL TEXT | ISI | PUBMED 3. Fujii J, Otsu K, Zorzato F, et al. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253:448-451. FREE FULL TEXT 4. Nelson TE, Lin M, Zapata-Sudo G, Sudo RT. Dantrolene sodium can increase or attenuate activity of skeletal muscle ryanodine receptor calcium release channel. Anesthesiology. 1996;84:1368-1379. FULL TEXT | ISI | PUBMED 5. Wappler F, Fiege M, Steinfath M, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology. 2001;94:95-100. FULL TEXT | ISI | PUBMED 6. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771-779. FULL TEXT | ISI | PUBMED

Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor.

JAMA. 2001;286:168-169.

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