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doi: 10.1097/01.anes.0000296107.23210.dd
Classic Papers Revisited

Malignant Hyperthermia

Denborough, Michael A. M.D., M.B., Ch.B., D.Phil., D.Sc., F.R.A.C.P., F.R.C.P., F.N.Z.C.A.*
Section Editor(s): Warner, David S. M.D., Editor

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Anesthetic deaths in a family. By M. A. Denborough, J. F. A. Forster, R. R. H. Lovell, P. A. Maplestone, and J. D. Villiers. Br J Anaesth 1962; 34:395–6. Reprinted with permission.
A local family is described in which there have been ten deaths attributable to general anesthesia. The pattern of inheritance of the abnormality is compatible with that due to an incompletely penetrant dominant gene or genes. Spinal anesthesia produced no ill effects when used in the one member of the family who survived a reaction following a general anesthetic.
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THE story of malignant hyperthermia began dramatically on April 8,1960, when a 21-yr-old engineering student at the University of Melbourne, Victoria, Australia, sustained compound fractures of his right tibia and fibula when he was hit by a car while walking to his lectures at the university.1 He was taken to the Casualty Department of the Royal Melbourne Hospital, which was nearby, and when he arrived there both he and his mother, who accompanied him, were less concerned about his leg than they were about the possibility of him having a general anesthetic because they said that 10 of his close relatives had died during or after anesthesia, usually administered for minor procedures. Because of this history, he had had his appendix removed under local anesthesia by his general practitioner when he was 12 yr old, and so had his sister when she developed appendicitis.
When the anesthetist, James Dermott Villiers, M.B., Ch.B., D.A., M.F.A.R.C.S., F.A.N.Z.C.A. (Department of Anesthesia, Royal Melbourne Hospital, Victoria, Australia), turned up for an all-day operating list, he was told that another case had been added to the list and that there was a story of 10 relatives dying from anesthesia. Dr. Villiers held up the start of the list to go to see the patient. He contacted the general practitioner and the Royal Children’s Hospital where the patient’s cousin had been safely anesthetized some months earlier. Because ether had been incriminated in all the deaths, Dr. Villiers eventually decided to use halothane and all the monitors available to him.
Unfortunately, after 10 min of anesthesia the patient became acutely ill. His blood pressure was falling, the pulse rate was rising, and the patient was cyanosed and felt very hot. The soda lime quickly expired and was changed. The fracture was quickly reduced and the anesthetic ceased. Dr. Villiers initially thought that the patient had lost blood because of the fracture, and a blood transfusion was started. Ice was being used in a nearby cardiac theater, and he packed the patient in ice. Within an hour of beginning the operation, the patient was awake and alert, and his subsequent course was uneventful. He was the first recorded patient to survive what we now know as malignant hyperthermia.
Dr. Villiers referred the patient to Richard Robert Haynes Lovell, M.D., F.R.C.P., F.R.A.C.P. (Professor, University of Melbourne Department of Medicine, Royal Melbourne Hospital, Victoria, Australia; 1918–2000), the next day, and because of my interest in Clinical Genetics, he asked me to see the patient. It soon became clear to me that this was a previously unrecognized inborn error of metabolism, which was obviously of considerable clinical importance. Detailed clinical examination and routine pathologic and biochemical tests revealed no abnormality. In the hope that others might have noted similar clinical events, I wrote to The Lancet about the reaction but there was no response.2
Inquiry showed that, of the 38 relatives of the propositus who had undergone general anesthesia, 10 had died. In all cases, it seemed that the anesthetic agents used were ethyl chloride and ether. Three of the affected members were cousins of the propositus and seven were uncles or aunts. For cases in which it was possible to obtain records of the deaths after anesthesia in this family, the course of events had been similar. In all except one patient, the operation had been minor and successful and so was very unlikely to have caused the death. In the three best documented patients, who were female and aged 39, 16, and 12 yr, each had been returned to the ward after the operation in apparently good condition, only to die after convulsions approximately 30 min later. In two, the temperature was 43°C and 42°C, respectively. At post mortem examination, no abnormality was found. The pattern of inheritance was compatible with that due to a dominant gene or genes, with one exception. The grandmother of the propositus, who might be expected to have been affected, survived the administration of chloroform for eclampsia. This suggested that sometimes there might be incomplete penetration of the gene or genes. Alternatively, affected members may be able to survive light anesthesia.
Almost a year later, the same young man needed another anesthetic for a stone impacted in the left ureter. John F. A. Forster, M.B., B.S. (Lond.), M.R.C.S., L.R.C.P., F.F.A.R.A.C.S. (Anesthetist, Department of Anesthesia, Royal Melbourne Hospital, Victoria, Australia; 1910–1985), was charged with administering the anesthetic, and he seemed well suited for this terrifying task, as he had won the Croix de Guerre as a parachutist in France in World War II. After considerable discussion, the patient was given a spinal anesthetic with cinchocaine, which he tolerated uneventfully. The knowledge that local, regional, and spinal anesthesia could be used safely in affected individuals was of great practical help to us subsequently. For this particular patient, it was to have great significance; for the rest of his life, he suffered from kidney stones and had multiple uneventful procedures under spinal anesthesia.
Subsequent developments in the understanding of malignant hyperthermia have been described in a review article.3
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1. Denborough MA, Forster JF, Lovell RRH, Maplestone PA, Villiers JD: Anaesthetic deaths in a family. Br J Anaesth 1962; 34:395–6

2. Denborough MA, Lovell RRH: Anaesthetic deaths in a family (Letter). Lancet 1960; 276:45

3. Denborough M: Malignant hyperthermia. Lancet 1998; 352:1131–6

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Filling in the Blanks
Warner, DS
Anesthesiology, 110(1): 10-11.
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