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Unravelling the mystery of malignant hyperthermia.


Malignant hyperthermia was an unknown condition in 1960 although there had always been occasional patients who died mysteriously under anaesthesia. The nature of the disease became apparent when a young Melbourne man presented that year with a compound fracture and a family history of deaths under anaesthesia. He survived his anaesthetic due to the combined efforts of the anaesthetist and the surgeon. His family history was then investigated by the physicians. Over the next 20 years the cause of the disease was discovered and eventually a treatment was found. This article is based around a senes of interviews with many of the participants in this story.


Ron Evans' story began in the 1950s when he developed appendicitis at the age of about 12. His mother could be forgiven a heightened level of anxiety, given that the family had a history of 10 inexplicable deaths under anaesthesia. Fortunately she had a good relationship with her local doctor in Williamstown, Victoria and he had a great reputation as a surgeon. All general practitioners in the 1950s provided a very comprehensive service but the doctor's service to this particular family was exceptional and no doubt saved the lives of several of the children. On this occasion he arrived at the house, transferred the child to the local hospital in his own car and, mindful of the family history, removed the appendix under local anaesthetic--or as the patient remembered it, "with four injections in my stomach". A similar fate befell his sister when she also developed appendicitis (R and L Evans, personal communication).

The family doctor was also contacted when the same patient was hit by a car in 1960 just outside the Royal Melbourne Hospital, sustaining a compound fracture of his tibia and fibula. His mother was there in no time to ensure that no-one gave her son an anaesthetic and insisted that their own doctor be called. It is well documented that they were assured that the problem seemed to lie with ether and that the new drug now available, halothane, was completely different and was unlikely to cause the same problem. The anaesthetist, Dr Jim Villiers, remembers it slightly differently. He and the orthopaedic surgeon, Mngsley Mills, both honorary specialists at the Royal Melbourne, had a regular afternoon operating list together. When he arrived on that particular afternoon the orthopaedic registrar was sitting in the corner of the tea-room and gave Jim Villiers the news that is familiar to all anaesthetists: "We've added a case to the list". He added that the patient was a young man with a broken leg with "some strange story about ten relatives dying from ether anesthesia". He concluded, 'Anyway, I told him that we don't use that any more and not to worry".



Jim Villiers and Mngsley Mills held up the start of the list so they could both go to visit the patient on the ward. Taking a history confirmed the story of familial anaesthetic deaths under ether anaesthesia. They discovered that the patient's cousin had been safely anaesthetised with "modern anaesthetics" and not ether some months earlier at the Royal Children's Hospital.

The patient's local doctor was contacted but could not add to the story. Porphyria was the only condition known at the time to be adversely affected by anaesthetics, so the urine was tested for porphyrins. "Ether convulsions" was a condition described in the literature so it seemed prudent to avoid ether and the patient was reassured that it would not be used. Villiers decided to use a thiopentone induction cautiously and maintain the anaesthetic with nitrous oxide and halothane, using all the monitors available to him--namely a blood pressure cuff and a heightened state of anxiety. Meanwhile the scrubbed up theatre team was anxiously awaiting the start of the elective list, one typical of those days with a high proportion of poor risk elderly patients with fractured hips.

It was late afternoon by the time Ron Evans reached theatre, and induction of anaesthesia and commencement of the operation were uneventful. However, within minutes of the halothane being introduced, it was clear there was a problem: the patient's blood pressure fell and his pulse rate rose. He was warm with a cyanotic tinge and was hyperventilating. The halothane was turned off immediately and the oxygen increased to 50%. The soda lime canister became very hot and the contents were renewed although the indicator had not changed. Dr Mills hastily reduced the fracture and closed the wound and the anaesthetic was ceased. The patient remained cyanosed and unresponsive. Dr Villiers thought there may have been blood loss due to the fracture and a blood transfusion was commenced. Ice was being used in a nearby cardiac theatre and, as the patient had now become hot and sweaty, he was packed in ice. Within an hour of the commencement of the operation, the patient was aware and alert. Miraculously he recovered completely, becoming the first recorded person to survive what we now know as malignant hyperthermia.

Jim Villiers subsequently interviewed the patents, obtaining further details concerning anaesthetic deaths in the family, and then referred Ron Evans to the then Professor of Medicine at Melbourne University, Professor Richard Lovell, for investigation. A barrage of tests was carried out and all were negative. At that time, Dr Michael Denborough had a research fellowship in the Department of Medicine and had expressed an interest in genetics. Professor Lovell suggested that he should investigate this patient and his family history. Some painstaking research followed. Denborough and Lovell wrote to the journals asking if anyone else had similar cases to report and Dr Denborough contacted many of the patient's relatives, trying to ascertain the cause of the deaths in the family. The patient's mother also wrote many letters.

Today the letters and their often lengthy replies are part of the family archive which also contains many newspaper clippings collected over the years. Clearly a very good relationship developed between this family and their doctors; letters go back and forth over the decades about further advances in treatment, testing and diagnosis. These are not formal and clinical but show that there was a true appreciation of the role the family played in helping to unravel this disease. It seems that they were always kept informed of developments and any testing that could be done.

It is important to recognise the anaesthetist involved in this procedure, Dr James Villiers. He was faced with a great challenge; a terrified patient and family, an unknown and untreatable disease and an elective list which everyone was anxious to start. Clearly he took a good history and was prepared for disaster: when it struck, he took sensible action, ceasing the anaesthetic and cooling the patient and thereby saving the patient's life. The role of the surgeon, Kingsley Mills, and his cooperative relationship with the anaesthetist is also important. He had joined his colleague at the preoperative consultation and was well aware of the potential crisis. He completed the operation promptly and efficiently and never questioned the need for the anaesthetic to cease. Michael Denborough is confident that, given the extensive family history, he would have been contacted even if the patient had not survived, but no doubt his task was made easier by a relieved rather than a grieving family (Michael Denborough, personal communication).

The other anaesthetist who deserves recognition in this story is another Melbourne anaesthetist, Dr John Forster. The same patient presented to the Royal Melbourne Hospital a year later with a ureteric stone. Now there was a double dilemma--the disease was recognised, the triggers were known and no treatment or prophylaxis was available. But, as Michael Denborough said of John Forster, "he was ideally suited for this terrifying task as he had won the Croix de Guerre as a parachutist in France in World War II" (1). For some reason he chose not to consult Jim Villiers about the case, but it seems he was known for a rather 'go-it-alone' approach (2). Nevertheless he elected to perform a spinal anaesthetic with cinchocaine, a brave move considering that it would not be easily reversed. The anaesthetic and operation were successful and there were no complications. This was ground-breaking as it showed that these patients could be safely anaesthetised with regional anaesthesia. 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 anaesthesia. He had only one general anaesthetic: that was for a nose problem and he assured me it was not done under spinal anaesthesia.

This case was the beginning of serious scientific study into the condition. Where possible, Michael Denborough obtained records of anaesthetics given to family members (3). Thirty-eight relatives had had general anaesthesia and 10 of those had died. All had been given ethyl chloride or ether. The operations had been minor and there was no reason to suspect that they were implicated in the deaths of the patients. In the three best documented cases, death had occurred in the ward, associated with convulsions. Two of these had their temperatures recorded and they were 42[degrees]C and 43[degrees]C respectively: no abnormality was found at post mortem. The pattern was one of autosomal dominance inherited via the patient's grandmother. She was presumed to have been affected despite having been given chloroform for eclampsia without any complications. Denborough concluded that this indicated that there was variable penetrance of the disease or that some patients could tolerate light anaesthesia (4).

Although the cause was unknown, the inheritance pattern was of great significance to the patient when he had his own children. Once again, the cooperative relationship they had built up with the doctors at the Royal Melbourne was of great benefit to them. Whenever the children required anaesthetics, doctors would go over from the Royal Melbourne to the Royal Children's Hospital and explain the problem presented to the anaesthetists. It must be remembered that at this time the condition was still largely unrecognised.

Case reports began to appear in the daily papers and the anaesthetic literature over the next few years. One of the more dramatic was an unfortunate man who survived a lion attack in Perth, not a common event in that state, only to die subsequently of malignant hyperthermia (5). Many of these patients did die but there was enough interest in the condition for the Canadian Anaesthetists Society Journal to publish a symposium on Malignant Hyperthermia in 19666 (6). At this time the cause was still not known, although it was clear that it was probably a response to anaesthetic drugs and that it was an inherited problem in some patients. Suxamethonium was certainly implicated by many at this time and a failure to achieve relaxation with suxamethoniumwas noted as aworrying symptom indicating the onset of malignant hyperthermia. It was clear that muscle rigidity was a factor in all the patients and therefore the development of muscle rigidity was seen as a warning sign that malignant hyperthermia may develop.


The symposium raised the awareness of the condition. Dr Robert Hare remembers a young boy who was anaesthetised by Dr John Mainland at the Alfred Hospital in Melbourne in the late 1960s. The boy became very unwell during the anaesthetic in association with very hot soda lime canisters. Bob, who just happened to be passing, had just read the symposium issue and suggested they take his temperature which was 44[degrees]C. They treated the boy with ice immersion, insulin and calcium. Unfortunately he still died. John Mainland presented the case report at a Faculty of Anaesthetists meeting, thus increasing general awareness of the condition.

In 1969, another patient presented at the Royal Melbourne Hospital (7). The patient had a short operation for trauma and was returned to the ward. When Michael Denborough was called to the ward to see the patient it was three hours since the commencement of anaesthesia. The patient was unconscious and very unwell, with symptoms suggestive of malignant hyperthermia. Since it was now suspected that the disease was somehow related to an abnormality of the muscles, a serum creatine-phosphokinase (CPK) assay was performed. It was elevated at 250 IU/1 but this was consistent with the trauma. Further CPK measurements were done over the next few hours and they ultimately rose to 20,000 IU/1 just prior to his death 24 hours postoperatively.


The next day, Denborough contacted Ron Evans and requested that he have a serum CPK measurement. It was elevated and subsequently all the associated family members had their CPK measurements done. Serum CPK rises with any damage to muscles and is therefore a non-specific test, but it was clear that it had at least some predictive value. In 1972 Denborough and colleagues published a report on all the known cases of malignant hyperthermia in Australia and New Zealand, looking at serum CPK and physical characteristics. They showed that most individuals had an inherited myopathy with a dominant transmission and elevated CPK. A second group was described with multiple physical abnormalities in which the relatives all had normal CPKs and no reaction to anaesthetics (8).

The discovery of an animal model for malignant hyperthermia, a certain breed of pigs, led to the realisation that the essential biochemistry of malignant hyperthermia was increased calcium in the myoplasm. In the early 1970s, Kalow and Britt (9,10) showed that muscle samples from affected individuals contracted to a greater extent than normal when exposed to caffeine in vitro. The following year, FR Ellis and colleagues (11) showed that similar results occurred with halothane in affected individuals with the result that in vitro testing with caffeine and halothane is now a routine screening test for malignant hyperthermia. Subsequently members of the original family had muscle biopsies, enabling Michael Denborough to produce a more comprehensive family tree (12).

In the early treatment regimens the most successful drugs were dexamethasone and procaine. Procaine was suggested because it inhibits caffeine contraction in frog skeletal muscle. Denborough and Moulds (12) conducted tests on vastus lateralis muscle from patients having elective surgery. Among this group was a member of the Evans family who has a particularly severe myopathy and was known to have malignant hyperthermia. In vitro, the specimen from the affected patient showed decreased contracture to all tests with the addition of procaine. In other reports, procaine was certainly found to be clinically useful but not universally curative. Procainamide was also effective but at the required dose produced too many side-effects. Lignocaine was found to have variable and unpredictable effects and was not useful clinically.

Dantrolene (13), now seen as the definitive treatment, was first used successfully in pigs in 1975 and clinical trials in humans were carried out between 1977 and 1979. The drug was introduced into clinical practice and once a usable compound had been produced, recommended for the first line treatment of malignant hyperthermia in 1980. It remains quite difficult to dissolve but has decreased the mortality of this condition to extremely low levels.

And so to the current times. The people in the story have moved on--Ron Evans died on September 19, 2006 but has left a legacy of three children and nine grandchildren who, together with his wife, retain a cooperative relationship with malignant hyperthermia researchers. Dr Villiers is now retired and living in Melbourne, as is Dr Mngsley Mills. Jim Forster died several years ago, while Michael Denborough retains a boundless enthusiasm for life, having diverted his energies from malignant hyperthermia to the Nuclear Disarmament Party which he founded in 1984. His passionate commitment to this party and the issues it represents has seen him run for Senate and organise political rallies and protests. He retains an appointment as Professor Emeritus at the Australian National University.

Malignant hyperthermia is now the domain of the geneticists, with promising genetic testing taking place. The in vitro muscle contracture test remains the definitive test for susceptibility to malignant hyperthermia, but progress is being made in developing a noninvasive genetic blood test. And importantly, due to the discovery of Dantrolene, malignant hyperthermia is treatable. The treatment can be acute, anxiety-provoking and complex, but it is now constantly rehearsed in anaesthetic simulators which must be contributing to the current very low mortality rate from malignant hyperthermia today.


I thank Ron and Lyn Evans for giving generously of their time and memories. Many thanks to Michael Denborough and Jim Villiers for their stories and for their help with the final manuscript, to Bob Hare and also the Australian and New Zealand College of Anaesthetists library staff, Shanti Nadaraja and Jenny Jolley, who tirelessly search for obscure archived references for all my projects. And, finally, thanks to Rod Tayler who sent me on this quest.

Accepted for publication on March 14, 2007.


(1.) Denborough MA. This week's citation classic. Current Contents 1986; 45, November 10:18.

(2.) Denborough MA, Forster JFA, Lovell RRH, Maplestone PA, Villiers JD. Anaesthetic deaths in a family. Br J Anaesth 1962; 34:395.

(3.) Denborough MA, Ebeling P, King JO, Zaff P Myopathy and malignant hyperpyrexia. Lancet 1970; May 30:1138-1143.

(4.) Denborough MA, Lovell RRH. Anaesthetic deaths in a family. Lancet1960;2:45.

(5.) TheAge. Monday, September 13, 1971.

(6.) Editorial. Malignant hyperthermia during general anaesthesia. Can Anaesth Soc J 1966.

(7.) Denborough MA, Forster JFA, Hudson CC. Biochemical changes in malignant hyperpyrexia. Lancet 1970; 1:1137-1138.

(8.) King JO, Denborough MA, Zaff PW Inheritance of malignant hyperpyrexia. Lancet 1972; February 12:365-370.

(9.) Britt B. Recent advances in malignant hyperthermia. Anesth Analg 1972; 51, 5:841-848.

(10.) Relton JES, Britt BA, Steward DJ. Malignant hyperpyrexia. Br J Anaesth 1973; 45:269-275.

(11.) Ellis FR, Harriman DGF, Keaney NP, Kyei-Mensah K, Tyrell JH. Halothane-induced muscle contracture as a cause of hyperpyrexia. Br J Anaesth 1971; 43:721-722.

(12.) Moulds RFW, Denborough MA. Procaine in malignant hyperpyrexia. BMJ 1972; 4:526-528.

(13.) Kolb ME. Dantrolene in human malignant hyperthermia. Anesthesiology 1982; 56:254-262.


Geoffrey Kaye Museum of Anaesthetic History, Australian and New Zealand College of Anaesthetists, Melbourne, Victoria,


* Assistant Curator, Geoffrey Kaye Museum of Anaesthetic History, Australian and New Zealand College of Anaesthetists, Melbourne, Victoria, Australia.

Permission to publish patient's full details, photograph and identity has been given.

Correspondence: Dr C. Ball, Assistant Curator, Geoffrey Kaye Museum, ANZCA, 630 St Kilda Rd, Melbourne, Vic. 3004.
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Author:Ball, C.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8AUST
Date:Jun 1, 2007
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