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Malignant Hyperthermia research in Germany: from past to recent advances
International Congress Series 1242 (2002) 577 – 585
Malignant Hyperthermia research in Germany: from past to recent advances M. Goerig*, F. Wappler Department of Anaesthesiology, University-Hospital Eppendorf, Hamburg, Martinstrasse 52, 20240 Hamburg, Germany
Keywords: Heat stress; Malignant Hyperthermia; Anesthesia; Germany
1. Introduction Adverse events like hyperthermia during anaesthesia have been known ever since anaesthesiologic techniques were invented. Already, John Snow reported on sudden unexpected elevation of body temperature during anaesthesia [1]. There has been a wave of cases with similar symptoms under the same circumstances. The involved physicians suspected allergic reactions, hormonal imbalances like hyperthyroidism, status lymphaticus or status menstruationis to have been the cause, just like elevated temperature in the operation theatre or faulty anaesthesiologic procedures [2]. It wasn’t until 1960 before certain pharmacological substances were traced to be essential in the development of foudroyant and even lethal hyperthermic crisis; hence, Malignant Hyperthermia was unveiled to be a disease in its own right [3]. Therefore, we would like to give an overview on the cognition of Malignant Hyperthermia to be a disease of its own and the advances in diagnosing and treating this malady. Moreover, we would like to recall some of the early papers on this topic, which were published in the German-speaking area.
2. Perioperatively elevated body temperature—early references in the literature Reports on hyperthermia during anaesthesia can first be found around the turn of the century. At a meeting of surgeons of the New York Academy of Medicine in November 1900, a discussion on a phenomenon that sometimes occurred unexpectedly was kindled: *
Corresponding author. Tel.: +49-40-428032450; fax: +49-40-42803-4571. E-mail address: [email protected] (M. Goerig).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 0 7 - 6
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M. Goerig, F. Wappler / International Congress Series 1242 (2002) 577–585
heatstroke as a post-operative complication [4]. The participants even reported lethal cases for the very first time. They suspected oppressive heat inside the operation theater to be the main cause; hence, as a matter of prophylaxis, such cases emphasized the necessity and importance of good air circulation in hot weather and electric fans were found to be a valuable auxiliary. The patients experienced states of restlessness and delirium, high body temperatures and a rapid pulse. As there had been a suppression of urine production, the supposition had been that death in some of these cases might have been the result of nephritis. An association to those patients who indulged freely in alcoholic drinks could not be excluded. General recommendations, i.e. not covering the patient completely, were the only result of this dialogue—next to active cooling in cases of elevated body temperature. Due to curiosity, post-mortem examinations were performed—unfortunately, no specific striking pathological findings could be observed: hyperemia of the meninges and a marked rigidity of all cerebral vessels like that in cases of a heat stroke were the only result. In any case, the possibility of septicemia or underlying kidney diseases could not be ruled out completely. In 1916, A.V. Moschcowitz [5], a surgeon of German descent from New York, published a summary comprising 12 cases of ‘‘perioperative heatstroke or sunstroke.’’ Like his colleagues, he did not have any explanation for this incident; hence, he insisted on further research in his re´sume´. The French surgeon L. Ombre´danne and his co-worker J. Armingeat [6] made a similar statement in 1929, referring to ‘‘Syndrome Paˆleur et Hyperthermie.’’ Ombre´danne described anaesthesia and pallor in children with significant mortality (Ombre´danne’s syndrome) but did not detect familial relationship [7]. The event of perioperatively occurring hyperpyrexia was first mentioned in a journal for anaesthesiology in 1940 by G.E. Burford [8]. In an article, that he wrote for ‘‘Anaesthesiology,’’ he pointed to the specific trias of this disease: hyperthermia, tachycardia and tachypnea. He suspected the long duration of an ether narcosis to have provoked this syndrome, even though he did not dismiss the idea of the sympathoadrenergic system being involved. This prompted him to suggest that the body temperature in every anaesthetized patient should be monitored thoroughly. An article published in 1960 by the Australian anaesthesiologists Michael Denborough (Fig. 1) and R.R.H. Lovell can be regarded as the beginning of the research in the field of Malignant Hyperthermia [3]. They reported on a case of a 21-year-old patient presenting with a family history of unexplained deaths during anaesthesia in
Fig. 1. Michael Denborough.
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more than 10 family members. This young man was run over by a car on April 14, 1960 and sustained compound fractures on his right leg. He was more anxious about anaesthesia than about surgery because of the anaesthesia-related deaths in his family. After a close survey, it became clear that all of them had obtained ether; thus, it was decided to proceed cautiously with halothane, a relatively new volatile anaesthetic. Even then, it took only 10 min for the patient to experience a severe drop of blood pressure and an increase in heart rate, he became cyanosed and his body temperature rose. On top of that, the soda –lime canister became hot, too; hence, it was changed. To conquer the symptoms that hinted towards a syndrome that today would be summarized as Malignant Hyperthermia, the anaesthetic was stopped and the patient was rubbed down with ice-cold packs. Fortunately, the patient survived this state and recovered completely. This strange incident prompted the physicians to perform further clinical and laboratory tests—all of which did not reveal any abnormality. It was only for the family history that the deaths indicated a previously undescribed inborn error of metabolism inherited as a dominant trait. It took only one year until the same patient required another anaesthesia for a stone impacted in his left ureter. With the patient’s history in mind, he was connected to every possible monitor and given a spinal anaesthesia which he tolerated uneventfully. This case naturally caused uproar amongst anaesthesiologists; thus, reports were published resulting in loads of other articles being published on similar events that were released during the following years pointing towards this syndrome and its familial predisposition. After a 2.5-year-old child tragically died from Malignant Hyperthermia while subjected to general anaesthesia for a conservative dentistry of a minor nature in 1987, another stirring historical fact on this disease came to light. After a muscle biopsy had been tested, the child and some of his relatives were found to be Malignant Hyperthermia-susceptible (MHS) in the in vitro contracture test. A pedigree had been put up and showed circumstantial evidence of MHS trait in four generations [9]. Upon thorough examination, letters could be detected that draw attention to a case of Dr. G.A. Jones from Buckinghamshire who did observe and record an example of a familial fatal idiosyncrasy to chloroform anaesthesia 40 years prior to Denborough’s and Lovell’s pace-setting discovery. Unfortunately, he never published his observations. H. Isaacs and M.B. Barlow from Johannesburg, South Africa, observed that some relatives of Malignant Hyperthermia patients presented with high creatine-phosphokinase values [9], a fact that had also been realized independently by physicians at the Royal Melbourne Hospital, Australia, in November 1969 from the findings of Isaacs and Barlow. In Melbourne, a 51-year-old patient was to undergo anaesthesia for a fracture of the right leg. He presented no family history of anaesthetic problems and had received general anaesthesia 30 years before for an appendectomy. Three hours after succinylcholine and halothane had been administered, his arm became rigid and he died 24 h after anaesthesia had been induced. Led by muscular rigidity, CK activity was measured and values were found to reach 20,500 IU/l just before he died. Hence, it was concluded that severe rhabdomylolysis had been induced and that muscular diseases might trigger the evolution of Malignant Hyperthermia. CK values were established in close relatives showing abnormal rates in a paternal aunt and the father who had clear evidence of a clinical myopathy [10].
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3. Early publications on the event of Malignant Hyperthermia in German-speaking countries Karl-Heinrich Braeutigam, an anaesthesiologist from Stuttgart, was probably the first person in the German-speaking area to publish an article on Malignant Hyperthermia in a medical journal in 1969 [11]—many more were to follow in the subsequent years spreading the news of this rare disease all over the country. The editors of the journal ‘‘Der Anaesthesist’’ invited the Canadian anaesthesiologist B.A. Britt to write a review article on the clinical and therapeutic aspects in Malignant Hyperthermia that was released by 1972 [12]. Therefore, physicians who had stuck to Britt’s recommendations published loads of literature over the next years on successfully treated cases of Malignant Hyperthermia. Keeping all this uproar in mind, it does not seem to be too surprising that it took only until 1980 for a German journal to publish an article on forensic and medico-legal aspects in the treatment of Malignant Hyperthermia [13].
4. Initial clues on perioperative elevated body temperature in textbooks of anaesthesiology It seems that Arthur Guedel was the first person to mention the problem of hyperthermia related to anaesthesia in a textbook of anaesthesia [14]. In his classic little monograph ‘‘Inhalation Anesthesia’’ published in 1937, the problem was outlined in just over a page. Today, reviews on the history of Malignant Hyperthermia repeatedly cite these quotations by Guedel, which might as well describe cases of this malady. On the other hand, doubts arise from the fact that he claims to have experienced six cases of Malignant Hyperthermia and to have gathered information from colleagues as well. Even then, it is very likely that he might well have faced Malignant Hyperthermia. Stewart C. Cullen again mentioned the syndrome of Malignant Hyperthermia in a monograph in 1951 [15]. The disease involving perioperative hyperthermia was not mentioned until 1959 when the fourth edition of A textbook that was very popular in Europe by J.A. Lee [16] was available. The syndrome first appeared in German textbooks in 1976 in a booklet titled ‘‘Narkose’’ (i.e., narcosis) by Ludwig Stoecker [17]; though, detailed information could be obtained in a monograph by Benzer-Frey-Huegin and Mayrhofer published in 1977 [18]. The author—Alfred Doenicke from Munich—had written an article on the international conference on Malignant Hyperthermia in Toronto and had published it in 1971 in the journal ‘‘Der Anaesthesist,’’ a few years prior to his chapter in the above-mentioned textbook [19]. The symptoms had also been extensively described in a monograph by the Swiss anaesthesiologist Bruno Tschirren titled ‘‘Der Narkosezwischenfall’’ (i.e., adverse events during anaesthesia) that had been published in 1976 and was considered to be the ‘‘gold-standard’’ in anaesthesiology [20]. After these early references in textbooks of anaesthesiology, more detailed information on this subject became available in recent publications that were inevitably to follow.
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5. Establishing the diagnosis of Malignant Hyperthermia In the mid-1960s, L.W. Hall and his colleagues [21] observed that British landrace pigs died after the administration of suxamethonium chloride, presenting signs of Malignant Hyperthermia if no therapeutic measures were taken. This finding could also be validated over the following years for cases of pigs that had been exposed to halothane [22]. Hence, animal models that have become essential to research on Malignant Hyperthermia entered scientific investigation [7]. Resting on this major advance, pace-setting discoveries on the pathogenesis of Malignant Hyperthermia could be revealed [2]. W. Kalow and B.A. Britt pursued a different line measuring the behavior of isolated muscle specimen in vitro. This test is based on the observation that dog muscle contracts on exposure to chloroform; thus, Kalow and Britt studied the caffeine-induced contraction in human muscle and found that caffeine-contracture was augmented in Malignant Hyperthermia-susceptible patients (MHS) as opposed to Malignant Hyperthermia-normal patients (MHN) [23]. F.R. Ellis and colleagues [24] managed to prove that this applied to halothane, too. In vitro contracture tests (IVCT) with both halothane and caffeine have become daily routine in establishing the diagnosis of Malignant Hyperthermia [10]. A recent development in diagnosing MHS is the inauguration of contracture tests using the more specific activators of the ryanodine receptor: ryanodine and 4-chloro-m-cresol. The primary approach was to employ ryanodine, a plant alkaloid with a specific binding site at the calcium-release channel for the IVCT. This test was developed in the early 1990s under the professional guidance of P.H. Hopkins from Leeds, E. Hartung from Wuerzburg and F. Wappler from Hamburg and has been introduced into the European test protocol in 1997 [25]. Upon detecting that 4-chloro-m-cresol produced sound contractions in MHS muscles as compared to MHN muscles, another IVCT was developed applying this agent, which has entered the European Malignant Hyperthermia test-protocol as well [26].
6. Therapeutic regimen in Malignant Hyperthermia For a long time, the only option to treat Malignant Hyperthermia was to fight the symptoms of this state, like cooling the patient, changing the respirator, mechanical ventilation in case the patient was not intubated yet, hyperventilation with pure oxygen, heparinization, conquering acidosis, etc. In the German-speaking area, the therapeutic proposals according to B.A. Britt [12], which had been published by 1972, were followed. They included the immediate application of procaine (Novocain) and calcium-antagonists like verapamil. In 1971, J. Beldavs, a co-worker of B.A. Britt, reported on the application of procaine in a patient suffering from Malignant Hyperthermia for the very fist time. Fortunately, this patient survived. The drug had been administered because it was known to delay the release of calcium out of the sarcoplasmic reticulum and to have a positive impact on arrhythmias that could not be handled otherwise. Adverse effects of high doses of procaine restricted its application in the treatment of Malignant Hyperthermia though [7]. The final breakthrough
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in the successful treatment of this state could only be achieved a few years later with the introduction of Dantrolene [2].
7. Dantrolene—a specific antidote in Malignant Hyperthermia The pace-setting innovation in the treatment of Malignant Hyperthermia was made by G.G. Harrison in 1975 who successfully terminated this state in pigs with the aid of Dantrolene [27]. Initially, it had been applied to patients with spastic diseases, but finally was recommended for the treatment and prophylaxis of Malignant Hyperthermia in 1974. By 1975, G.A. Gronert and his group employed this drug orally to prevent Malignant Hyperthermia [28]. Unfortunately, the prophylactic oral administration did not seem to offer significant advantages and cases of Malignant Hyperthermia still occurred; thus, efforts were made to manufacture this remedy in an intravenously applicable mode. After succeeding to do so by 1979, M. Kolb and her co-workers from Toronto proved the efficacy of this medication in states of Malignant Hyperthermia; hence it has been administered ever since all over the world [29]. In the same year, Hans-Joachim Eberlein, an anaesthesiologist from Berlin, published a short note in a German journal on the availability of Dantrolene for intravenous application, which enabled him to save a patient’s life only a short time after his memorandum had been printed [30]. Nevertheless, Eberlein’s colleagues Uwe Schulte-Sasse and Jo¨rg Tarnow did not publish this case report until 1982. They also mentioned that the same patient underwent another anaesthesia after oral prophylaxis with Dantrolene without any troubles [31]. Today, this procedure is regarded to be obsolete, since cases of Malignant Hyperthermia have been described despite prophylaxis. The group from Berlin has repeatedly released updates on regimen on the treatment of Malignant Hyperthermia that are available without any charge with the aid of the pharmaceutical industry.
8. Establishing Malignant Hyperthermia laboratories in the German-speaking area More and more institutions in Germany decided to follow the example after the very first laboratory for Malignant Hyperthermia had been established at the pediatric department in Wuppertal, which by the way has now been moved to Bochum. Just to mention a few: specialized institutes were opened in Ulm, Bonn, Hanover, Leipzig, Mainz and Wuerzburg. J. Schulte am Esch, who became chairman of the Department of Anaesthesiology at the University-Hospital Eppendorf in 1982 initiated the foundation of a group for advising and counseling Malignant Hyperthermia susceptible patients only a year after his arrival. Along with his colleagues Norbert Roewer, who was a pupil of the physiologist Albrecht Fleckenstein from Freiburg, and Eberhard Kochs they primarily focused on the pathophysiologic effects of Malignant Hyperthermia on the heart muscle and the central nervous system. In 1991 they additionally established the laboratory in order to be able to carry out basic research on this disease where all the assessments according to the protocol of the European Malignant Hyperpyrexia Group could be performed. Since this institution
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has been set up more than 600 patients have been examined and approximately 100 muscle biopsies from control persons have been taken and investigated [32]. Meanwhile, centers in the German-speaking area have decided to no longer store their data in their own individual cache. They intend to unite as the ‘‘Arbeitsgemeinschaft Maligne Hyperthermie e.V.’’ The data is to be pooled and assembled at the University hospital in Leipzig. Thus, plenty of information can be gathered at any time via telephone or Internet [32].
9. Symposia on Malignant Hyperthermia The Canadian anaesthesiologist R. A. Gordon initiated the first symposium on Malignant Hyperthermia in 1964 in Toronto with the results being published in the Journal of the Canadian Anaesthetists Society [33]. The very first international symposium on Malignant Hyperthermia drew researchers from all over the world to Toronto again in 1971—and again it was R.A. Gordon and co-worker B.A. Britt who organized this meeting. It took two years until the proceedings band was released comprising all the lectures and panels [34]. Similar international conferences were to follow, just to mention a few of them: 1977—Denver, CO, USA; 1994—Hiroshima, Japan; and 1999—Copenhagen, Denmark [32].
10. Linz, 1973—the first meeting of Malignant Hyperthermia in German-speaking countries The first international conference on Malignant Hyperthermia in the German-speaking area was to be held in Linz, Austria. Major discussions on the disease itself and on its treatment were set ablaze. This meeting had been organized by the German, Swiss and Austrian Societies for Anaesthesiology and Resuscitation and gave birth to another congress band in 1975 [35]. Other comparable international summits in the Germanspeaking area were held in Mainz in 1986 and in Wuerzburg in 1994 [7,32]. This topic also managed to obtain a place in annual anaesthesiologic assemblies; hence, the knowledge about the syndrome of Malignant Hyperthermia and the therapeutic measures that had to be taken were spread all over the country.
11. Summary Authors repeatedly characterized Malignant Hyperthermia to be the most dangerous complication of general anaesthesia. A tremendous amount has been learned about Malignant Hyperthermia since its existence was first clearly demonstrated by M.A. Denborough in 1962, though initial clues might be traced down to about 40 years prior to this event in an unpublished case report by G.A. Jones. Measures have been taken to reduce the incidence of this clinical pharmacogenetic entity, like total intravenous anaesthesia, genetic testing and muscle biopsies that are being subjected to specific
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contracture tests since 1970. Crucial improvement has been achieved over the past decades turning this impending fatal state into a potentially manageable adverse event during general anaesthesia. The mortality rate has been reduced from more than 80% in the first half of this century to near vanishing point today. Regardless of the pace-setting invention of Dantrolene in 1975 as a specific antidote capable of life-saving interference, a lot of questions remain unanswered; hence, further research is required in order to better define the ryanodine receptor defect, to develop a non-invasive test and to better educate patients, medical personnel and the public about this inborn disease. References [1] G.B. Rushman, A Short History of Anaesthesia—The First 150 Years, Butterworth Heinemann, Oxford, Boston, Johannesburg, Melbourne, New Delhi, Singapore, 1998. [2] B. Helpap, F. Gullotta, J. Schulte am Esch, Maligne Hyperthermie. INA, Georg Thieme Verlag, Stuttgart, 1983. [3] M.A. Denborough, R.R.H. Lovell, Anaesthetic deaths in a family, Lancet ii (1960) 45. [4] C. Gibson, et al., Meeting of the surgical section of the New York Academy of Medicine, JAMA J. Am. Med. Assoc. 35 (1900) 1685. [5] A.V. Moschcowitz, Postoperative heat stroke, Surg. Gynecol. Obstet. 3 (1916) 443 – 451. [6] L. Ombre´danne, J. Armingeat, Le syndrome paˆleur et hyperthermie chez nourissons ope´re´s, Presse Med. 37 (1929) 1435. [7] J.P.A.H. Jantzen, S. Gottmann, Maligne Hyperthermie. Rueckblick, derzeitiger Stand, Entwicklungen. Symposium 25 Jahre Maligne Hyperthermie. Mainz, Georg Thieme Verlag, Stuttgart, 1986. [8] G.E. Burford, Hyperpyrexia following anesthesia. A consideration of control of body temperature during anesthesia, Anesthesiology 1 (1940) 208 – 215. [9] H. Isaacs, M.B. Barlow, The genetic background to malignant hyperpyrexia revealed by serum creatine phosphokinase estimations in asymptomatic relatives, Br. J. Anaesth. 41 (1970) 1077 – 1084. [10] B.A. Britt, History of Malignant Hyperthermia, in: M. Morio, H. Kikuchi, O. Yuge (Eds.), Malignant Hyperthermia—Proceedings of the 3rd International Symposium on Malignant Hyperthermia, Springer, Berlin, 1994. [11] K.H. Braeutigam, R. Seybold, Hyperthermie durch Allgemeinanaesthesie, Anaesthesist 18 (1969) 337 – 340. [12] B.A. Britt, Zur Behandlung der malignen Hyperthermie, Anaesthesist 5 (1972) 201 – 205. [13] K. Pueschel, W. Brinkmann, Zum derzeitigen Stand der Bewertung des Narkosezwischenfalls. Maligne Hyperthermie aus forensisch – medizinischer Sicht, Anaesthesist 29 (1980) 99 – 102. [14] A. Guedel, Postoperative hyperthermia, Inhalation Anesthesia. A Fundamental Guide, Macmillan, New York, 1937, p. 133. [15] S.C. Cullen, Anesthesia in General Practice, 3rd edn., Yearbook, Medical Publishers, Chicago, 1951, p. 88. [16] J.A. Lee, A Synopsis of Anaesthesia, 4th edn., Wright, Bristol, 1959. [17] L. Stoecker, Narkose, Thieme, Stuttgart, 1976. [18] A. Doenicke, B. Grote, Maligne Hyperthermie, in: H. Benzer, R. Frey, W. Huegin, O. Mayrhofer (Eds.), Lehrbuch der Anaesthesiologie, Reanimation und Intensivtherapie, Springer Verlag, Berlin, 1977, pp. 234 – 237. [19] A. Doenicke, Bericht ueber das erste internationale Symposium ‘‘Maligne Hyperthermie’’ in Toronto am 14. und 15. Mai 1971, Anaesthesist 8 (1971) 322 – 327. [20] B. Tschirren, Der Narkosezwischenfall, Huber, Bern, 1976. [21] L.W. Hall, N. Wolf, J.W.P. Bradley, D.W. Jolly, Unusual reaction to suxamethonium chloride, Br. Med. J. ii (1955) 1305. [22] M.C. Berman, G.G. Harrison, P. Dutoit, J.E. Bull, J.E. Keuch, Halothane induced hyperpyrexia in landrace pigs, S. Afr. Med. J. 43 (1969) 545 – 546. [23] W. Kalow, B.A. Britt, M.E. Terraeu, C. Haist, Metabolic error of muscle metabolism after recovery from malignant hyperthermia, Lancet ii (1970) 895 – 898.
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[24] F.R. Ellis, D.G.F. Harriman, N.P. Keaney, K. Kyei-Mensah, J.H. Tyrell, Halothane induced muscle contracture as a cause of hyperpyrexia, Br. J. Anaesth. 43 (1971) 721 – 722. [25] P.M. Hopkins, E. Hartung, F. Wappler, the European Malignant Hyperthermia Group, Multicenter Evaluation of Ryanodine contracture testing in Malignant Hyperthermia, Br. J. Anaesth. 10 (1998) 389 – 394. [26] F. Wappler, Malignant Hyperthermia, Eur. J. Anaesthesiol. 18 (2001) 632 – 652. [27] G.G. Harrison, H. Isaacs, Malignant Hyperthermia. An historical vignette, Anaesthesia 47 (1992) 54 – 56. [28] G.A. Gronert, R.L. Thompson, B.M. Onofrio, Human malignant hyperthermia: awake episodes and correction by dantrolene, Anesth. Analg. 59 (1980) 377 – 378. [29] M.A. Kolb, M.L. Horn, R. Martz, Dantrolene in human malignant hyperthermia: a multicenter study, Anesthesiology 6 (1986) 254 – 262. [30] H.J. Eberlein, Therapie der Malignen Hyperthermie, Anaesthesist 28 (1979) 247 – 248. [31] U. Schulte-Sasse, J. Tarnow, H.J. Eberlein, Bericht ueber die erfolgreiche Behandlung einer malignen Hyperthermie mit Dantrolen und komplikationsloser Zweitnarkose nach oraler Dantrolen-Prophylaxe, Anaesthesist 31 (1982) 241 – 244. [32] F. Wappler, Department of Anaesthesiology, University Hospital Hamburg, Germany, personal communication. [33] R.A. Gordon, B.A. Britt, W. Kalow, International Symposium on Malignant Hyperthermia, Charles C. Thomas, Springfield, IL, 1973. [34] R.A. Gordon, Malignant Hyperthermia during general anaesthesia, Can. Anaesth. Soc. J. 13 (1966) 415 – 446. [35] H. Bergmann, B. Blauhut, Maligne Hyperthermie, Akupunktur, Biomedizinische Technik, Abdominelle Intensivmedizin, Anaesthesiology and Resuscitation, vol. 91, Springer Verlag, Berlin, 1975.
Malignant Hyperthermia research in Germany: from past to recent advances M. Goerig*, F. Wappler Department of Anaesthesiology, University-Hospital Eppendorf, Hamburg, Martinstrasse 52, 20240 Hamburg, Germany
Keywords: Heat stress; Malignant Hyperthermia; Anesthesia; Germany
1. Introduction Adverse events like hyperthermia during anaesthesia have been known ever since anaesthesiologic techniques were invented. Already, John Snow reported on sudden unexpected elevation of body temperature during anaesthesia [1]. There has been a wave of cases with similar symptoms under the same circumstances. The involved physicians suspected allergic reactions, hormonal imbalances like hyperthyroidism, status lymphaticus or status menstruationis to have been the cause, just like elevated temperature in the operation theatre or faulty anaesthesiologic procedures [2]. It wasn’t until 1960 before certain pharmacological substances were traced to be essential in the development of foudroyant and even lethal hyperthermic crisis; hence, Malignant Hyperthermia was unveiled to be a disease in its own right [3]. Therefore, we would like to give an overview on the cognition of Malignant Hyperthermia to be a disease of its own and the advances in diagnosing and treating this malady. Moreover, we would like to recall some of the early papers on this topic, which were published in the German-speaking area.
2. Perioperatively elevated body temperature—early references in the literature Reports on hyperthermia during anaesthesia can first be found around the turn of the century. At a meeting of surgeons of the New York Academy of Medicine in November 1900, a discussion on a phenomenon that sometimes occurred unexpectedly was kindled: *
Corresponding author. Tel.: +49-40-428032450; fax: +49-40-42803-4571. E-mail address: [email protected] (M. Goerig).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 0 7 - 6
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heatstroke as a post-operative complication [4]. The participants even reported lethal cases for the very first time. They suspected oppressive heat inside the operation theater to be the main cause; hence, as a matter of prophylaxis, such cases emphasized the necessity and importance of good air circulation in hot weather and electric fans were found to be a valuable auxiliary. The patients experienced states of restlessness and delirium, high body temperatures and a rapid pulse. As there had been a suppression of urine production, the supposition had been that death in some of these cases might have been the result of nephritis. An association to those patients who indulged freely in alcoholic drinks could not be excluded. General recommendations, i.e. not covering the patient completely, were the only result of this dialogue—next to active cooling in cases of elevated body temperature. Due to curiosity, post-mortem examinations were performed—unfortunately, no specific striking pathological findings could be observed: hyperemia of the meninges and a marked rigidity of all cerebral vessels like that in cases of a heat stroke were the only result. In any case, the possibility of septicemia or underlying kidney diseases could not be ruled out completely. In 1916, A.V. Moschcowitz [5], a surgeon of German descent from New York, published a summary comprising 12 cases of ‘‘perioperative heatstroke or sunstroke.’’ Like his colleagues, he did not have any explanation for this incident; hence, he insisted on further research in his re´sume´. The French surgeon L. Ombre´danne and his co-worker J. Armingeat [6] made a similar statement in 1929, referring to ‘‘Syndrome Paˆleur et Hyperthermie.’’ Ombre´danne described anaesthesia and pallor in children with significant mortality (Ombre´danne’s syndrome) but did not detect familial relationship [7]. The event of perioperatively occurring hyperpyrexia was first mentioned in a journal for anaesthesiology in 1940 by G.E. Burford [8]. In an article, that he wrote for ‘‘Anaesthesiology,’’ he pointed to the specific trias of this disease: hyperthermia, tachycardia and tachypnea. He suspected the long duration of an ether narcosis to have provoked this syndrome, even though he did not dismiss the idea of the sympathoadrenergic system being involved. This prompted him to suggest that the body temperature in every anaesthetized patient should be monitored thoroughly. An article published in 1960 by the Australian anaesthesiologists Michael Denborough (Fig. 1) and R.R.H. Lovell can be regarded as the beginning of the research in the field of Malignant Hyperthermia [3]. They reported on a case of a 21-year-old patient presenting with a family history of unexplained deaths during anaesthesia in
Fig. 1. Michael Denborough.
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more than 10 family members. This young man was run over by a car on April 14, 1960 and sustained compound fractures on his right leg. He was more anxious about anaesthesia than about surgery because of the anaesthesia-related deaths in his family. After a close survey, it became clear that all of them had obtained ether; thus, it was decided to proceed cautiously with halothane, a relatively new volatile anaesthetic. Even then, it took only 10 min for the patient to experience a severe drop of blood pressure and an increase in heart rate, he became cyanosed and his body temperature rose. On top of that, the soda –lime canister became hot, too; hence, it was changed. To conquer the symptoms that hinted towards a syndrome that today would be summarized as Malignant Hyperthermia, the anaesthetic was stopped and the patient was rubbed down with ice-cold packs. Fortunately, the patient survived this state and recovered completely. This strange incident prompted the physicians to perform further clinical and laboratory tests—all of which did not reveal any abnormality. It was only for the family history that the deaths indicated a previously undescribed inborn error of metabolism inherited as a dominant trait. It took only one year until the same patient required another anaesthesia for a stone impacted in his left ureter. With the patient’s history in mind, he was connected to every possible monitor and given a spinal anaesthesia which he tolerated uneventfully. This case naturally caused uproar amongst anaesthesiologists; thus, reports were published resulting in loads of other articles being published on similar events that were released during the following years pointing towards this syndrome and its familial predisposition. After a 2.5-year-old child tragically died from Malignant Hyperthermia while subjected to general anaesthesia for a conservative dentistry of a minor nature in 1987, another stirring historical fact on this disease came to light. After a muscle biopsy had been tested, the child and some of his relatives were found to be Malignant Hyperthermia-susceptible (MHS) in the in vitro contracture test. A pedigree had been put up and showed circumstantial evidence of MHS trait in four generations [9]. Upon thorough examination, letters could be detected that draw attention to a case of Dr. G.A. Jones from Buckinghamshire who did observe and record an example of a familial fatal idiosyncrasy to chloroform anaesthesia 40 years prior to Denborough’s and Lovell’s pace-setting discovery. Unfortunately, he never published his observations. H. Isaacs and M.B. Barlow from Johannesburg, South Africa, observed that some relatives of Malignant Hyperthermia patients presented with high creatine-phosphokinase values [9], a fact that had also been realized independently by physicians at the Royal Melbourne Hospital, Australia, in November 1969 from the findings of Isaacs and Barlow. In Melbourne, a 51-year-old patient was to undergo anaesthesia for a fracture of the right leg. He presented no family history of anaesthetic problems and had received general anaesthesia 30 years before for an appendectomy. Three hours after succinylcholine and halothane had been administered, his arm became rigid and he died 24 h after anaesthesia had been induced. Led by muscular rigidity, CK activity was measured and values were found to reach 20,500 IU/l just before he died. Hence, it was concluded that severe rhabdomylolysis had been induced and that muscular diseases might trigger the evolution of Malignant Hyperthermia. CK values were established in close relatives showing abnormal rates in a paternal aunt and the father who had clear evidence of a clinical myopathy [10].
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3. Early publications on the event of Malignant Hyperthermia in German-speaking countries Karl-Heinrich Braeutigam, an anaesthesiologist from Stuttgart, was probably the first person in the German-speaking area to publish an article on Malignant Hyperthermia in a medical journal in 1969 [11]—many more were to follow in the subsequent years spreading the news of this rare disease all over the country. The editors of the journal ‘‘Der Anaesthesist’’ invited the Canadian anaesthesiologist B.A. Britt to write a review article on the clinical and therapeutic aspects in Malignant Hyperthermia that was released by 1972 [12]. Therefore, physicians who had stuck to Britt’s recommendations published loads of literature over the next years on successfully treated cases of Malignant Hyperthermia. Keeping all this uproar in mind, it does not seem to be too surprising that it took only until 1980 for a German journal to publish an article on forensic and medico-legal aspects in the treatment of Malignant Hyperthermia [13].
4. Initial clues on perioperative elevated body temperature in textbooks of anaesthesiology It seems that Arthur Guedel was the first person to mention the problem of hyperthermia related to anaesthesia in a textbook of anaesthesia [14]. In his classic little monograph ‘‘Inhalation Anesthesia’’ published in 1937, the problem was outlined in just over a page. Today, reviews on the history of Malignant Hyperthermia repeatedly cite these quotations by Guedel, which might as well describe cases of this malady. On the other hand, doubts arise from the fact that he claims to have experienced six cases of Malignant Hyperthermia and to have gathered information from colleagues as well. Even then, it is very likely that he might well have faced Malignant Hyperthermia. Stewart C. Cullen again mentioned the syndrome of Malignant Hyperthermia in a monograph in 1951 [15]. The disease involving perioperative hyperthermia was not mentioned until 1959 when the fourth edition of A textbook that was very popular in Europe by J.A. Lee [16] was available. The syndrome first appeared in German textbooks in 1976 in a booklet titled ‘‘Narkose’’ (i.e., narcosis) by Ludwig Stoecker [17]; though, detailed information could be obtained in a monograph by Benzer-Frey-Huegin and Mayrhofer published in 1977 [18]. The author—Alfred Doenicke from Munich—had written an article on the international conference on Malignant Hyperthermia in Toronto and had published it in 1971 in the journal ‘‘Der Anaesthesist,’’ a few years prior to his chapter in the above-mentioned textbook [19]. The symptoms had also been extensively described in a monograph by the Swiss anaesthesiologist Bruno Tschirren titled ‘‘Der Narkosezwischenfall’’ (i.e., adverse events during anaesthesia) that had been published in 1976 and was considered to be the ‘‘gold-standard’’ in anaesthesiology [20]. After these early references in textbooks of anaesthesiology, more detailed information on this subject became available in recent publications that were inevitably to follow.
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5. Establishing the diagnosis of Malignant Hyperthermia In the mid-1960s, L.W. Hall and his colleagues [21] observed that British landrace pigs died after the administration of suxamethonium chloride, presenting signs of Malignant Hyperthermia if no therapeutic measures were taken. This finding could also be validated over the following years for cases of pigs that had been exposed to halothane [22]. Hence, animal models that have become essential to research on Malignant Hyperthermia entered scientific investigation [7]. Resting on this major advance, pace-setting discoveries on the pathogenesis of Malignant Hyperthermia could be revealed [2]. W. Kalow and B.A. Britt pursued a different line measuring the behavior of isolated muscle specimen in vitro. This test is based on the observation that dog muscle contracts on exposure to chloroform; thus, Kalow and Britt studied the caffeine-induced contraction in human muscle and found that caffeine-contracture was augmented in Malignant Hyperthermia-susceptible patients (MHS) as opposed to Malignant Hyperthermia-normal patients (MHN) [23]. F.R. Ellis and colleagues [24] managed to prove that this applied to halothane, too. In vitro contracture tests (IVCT) with both halothane and caffeine have become daily routine in establishing the diagnosis of Malignant Hyperthermia [10]. A recent development in diagnosing MHS is the inauguration of contracture tests using the more specific activators of the ryanodine receptor: ryanodine and 4-chloro-m-cresol. The primary approach was to employ ryanodine, a plant alkaloid with a specific binding site at the calcium-release channel for the IVCT. This test was developed in the early 1990s under the professional guidance of P.H. Hopkins from Leeds, E. Hartung from Wuerzburg and F. Wappler from Hamburg and has been introduced into the European test protocol in 1997 [25]. Upon detecting that 4-chloro-m-cresol produced sound contractions in MHS muscles as compared to MHN muscles, another IVCT was developed applying this agent, which has entered the European Malignant Hyperthermia test-protocol as well [26].
6. Therapeutic regimen in Malignant Hyperthermia For a long time, the only option to treat Malignant Hyperthermia was to fight the symptoms of this state, like cooling the patient, changing the respirator, mechanical ventilation in case the patient was not intubated yet, hyperventilation with pure oxygen, heparinization, conquering acidosis, etc. In the German-speaking area, the therapeutic proposals according to B.A. Britt [12], which had been published by 1972, were followed. They included the immediate application of procaine (Novocain) and calcium-antagonists like verapamil. In 1971, J. Beldavs, a co-worker of B.A. Britt, reported on the application of procaine in a patient suffering from Malignant Hyperthermia for the very fist time. Fortunately, this patient survived. The drug had been administered because it was known to delay the release of calcium out of the sarcoplasmic reticulum and to have a positive impact on arrhythmias that could not be handled otherwise. Adverse effects of high doses of procaine restricted its application in the treatment of Malignant Hyperthermia though [7]. The final breakthrough
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in the successful treatment of this state could only be achieved a few years later with the introduction of Dantrolene [2].
7. Dantrolene—a specific antidote in Malignant Hyperthermia The pace-setting innovation in the treatment of Malignant Hyperthermia was made by G.G. Harrison in 1975 who successfully terminated this state in pigs with the aid of Dantrolene [27]. Initially, it had been applied to patients with spastic diseases, but finally was recommended for the treatment and prophylaxis of Malignant Hyperthermia in 1974. By 1975, G.A. Gronert and his group employed this drug orally to prevent Malignant Hyperthermia [28]. Unfortunately, the prophylactic oral administration did not seem to offer significant advantages and cases of Malignant Hyperthermia still occurred; thus, efforts were made to manufacture this remedy in an intravenously applicable mode. After succeeding to do so by 1979, M. Kolb and her co-workers from Toronto proved the efficacy of this medication in states of Malignant Hyperthermia; hence it has been administered ever since all over the world [29]. In the same year, Hans-Joachim Eberlein, an anaesthesiologist from Berlin, published a short note in a German journal on the availability of Dantrolene for intravenous application, which enabled him to save a patient’s life only a short time after his memorandum had been printed [30]. Nevertheless, Eberlein’s colleagues Uwe Schulte-Sasse and Jo¨rg Tarnow did not publish this case report until 1982. They also mentioned that the same patient underwent another anaesthesia after oral prophylaxis with Dantrolene without any troubles [31]. Today, this procedure is regarded to be obsolete, since cases of Malignant Hyperthermia have been described despite prophylaxis. The group from Berlin has repeatedly released updates on regimen on the treatment of Malignant Hyperthermia that are available without any charge with the aid of the pharmaceutical industry.
8. Establishing Malignant Hyperthermia laboratories in the German-speaking area More and more institutions in Germany decided to follow the example after the very first laboratory for Malignant Hyperthermia had been established at the pediatric department in Wuppertal, which by the way has now been moved to Bochum. Just to mention a few: specialized institutes were opened in Ulm, Bonn, Hanover, Leipzig, Mainz and Wuerzburg. J. Schulte am Esch, who became chairman of the Department of Anaesthesiology at the University-Hospital Eppendorf in 1982 initiated the foundation of a group for advising and counseling Malignant Hyperthermia susceptible patients only a year after his arrival. Along with his colleagues Norbert Roewer, who was a pupil of the physiologist Albrecht Fleckenstein from Freiburg, and Eberhard Kochs they primarily focused on the pathophysiologic effects of Malignant Hyperthermia on the heart muscle and the central nervous system. In 1991 they additionally established the laboratory in order to be able to carry out basic research on this disease where all the assessments according to the protocol of the European Malignant Hyperpyrexia Group could be performed. Since this institution
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has been set up more than 600 patients have been examined and approximately 100 muscle biopsies from control persons have been taken and investigated [32]. Meanwhile, centers in the German-speaking area have decided to no longer store their data in their own individual cache. They intend to unite as the ‘‘Arbeitsgemeinschaft Maligne Hyperthermie e.V.’’ The data is to be pooled and assembled at the University hospital in Leipzig. Thus, plenty of information can be gathered at any time via telephone or Internet [32].
9. Symposia on Malignant Hyperthermia The Canadian anaesthesiologist R. A. Gordon initiated the first symposium on Malignant Hyperthermia in 1964 in Toronto with the results being published in the Journal of the Canadian Anaesthetists Society [33]. The very first international symposium on Malignant Hyperthermia drew researchers from all over the world to Toronto again in 1971—and again it was R.A. Gordon and co-worker B.A. Britt who organized this meeting. It took two years until the proceedings band was released comprising all the lectures and panels [34]. Similar international conferences were to follow, just to mention a few of them: 1977—Denver, CO, USA; 1994—Hiroshima, Japan; and 1999—Copenhagen, Denmark [32].
10. Linz, 1973—the first meeting of Malignant Hyperthermia in German-speaking countries The first international conference on Malignant Hyperthermia in the German-speaking area was to be held in Linz, Austria. Major discussions on the disease itself and on its treatment were set ablaze. This meeting had been organized by the German, Swiss and Austrian Societies for Anaesthesiology and Resuscitation and gave birth to another congress band in 1975 [35]. Other comparable international summits in the Germanspeaking area were held in Mainz in 1986 and in Wuerzburg in 1994 [7,32]. This topic also managed to obtain a place in annual anaesthesiologic assemblies; hence, the knowledge about the syndrome of Malignant Hyperthermia and the therapeutic measures that had to be taken were spread all over the country.
11. Summary Authors repeatedly characterized Malignant Hyperthermia to be the most dangerous complication of general anaesthesia. A tremendous amount has been learned about Malignant Hyperthermia since its existence was first clearly demonstrated by M.A. Denborough in 1962, though initial clues might be traced down to about 40 years prior to this event in an unpublished case report by G.A. Jones. Measures have been taken to reduce the incidence of this clinical pharmacogenetic entity, like total intravenous anaesthesia, genetic testing and muscle biopsies that are being subjected to specific
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contracture tests since 1970. Crucial improvement has been achieved over the past decades turning this impending fatal state into a potentially manageable adverse event during general anaesthesia. The mortality rate has been reduced from more than 80% in the first half of this century to near vanishing point today. Regardless of the pace-setting invention of Dantrolene in 1975 as a specific antidote capable of life-saving interference, a lot of questions remain unanswered; hence, further research is required in order to better define the ryanodine receptor defect, to develop a non-invasive test and to better educate patients, medical personnel and the public about this inborn disease. References [1] G.B. Rushman, A Short History of Anaesthesia—The First 150 Years, Butterworth Heinemann, Oxford, Boston, Johannesburg, Melbourne, New Delhi, Singapore, 1998. [2] B. Helpap, F. Gullotta, J. Schulte am Esch, Maligne Hyperthermie. INA, Georg Thieme Verlag, Stuttgart, 1983. [3] M.A. Denborough, R.R.H. Lovell, Anaesthetic deaths in a family, Lancet ii (1960) 45. [4] C. Gibson, et al., Meeting of the surgical section of the New York Academy of Medicine, JAMA J. Am. Med. Assoc. 35 (1900) 1685. [5] A.V. Moschcowitz, Postoperative heat stroke, Surg. Gynecol. Obstet. 3 (1916) 443 – 451. [6] L. Ombre´danne, J. Armingeat, Le syndrome paˆleur et hyperthermie chez nourissons ope´re´s, Presse Med. 37 (1929) 1435. [7] J.P.A.H. Jantzen, S. Gottmann, Maligne Hyperthermie. Rueckblick, derzeitiger Stand, Entwicklungen. Symposium 25 Jahre Maligne Hyperthermie. Mainz, Georg Thieme Verlag, Stuttgart, 1986. [8] G.E. Burford, Hyperpyrexia following anesthesia. A consideration of control of body temperature during anesthesia, Anesthesiology 1 (1940) 208 – 215. [9] H. Isaacs, M.B. Barlow, The genetic background to malignant hyperpyrexia revealed by serum creatine phosphokinase estimations in asymptomatic relatives, Br. J. Anaesth. 41 (1970) 1077 – 1084. [10] B.A. Britt, History of Malignant Hyperthermia, in: M. Morio, H. Kikuchi, O. Yuge (Eds.), Malignant Hyperthermia—Proceedings of the 3rd International Symposium on Malignant Hyperthermia, Springer, Berlin, 1994. [11] K.H. Braeutigam, R. Seybold, Hyperthermie durch Allgemeinanaesthesie, Anaesthesist 18 (1969) 337 – 340. [12] B.A. Britt, Zur Behandlung der malignen Hyperthermie, Anaesthesist 5 (1972) 201 – 205. [13] K. Pueschel, W. Brinkmann, Zum derzeitigen Stand der Bewertung des Narkosezwischenfalls. Maligne Hyperthermie aus forensisch – medizinischer Sicht, Anaesthesist 29 (1980) 99 – 102. [14] A. Guedel, Postoperative hyperthermia, Inhalation Anesthesia. A Fundamental Guide, Macmillan, New York, 1937, p. 133. [15] S.C. Cullen, Anesthesia in General Practice, 3rd edn., Yearbook, Medical Publishers, Chicago, 1951, p. 88. [16] J.A. Lee, A Synopsis of Anaesthesia, 4th edn., Wright, Bristol, 1959. [17] L. Stoecker, Narkose, Thieme, Stuttgart, 1976. [18] A. Doenicke, B. Grote, Maligne Hyperthermie, in: H. Benzer, R. Frey, W. Huegin, O. Mayrhofer (Eds.), Lehrbuch der Anaesthesiologie, Reanimation und Intensivtherapie, Springer Verlag, Berlin, 1977, pp. 234 – 237. [19] A. Doenicke, Bericht ueber das erste internationale Symposium ‘‘Maligne Hyperthermie’’ in Toronto am 14. und 15. Mai 1971, Anaesthesist 8 (1971) 322 – 327. [20] B. Tschirren, Der Narkosezwischenfall, Huber, Bern, 1976. [21] L.W. Hall, N. Wolf, J.W.P. Bradley, D.W. Jolly, Unusual reaction to suxamethonium chloride, Br. Med. J. ii (1955) 1305. [22] M.C. Berman, G.G. Harrison, P. Dutoit, J.E. Bull, J.E. Keuch, Halothane induced hyperpyrexia in landrace pigs, S. Afr. Med. J. 43 (1969) 545 – 546. [23] W. Kalow, B.A. Britt, M.E. Terraeu, C. Haist, Metabolic error of muscle metabolism after recovery from malignant hyperthermia, Lancet ii (1970) 895 – 898.
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[24] F.R. Ellis, D.G.F. Harriman, N.P. Keaney, K. Kyei-Mensah, J.H. Tyrell, Halothane induced muscle contracture as a cause of hyperpyrexia, Br. J. Anaesth. 43 (1971) 721 – 722. [25] P.M. Hopkins, E. Hartung, F. Wappler, the European Malignant Hyperthermia Group, Multicenter Evaluation of Ryanodine contracture testing in Malignant Hyperthermia, Br. J. Anaesth. 10 (1998) 389 – 394. [26] F. Wappler, Malignant Hyperthermia, Eur. J. Anaesthesiol. 18 (2001) 632 – 652. [27] G.G. Harrison, H. Isaacs, Malignant Hyperthermia. An historical vignette, Anaesthesia 47 (1992) 54 – 56. [28] G.A. Gronert, R.L. Thompson, B.M. Onofrio, Human malignant hyperthermia: awake episodes and correction by dantrolene, Anesth. Analg. 59 (1980) 377 – 378. [29] M.A. Kolb, M.L. Horn, R. Martz, Dantrolene in human malignant hyperthermia: a multicenter study, Anesthesiology 6 (1986) 254 – 262. [30] H.J. Eberlein, Therapie der Malignen Hyperthermie, Anaesthesist 28 (1979) 247 – 248. [31] U. Schulte-Sasse, J. Tarnow, H.J. Eberlein, Bericht ueber die erfolgreiche Behandlung einer malignen Hyperthermie mit Dantrolen und komplikationsloser Zweitnarkose nach oraler Dantrolen-Prophylaxe, Anaesthesist 31 (1982) 241 – 244. [32] F. Wappler, Department of Anaesthesiology, University Hospital Hamburg, Germany, personal communication. [33] R.A. Gordon, B.A. Britt, W. Kalow, International Symposium on Malignant Hyperthermia, Charles C. Thomas, Springfield, IL, 1973. [34] R.A. Gordon, Malignant Hyperthermia during general anaesthesia, Can. Anaesth. Soc. J. 13 (1966) 415 – 446. [35] H. Bergmann, B. Blauhut, Maligne Hyperthermie, Akupunktur, Biomedizinische Technik, Abdominelle Intensivmedizin, Anaesthesiology and Resuscitation, vol. 91, Springer Verlag, Berlin, 1975.