Intraoperative hyperthermia in a paediatric patient with cystinosis

Cystinosis is a rare autosomal recessive inherited disorder of amino acid metabolism. Little is known of the affects of general anaesthesia on the disease (Tobias 1993) and complications relating to anaesthesia have not been previously reported. Infantile cystinosis presents as progressive renal failure and the Fanconi syndrome and metabolic bone disease often develop. We describe the case of a child who presented with signs of apparent malignant hyperthermia (MH) under general anaesthesia and was treated with dantrolene. During a repeat ‘trigger-free’ general anaesthetic he developed a fever which responded to paracetamol. The metabolic effects of cystinosis and its similarity to MH will be discussed.     

Malignant hyperthermia and day stay surgery

Patients who are malignant hyperthermia susceptible are often admitted overnight for observation, even after minor surgery. They may be declined care in a stand-alone day stay unit. This prospective audit set out to investigate whether patients susceptible to malignant hyperthermia can be safely treated as day stay patients. The audit was conducted for four years from late 2000. All patients who were known to be susceptible to malignant hyperthermia, and their untested relatives, who received day stay anaesthesia were included in the audit. Malignant hyperthermia status, age, duration of anaesthesia, anaesthetic technique, type of procedure, intraoperative and postanaesthesia care unit observations and complications were recorded. All patients received a trigger-free anaesthetic technique. Detailed postanaesthesia care unit monitoring was undertaken and patients were observed for two and a half hours postoperatively. Seventy-two patients were included in the audit. General anaesthesia was administered to 85% and regional to 15%. Only minor complications arose in the postoperative period, and none suggested a malignant hyperthermia reaction. Postanaesthesia care unit nursing staff contacted 49 (68%) of the patients the following day, and there was no evidence of malignant hyperthermia reactions. This audit suggests that malignant hyperthermia susceptible patients can be safely managed as day stay patients in appropriate facilities, with appropriate postoperative care.     

Porcine malignant hyperthermia — failure of dantrolene dose response to diagnose susceptibility (halothane effect)

Dantrolene, a skeletal muscle relaxant, has been proven prophylactic and therapeutic for malignant hyperthermia (MH) in swine. This study examined the feasibility of using a dantrolene dose response as measured by indirectly evoked foretoe twitch depression as a means to safely discriminate MH susceptibility in swine. The effect of halothane on the dantrolene response was quantified. Subjects were five Poland China malignant hyperthermia susceptible (MHS) and five Hampshire malignant hyperthermia resistant (MHR) swine. Dantrolene dose response was determined twice in each anaesthetized subject, once with thiopentone and subsequently with thiopentone and halothane. Dantrolene in incremental doses, 0.15mg kg^-1, was given to a cumulative dose of 2-3 mg kg^-1. Under thiopentone anaesthesia, the dantrolene dose responses were similar in MHS and MHR animals. The presence of halothane augmented dantrolene twitch depression in MHS but not MHR animals when compared to their response under thiopentone. Under halothane, the MHS animals had significantly augmented dantrolene response compared to MHR pigs, but three MHS animals had developed the MH syndrome prior to receiving dantrolene. We conclude that dantrolene muscle relaxant dose response cannot be used as a diagnostic test for MHS in swine. Halothane augments dantrolene twitch depression in MHS swine.     

Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and moderate hypothermia

A 56-year old man was admitted for elective mitral valve repair and coronary artery bypass surgery due to mitral valve leakage and unstable angina. After induction of anaesthesia he developed a combined metabolic and respiratory acidosis. Different diagnosis were considered and we decided to treat the patient with dantrolene due to suspicion of malignant hyperthermia (MH). The patient received one dose of dantrolene 2,5 mg/kg during cardiopulmonary bypass (CPB) and a second dose of dantrolene 2,5 mg/kg during weaning from CPB. The first arterial blood gas sample taken in the intensive care unit showed relapse of the acidosis and we administered an infusion of 150 mg dantrolene over 3 hours. The patient gradually recovered without sequel and MH was verified by muscle biopsy testing.     

Dantrolene. Pharmacological and therapeutic aspects

Malignant hyperthermia (MH) is a genetic, potentially life-threatening disorder of the skeletal muscle presenting during or following general anaesthesia. Trigger agents are volatile anaesthetics and depolarising muscle relaxants. Dantrolene is the only available drug for effective and specific MH therapy, which reduces significantly the mortality rate. Dantrolene is a skeletal muscle relaxant that depresses the excitation-contraction coupling,however, the specificity of action remains unknown. Recent studies identified the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum, as the direct molecular target of dantrolene. In addition to its use for MH, dantrolene is used in other disorders such as neuroleptic malignant syndrome and spasticity. Since dantrolene is weakly water soluble, the clinical preparation is time and manpower consuming. New agents have been synthesized, but because of economic considerations no registration for clinical usage has been realised.     

McArdle's disease and anaesthesia: case reports. Review of potential problems and association with malignant hyperthermia

BACKGROUND: McArdle's disease of isolated deficiency in glycogen degradation in skeletal muscles has the potential of creating perioperative anaesthesiological problems; such as hypoglycaemia, rhabdomyolysis, myoglobinuria, acute renal failure and possibly malignant hyperthermia. METHODS: Eight patients with McArdle's disease were asked about previous surgery, anaesthesia and perioperative problems, and available hospital records were reviewed. Existing literature was reviewed for reports on McArdle's disease and anaesthesia. RESULTS: The eight patients had 35 anaesthesias (23 general anaesthesias, three regional anaesthesias and nine local anaesthesias). Perioperative problems of a non-specific nature were mentioned in three cases of general anaesthesia: two with postoperative nausea/vomiting, and one with an episode of tachycardia and low blood pressure. Three patients were tested for malignant hyperthermia (MH) using the in vitro contracture test (IVCT); two of them with a positive result. The literature search revealed seven case reports of McArdle's disease and anaesthesia. Apart from one report of hyperthermia, pulmonary oedema and rhabdomyolysis; probably not associated with MH, no problems were encountered from the literature search. CONCLUSION: McArdle's disease does not seem to cause severe perioperative problems in routine anaesthetic care. However, measures for preventing muscle ischaemia and rhabdomyolysis should be kept in mind, as well as the potential for these patients to develop postoperative fatigue, myoglobinuria and renal failure. Although no clinical association with malignant hyperthermia has been established, many of these patients can have a positive in vitro contracture test, and simple prophylactic measures, as with malignant hyperthermia, may be recommended if otherwise not contraindicated.     

Dantrolene -In vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle

Dantrolene sodium, a hydantoin analogue, is efficacious in the therapy of malignant hyperthermia (MH). In order to improve our knowledge of the mode of action of dantrolene, we have examined the influence of dantrolene sodium on; (1) twitch and resting tensions, in the absence and the presence of caffeine, of intact skeletal muscle fascicles; and (2) caffeine induced tension rises of single chemically skinned skeletal muscle fascicles. We have found that dantrolene appears to exert its beneficial action on malignant hyperthermia susceptible (MHS) skeletal muscle by an indirect action on the sarcoplasmic reticulum (SR). Thus dantrolene inhibits twitch tensions of skeletal muscle fascicles, probably by indirectly preventing the release of calcium from the SR. To a lesser extent dantrolene inhibits caffeine induced contractures of skeletal muscle fascicles, probably by indirectly accelerating the uptake of calcium into the SR. Because the former effect is greater than the latter in vivo dantrolene sodium is effective only when given prior to total loss of calcium from the SR. Vigilant temperature and EKG monitoring of all patients during anaesthesia is, therefore, essential.     

Follow-up of patients tested for malignant hyperthermia susceptibility

BACKGROUND AND OBJECTIVE: Malignant hyperthermia is an inherited disorder of skeletal muscle characterized by muscle contracture and hypermetabolic crisis following exposure to halogenated anaesthetics and depolarizing muscle relaxants. We planned this follow-up to get more information about the safety of non-triggering anaesthesia in susceptible patients; the safety of the use of trigger agents in non-susceptible patients and any minor sequelae following the biopsy. METHODS: A questionnaire was sent to 244 patients tested for susceptibility between 1998 and 2004 enquiring about sequelae from the biopsy, subsequent experience with anaesthesia and difficulties encountered because of the investigation. RESULTS: Replies were received from 129 patients. Thirty-four complained about sequelae from the biopsy: 10 reported headache and nausea; 16 experienced pain and a lack of strength in the biopsed leg and 8 found the scar less than satisfactory. Ten patients found it difficult to find a diagnostic centre. Eighteen reported problems and/or delay when they had needed a subsequent anaesthetic. Fourteen patients found the anaesthesiologist reluctant to anaesthetize them and four experienced a delay. Forty-three patients received anaesthesia since their biopsy. Complete medical records were available for 24 anaesthetic exposures in 23 patients. No documented perioperative complications occurred. Only three non-susceptible patients received one trigger agent. CONCLUSIONS: It is safe to use trigger-free anaesthesia in susceptible patients. The difficulties encountered by patients to be anaesthetized and the management of the majority of non-susceptible patients during general anaesthesia show the need of more accurate educational programmes and methods for promoting patient-centred care.     

Safety of general anesthesia in patients previously tested negative for malignant hyperthermia susceptibility

Anesthetic management and outcome were examined in patients with negative in vitro contracture tests for malignant hyperthermia (MH). Contracture testing was performed in a standardized fashion using 3% halothane alone and incremental doses of caffeine alone. Medical records were examined for 54 anesthetic exposures in 42 MH(-) patients who had received anesthesia since their MH testing. Sixteen patients received anesthesia with known MH triggering agents on 23 occasions, all without incident. In six MH(-) patients with previous masseter muscle rigidity, no adverse reactions occurred in response to volatile anesthetic agents. Succinylcholine was avoided in these patients. Eleven MH(-) patients were managed as if MH-susceptible, although it was known that these patients had tested MH(-). Two of these patients also receive prophylactic iv dantrolene. These results suggest that "triggering" anesthetic agents may be safely administered to patients who test MH(-) by in vitro contracture testing. However, until the anesthetic experience of larger numbers of MH(-) patients is known, these results should be interpreted cautiously.     

Malignant hyperthermia

Malignant hyperthermia (MH) is a rare autosomal dominant genetic disease of calcium (Ca²⁺) metabolism in skeletal muscle. Its manifestations are normally silent and only made evident when susceptible patients receive general anaesthesia with volatile anaesthetic agents or succinyldicholine. Skeletal muscle hypermetabolism triggered by exposure to these agents causes a cascade of clinical events, rapidly leading to death. Early treatment with dantrolene can abort the syndrome. Muscle from MH patients is abnormally sensitive to caffeine, and this forms the basis of the halothane/caffeine contracture diagnostic test. MH susceptibility has been linked to the skeletal muscle Ca²⁺release channel gene (ryanodine receptor, RYR1) on chromosome 19 and four other loci related to skeletal muscle excitation contraction coupling. Over 30 RyR1 mutations from three ‘hot spot’ regions have been found. Discordance between some mutations and MH susceptibility has prevented genetic testing from being generally useful for diagnosis. The effects of MH mutations on RyR1 channel physiology will be presented. The roles of other proteins including FKBP12, the slow voltage-gated channel, and calsequestrin on MH will be discussed.     

Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test

Background: It is well known that patients susceptible to malignant hyperthermia (MH) do not always develop clinical signs of MH at their first anaesthetic. Large material concerning this epidemiological problem do not exist. Therefore, we undertook the present investigation at the Danish Malignant Hyperthermia Register.
Methods: Retrospective analysis of anaesthetics given to 371 patients before in vitro contracture test (IVCT) for susceptibility to MH or before death of MH. Patients (or relatives in the case of a dead patient) gave information about previous anaesthetics and anaesthetic charts were collected and reviewed.
Results: Fifteen patients died of clinical MH, 112 patients survived an episode of suspected MH, and 244 patients were relatives of the above. Of the 127 patients with clinical signs of MH, 37% had received anaesthesia before, and trigger agents (potent inhalational agents and /or suxamethonium) were used in 98% of patients with no statistical difference between MH-susceptible (MHS) and non-susceptible (MHN) patients. Emergency anaesthesia was more frequent in patients with fulminant MH compared to those with abortive forms of MH ( P < 0.01). Of the 244 relatives, 48% had received anaesthesia before MH was suspected in the family and trigger agents were used in 44% of the anaesthetics without statistical difference between MHS and MHN relatives. In 17 cases, trigger agents were used for anaesthesia after MH was suspected in the family, but before IVCT.
Conclusion: The clinical expressivity of the MHS phenotype was found to be 34%-54%.     

Safe duration of postoperative monitoring for malignant hyperthermia susceptible patients

Postoperative management of malignant hyperthermia (MH) susceptible patients has changed substantially over the last 20 years, with many patients now managed as day cases. Our previous policy was to monitor known MH susceptible patients (and relatives of known MH susceptible individuals not yet investigated by muscle biopsy) for four hours in the Post Anaesthetic Care Unit. However, anaesthetic literature reports suggest that MH reactions usually commence within one hour of anaesthesia. For this reason we conducted a retrospective review of Post Anaesthetic Care Unit data in 254 MH susceptible/related patients treated between 1991 and late 2000. On the basis of this review we instituted a policy change and reduced our monitoring time to one hour in the Post Anaesthetic Care Unit with a further 1.5h in a step-down unit if indicated. A prospective study in a further 68 MH susceptible/related patients showed that no MH reactions were missed due to the shorter monitoring period.     

Postoperative malignant hyperthermia episodes in patients who received “safe” anaesthetics

Three cases of postoperative malignant hyperthermia (MH) episodes, after what was considered to be a “safe” anaesthetic, are described. In each case the temperature rose in a delayed fashion after an uneventful anaesthetic. Treatment included intravenous dantrolene, surface cooling and ventilation with 100 per cent oxygen. Stress in the postoperative period may have been the triggering factor responsible for these reactions. Patients should be monitored well into the postoperative period as MH episodes may occur long after surgery is completed. If stress represents a significant triggering mechanism then no anaesthetic technique can be considered entirely safe.     

Treatment of malignant hyperthermia crisis during anesthesia

Malignant hyperthermia (MH), triggered by anaesthesia, is a rare and potentially fatal condition. It requires immediate and specific treatment. This review focuses on anticipation and organisation of treatment. Anticipation means that dantrolene should be available, that an anaesthetic machine should be kept free from all vapours of halogenated anaesthetics, and methods of cooling should be planned. A prompt availability in all operating theatres of dantrolene and the required machines is emphasized. Treatment of a MH episode includes stopping the administration of triggering agents, administering dantrolene, correcting metabolic and respiratory acidosis, and cooling. Different aspects of the cardiovascular pharmacology of dantrolene are discussed. Other drugs are seldom required if proper treatment is started soon enough after the crisis. Complications may arise during a fulminant episode. They are difficult to treat, and may lead to sequelae. A rational approach to the treatment of hyperkalaemia, circulatory and renal failure is discussed. After the crisis, dantrolene should be continued for a short time. Finally, the nonspecific signs which can give the earliest diagnosis possible of MH are discussed: an early diagnosis and early treatment with dantrolene are essential in reducing the mortality of malignant hyperthermia.     

Duchenne muscular dystrophy and malignant hyperthermia -two case reports

The case histories are presented including the anaesthetic and postoperative management, of two children, a two-year-old with undiagnosed Duchenne muscular dystrophy (DMD) and a three-year-old with known DMD. The child with undiagnosed DMD had no symptoms of DMD and had received halothane twice before, without succinylcholine, with no apparent difficulty. Following an uneventful induction of anaesthesia with halothane, nitrous oxide and O₂, succinylcholine resulted in bilateral masseter muscle spasm and then, in rapid se-quence, ventricular tachycardia and cardiac arrest. Resuscitation was difficult, prolonged and associated with hyperkalaemia (K⁺ = 12.57 mEq·L^-1), severe metabolic and respiratory acidosis, high peripheral venous pressure and massive hepatospleenomegaly, but not hyperthermia. The patient was finally resuscitated but died two days later. Skeletal muscle biopsy results were consistent with malignant hyperthermia. The second patient was known to have DMD but did not receive prophylactic or intraoperative dantrolene nor have his anaesthetic machine flushed with oxygen for an extended period prior to induction of anaesthesia. This child was anaesthetized withfentanyl and N₂O and, with the exception of a high intraoperative heart rate (155–160 beats-min^-1 ), had an uncomplicated anaesthetic and operation (intraoperative axillary temperatures ranged between 36.8–37.9° C). Postoperatively his temperature rapidly increased to 38.8° C and then 40.3° C and he became metabolically acidotic. Intravenous administration of dantrolene for 48 hours reduced the temperature and allowed normal recovery and discharge. A postoperative muscle biopsy was consistent with DMD. These case reports confirm that children with DMD have the potential for developing malignant hyperthermia during or after anaesthesia and therefore should be prepared pre-operatively and managed intraoperatively accordingly.     

Orthotopic liver transplantation in a malignant hyperthermia susceptible patient

We present a patient with hepatitis C and D and hepatocellular carcinoma who underwent preoperative evaluation for orthotopic liver transplantation. In his past medical history, he reported a life-threatening event during tonsillectomy in 1975. Intubation was impossible due to extreme jaw muscle tension, followed by excessive elevation in body temperature, tachycardia, and coma for a few days. We evaluated him for malignant hyperthermia, according to the European Malignant Hyperthermia Group Protocol, and found him highly positive in both the halothane and caffeine test, respectively. Three months later, we performed an orthotopic liver transplantation. During retransplantation 4 years later, due to ischemic-type biliary lesions, he suffered massive intraoperative bleeding. Blood products, as well as coagulation factors and aprotinin, were well tolerated. Anesthesia was performed in a trigger-free total intravenous technique without dantrolene prophylaxis, but dantrolene was readily available in sufficient quantities in the operating room. The patient did not encounter a malignant hyperthermia crisis in either perioperative period.     

Malignant hyperthermia: new developments in diagnosis and clinical management]

OBJECTIVE: To analyse the current knowledge concerning anaesthetic malignant hyperthermia. DATA SOURCES: References were obtained from computerized bibliographic research (Medline), recent review articles, the library of the service and personal files. DATA SYNTHESIS: Knowledge to possess, about the diagnosis and treatment of the acute hyperthermia crises and about "safe-anaesthesia" for malignant hyperthermia susceptible patients, are explained. The pathophysiology chapter give information about the calcium's transport and the defect existing in MH. Molecular genetics of MH find linkage to the region encoding the RyR1. The profile of hyperthermia episodes has changed over time due to the endtidal carbon dioxide-monitoring. Clinical aspects of MH are exposed. The treatment of the acute hyperthermia crises consist mainly to stop all triggering agents instantly and infuse dantrolene sodium. The gold standard for the diagnosis of malignant hyperthermia susceptibility relies on the in vitro contracture test (halothane and caffeine). Associated to genetic studies, it could lead to an non-invasive screening of the MH susceptibility. A protocol for "safe-anaesthesia" is proposed. Some syndromes with features similar to those of MH should be known (central core disease and exertionnal rhabdomyolysis).     

Effects of midazolam on directly stimulated muscle biopsies from control and malignant hyperthermia positive patients

Midazolam is a water soluble benzodiazepine of interest to the anaesthetist for use as a premedicant and for induction of anaesthesia. The effects of midazolam were observed on the resting tension of directly stimulated muscle biopsied from control and malignant hyperthermia (MH) susceptible patients. In addition, interactions between midazolam and the two most commonly used MH diagnostic agents (halothane and caffeine) were examined. Midazolam, at maximum therapeutic concentrations (ca. 0.5 microgram X ml-1), had no detectable effects on muscle contraction in preparations from control or MH positive patients. Midazolam did elicit a contracture from control and MH positive preparations when used in a concentration range of 160-1280 micrograms X ml-1. There was no significant difference between control and MH positive patients in minimum concentration of midazolam causing contracture or the strength of contracture at the respective eliciting concentration. There appears to be no interaction between midazolam and either halothane or caffeine on the resting tension of the directly stimulated muscle twitch preparation.     

Duchenne muscular dystrophy and malignant hyperthermia--two case reports

The case histories are presented including the anaesthetic and postoperative management, of two children, a two-year-old with undiagnosed Duchenne muscular dystrophy (DMD) and a three-year-old with known DMD. The child with undiagnosed DMD had no symptoms of DMD and had received halothane twice before, without succinylcholine, with no apparent difficulty. Following an uneventful induction of anaesthesia with halothane, nitrous oxide and O2, succinylcholine resulted in bilateral masseter muscle spasm and then, in rapid sequence, ventricular tachycardia and cardiac arrest. Resuscitation was difficult, prolonged and associated with hyperkalaemia (K+ = 12.57 mEq X L-1), severe metabolic and respiratory acidosis, high peripheral venous pressure and massive hepatosplenomegaly, but not hyperthermia. The patient was finally resuscitated but died two days later. Skeletal muscle biopsy results were consistent with malignant hyperthermia. The second patient was known to have DMD but did not receive prophylactic or intraoperative dantrolene nor have his anaesthetic machine flushed with oxygen for an extended period prior to induction of anaesthesia. This child was anaesthetized with fentanyl and N2O and, with the exception of a high intraoperative heart rate (155-160 beats X min-1), had an uncomplicated anaesthetic and operation (intraoperative axillary temperatures ranged between 36.8-37.9 degrees C). Postoperatively his temperature rapidly increased to 38.8 degrees C and then 40.3 degrees C and he became metabolically acidotic. Intravenous administration of dantrolene for 48 hours reduced the temperature and allowed normal recovery and discharge. A postoperative muscle biopsy was consistent with DMD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention and treatment of malignant hyperthermia in certified training hospitals in Japan: a questionnaire

Purpose. To assess the preparedness of hospitals in Japan for cases of malignant hyperthermia (MH). Method. A survey was sent to 884 training hospitals certified by the Japan Society of Anesthesiologists (JSA) in June and July 2000. Useful answers were received from 431 (48.8%) institutions. Results. For general anesthesia, inhalation anesthetics were widely used in 283 (65.7%) hospitals, and succinylcholine was the most commonly used muscle relaxant, which was used in 270 hospitals (62.5%). For patient monitoring, 422 (97.9%) hospitals used a pulse oximeter for all general anesthesia cases. A capnogram was used in 152 (35.3%) hospitals, and continuous body temperature was measured in 128 (29.7%). Two hundred and eighty-eight (66.8%) hospitals had more than six vials of dantrolene prepared for use, whereas 13 (3.0%) had none. Conclusion. The results of the survery revealed that some hospitals had inadequate monitoring methods and a lack of prepared dantrolene for cases of MH under general anesthesia. We recommend that essential monitors be deployed and adequate preparations of dantrolene be maintained for effective early diagnosis and treatment of MH. Received: October 5, 2001 / Accepted: February 18, 2002