Article

Anesthetic Drugs and Onset of Malignant Hyperthermia

Authors:
  • North American MH Registry of MHAUS
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Abstract

The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.

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... than it had been previously [2]. Using reports of MH cases Adverse Metabolic/Muscular Reaction to Anesthesia reports (AMRAs) voluntarily submitted to the North American Malignant Hyperthermia Registry (NAMHR) Visoiu et al. observed that time to the first sign of MH differed between anesthetic agents. ...
... Anesthetics utilizing halothane and succinylcholine produced the first sign of MH the fastest. In the presence of isoflurane or desflurane the first sign of MH more often occurred in the second or third hour of the anesthetic [2]. However, the MH deaths known to the NAMHR after 2006 suggest that the death rate from MH due to anesthetic exposure has increased [10]. ...
... Acute Malignant Hyperthermia (MH) is a rare but potentially fatal pharmacogenetic disorder that most often occurs after the administration of volatile anesthetics and/or succinylcholine [1,2]. Dantrolene reduces intracellular calcium in skeletal muscle through inhibition of the Ryanodine Receptor (RYR1) and possibly other mechanisms [3][4][5]. ...
... Inhaled anesthetics and succinylcholine had been administered in 53.9% of cases, inhaled anesthetics in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in seven MH cases [3]. Signs of MH often appear at later time points, in the second or third hour of anesthesia [3]. ...
... No causative anesthetic drugs were reported in seven MH cases [3]. Signs of MH often appear at later time points, in the second or third hour of anesthesia [3]. The frequency of MH occurrence is extremely rare, being observed in 1 in 50,000-150,000 general anesthesia cases, and analysis of the RYR1 gene has indicated that approximately 1 in 2000 people have a predisposition to MH [3]. ...
... Signs of MH often appear at later time points, in the second or third hour of anesthesia [3]. The frequency of MH occurrence is extremely rare, being observed in 1 in 50,000-150,000 general anesthesia cases, and analysis of the RYR1 gene has indicated that approximately 1 in 2000 people have a predisposition to MH [3]. The occurrence of MH may be life-threatening, and genetic testing and muscle biopsy are required for a definite diagnosis. ...
Article
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Background Malignant hyperthermia (MH) is a rare genetic disease characterized by the development of very serious symptoms, and hence prompt and appropriate treatment is required. However, postoperative MH is very rare, representing only 1.9% of cases as reported in the North American Malignant Hyperthermia Registry (NAMHR). We report a rare case of a patient who developed sudden postoperative hyperthermia after mastectomy, which was definitively diagnosed as MH by the calcium-induced calcium release rate (CICR) measurement test. Case presentation A 61-year-old Japanese woman with a history of stroke was hospitalized for breast cancer surgery. General anesthesia was introduced by propofol, remifentanil, and rocuronium. After intubation, anesthesia was maintained using propofol and remifentanil, and mastectomy and muscle flap reconstruction surgery was performed and completed without any major problems. After confirming her spontaneous breathing, sugammadex was administered and she was extubated. Thereafter, systemic shivering and masseter spasm appeared, and a rapid increase in body temperature (maximum: 38.9 °C) and end-tidal carbon dioxide (ETCO2) (maximum: 59 mmHg) was noted. We suspected MH and started cooling the body surface of the axilla, cervix, and body trunk, and administered chilled potassium-free fluid and dantrolene. After her body temperature dropped and her shivering improved, dantrolene administration was ended, and finally she was taken to the intensive care unit (ICU). Body cooling was continued within the target range of 36–37 °C in the ICU. No consciousness disorder, hypotension, increased serum potassium level, metabolic acidosis, or cola-colored urine was observed during her ICU stay. Subsequently, her general condition improved and she was discharged on day 12. Muscle biopsy after discharge was performed and provided a definitive diagnosis of MH. Conclusions The occurrence of MH can be life-threatening, but its frequency is very low, and genetic testing and muscle biopsy are required to confirm the diagnosis. On retrospective evaluation using the malignant hyperthermia scale, the present case was almost certainly that of a patient with MH. Prompt recognition and immediate treatment with dantrolene administration and body cooling effectively reversed a potentially fatal syndrome. This was hence a valuable case of a patient with postoperative MH that led to a confirmed diagnosis by CICR.
... Induction to onset time in 75 MH episodes documented in New Zealand averaged 48 minutes (unpublished data, N Pollock); the average anaesthetic exposure in this study was 45 minutes, which should have been sufficient exposure to trigger an MH episode in the majority of patients. In view of reports of delayed presentation of MH episodes [15][16][17][18] , and as there are reports of MH episodes becoming manifest following termination of anaesthesia, PACU recordings are documented in the present study. Litman reviewed 528 suspected MH episodes contained in the North American MH Registry. ...
... Around 20 percent of anaesthetics in this study included halothane. Both desflurane and sevoflurane are regarded as less potent triggers but Yuge found sevoflurane more potent in vivo than in vitro 40 and other studies found sevoflurane equivalent to isoflurane in severity of reaction 15,41 . Information from the NAMHG indicates that sevoflurane is currently the most common trigger of an MH episode (personal communication, B Brandom, NAMHG). ...
Article
Testing for malignant hyperthermia in New Zealand involves two tests-in vitro contracture testing of excised lateral quadriceps muscle and DNA analysis. In vitro contracture testing is regarded as the gold standard in malignant hyperthermia diagnosis but several publications have questioned the reliability of a normal result. Analysis of 479 anaesthetic records in 280 patients or their descendants throughout New Zealand who had tested negative for malignant hyperthermia, demonstrated there was no evidence of malignant hyperthermia episodes in this group who had been administered anaesthetic triggering agents. A wide range of anaesthetics were used over the study period. Analysis of each anaesthetic record was undertaken using the malignant hyperthermia grading scale which determines the likelihood that an anaesthetic event represents a malignant hyperthermia episode. Confirmation of the negative results was further supported by normal DNA analysis of patients in 48% of anaesthetics. There are advantages to using inhalational agents in certain situations and although demonstrating a zero risk of a malignant hyperthermia episode is not statistically possible, evidence in this large series suggests that the risk of an episode in these patients is extremely low and may be negligible. We suggest that anaesthetic triggering agents can be used safely in patients with normal in vitro contracture tests, and in their descendants.
... The hyper-acute onset of MH is very rare, even though sevoflurane rather than isoflurane, and younger subjects <20 years may manifest faster onset of MH. [26] MH associated with less potent volatile anesthetics such as sevoflurane or desflurane is known to present relatively gradual onset of symptoms. [27,28] Several studies reported that the median MH occurrence time following exposure to sevoflurane without succinylcholine ranged from 45 to 72.5 minutes. ...
... [27,28] Several studies reported that the median MH occurrence time following exposure to sevoflurane without succinylcholine ranged from 45 to 72.5 minutes. [26,29] Our patient presented abrupt manifestation of hypercarbia, tachycardia, and muscular rigidity of both hand as early signs of MH in approximately 5 minutes following beginning of sevoflurane administration. Although temperature increase is an important confirmatory In our case, the core temperature of the patient maintained within normal range and the patient had only mild temperature rise <37.5°C until discharge from the ICU. ...
Article
Full-text available
Rationale: Several hereditary myopathies that can predispose to malignant hyperthermia (MH) are reported. However, the risk of MH in myotonic dystrophy type I (DM1) has been suggested equal to general population, although the evidence is limited to only a few case reports. Patient concerns: We encountered a rare case of MH during anesthesia induction with sevoflurane in a male adolescent with previously undiagnosed DM1. Diagnoses: After the event, genetic testing revealed the presence of a previously unknown heterozygous missense mutation in ryanodine receptor 1 (RYR1) associated with MH (c.6898T > C; p.ser2300Pro). Concomitantly, the patient was diagnosed with DM1 with abnormal cytosine-thymine-guanine triplet expansion in the DMPK gene. Interventions: Dantrolene was administered to treat the hypermetabolic manifestations in 20 minutes after the identification of MH. Outcomes: The patient was successfully treated and discharged without any complications. Laboratory abnormalities were recovered to baseline at postoperative 4 days. Lessons: The authors suggest that possible MH susceptibility in DM1 patients may be refocused. Genetic testing can be a screening tool for MH susceptibility in these population, prior to receiving general anesthesia.
... In light of the etiology and triggering factor in this case, one may incorrectly assume it was precipitated by succinylcholine alone, since the patient previously received sevoflurane without incident. However, the literature suggests that different inhaled anesthetics may trigger MH at different rates, and his initial sevoflurane exposure was not sufficient [8]. Furthermore, studies have shown that a triggering inhalation agent plus the use of succinylcholine may cause a more marked response than a single agent [9]. ...
... This allowed In light of the etiology and triggering factor in this case, one may incorrectly assume it was precipitated by succinylcholine alone, since the patient previously received sevoflurane without incident. However, the literature suggests that different inhaled anesthetics may trigger MH at different rates, and his initial sevoflurane exposure was not sufficient [8]. Furthermore, studies have shown that a triggering inhalation agent plus the use of succinylcholine may cause a more marked response than a single agent [9]. ...
Article
Full-text available
Purpose: Malignant hyperthermia (MH) is a critical and potentially life-threatening emergency associated with inhaled anesthetic and depolarizing neuromuscular blocker administration. This is a single center's response to MH. Summary: When signs of MH are observed, a page for "anesthesia STAT-MH crisis" is called, triggering a multidisciplinary response, including the deployment of a Malignant Hyperthermia Cart. The MH cart and the delegation of duties allows nurses, physicians and pharmacists to quickly understand their role in the stabilization, transition and recovery of a suspected MH patient. Conclusion: This case highlights the importance of multi-disciplinary involvement in these rare, but potentially fatal, cases.
... Acute Malignant Hyperthermia (MH) is a rare but potentially fatal pharmacogenetic disorder that most often occurs after the administration of volatile anesthetics and/or succinylcholine[1,2]. Dantrolene reduces intracellular calcium in skeletal muscle through inhibition of the Ryanodine Receptor (RYR1) and possibly other mechanisms[3][4][5]. ...
... Thus, there may have been a lower clinical suspicion of MH at the beginning of these MH episodes. The presentation of acute anesthetic induced MH is variable[1,2,8]. In the IntensiveCare Unit changes in hemodynamic stability of a patient may be attributed to post operative stress, emergence from anesthesia, underlying life-threatening conditions or factors other than MH. ...
... In the current situation, it is suspected that the malignant hyperthermia was caused by the sevoflraune. However, MH onset time was faster during sevoflurane (median time, 45 minutes) than isoflurane (median time, 135 minutes) or desflurane (median time, 113.5 minutes) anesthesia [10]. No causative anesthetic drugs were reported in 7 MH cases [10]. ...
... However, MH onset time was faster during sevoflurane (median time, 45 minutes) than isoflurane (median time, 135 minutes) or desflurane (median time, 113.5 minutes) anesthesia [10]. No causative anesthetic drugs were reported in 7 MH cases [10]. ...
... This pattern is more common than generally assumed, as evidenced by several similar reports over the last few years [6][7][8][9][10][11] . Regarding the more 'indolent character' of MH, a recent paper provides, for the first time, statistical evidence that the MH median onset time was significantly shorter for the cases that occurred before 1998, compared to the cases that occurred later 12 . ...
Article
Full-text available
Modern anaesthetic techniques have resulted in the clinical presentation of malignant hyperthermia to be more often indolent and/or insidious than truly fulminant, as previously known in the anaesthetic community. We present four recently referred cases to illustrate this point: one late-onset case, two patients with slowly progressive hypercapnia as the sole sign and a fourth patient with postoperative myalgias and elevated creatine kinase. We also discuss the reasons for the shift in typical clinical presentation. The more insidious character of malignant hyperthermia is most likely due to the lower triggering potency of modern volatile anaesthetics, the mitigating effects of several intravenous drugs (neuromuscular blocking agents, alpha 2 adrenergic receptor agonists, beta adrenergic blockade) or techniques (neuraxial anaesthesia) and the routine use of end-tidal CO2 monitoring leading to the early withdrawal of triggering drugs. Awareness among anaesthetists of this change in presentation is important since the clinical diagnosis is often more doubtful and, if corroborative evidence is not sought, the diagnosis may be delayed or missed altogether.
... 5,6 A recent review determined that the median onset time of MH after trigger exposure in the absence of succinylcholine was 113.5 minutes for desflurane (consistent with our case), 45 minutes for sevoflurane, and 15.5 minutes for halothane. 7 Early research in swine demonstrated that IV dantrolene was effective for MH. 8 Subsequently dantrolene was found to be effective in human MH. 9 Malignant Hyperthermia Association of the United States (MHAUS) recommends a minimum of thirty-six 20-mg vials be available and to dose dantrolene based on actual rather than ideal or lean body weight. 10 In our case, a single bolus of dantrolene entailed 380 mg or 19 vials. ...
Article
During resection of a duodenal carcinoid tumor, a 28-year-old morbidly obese woman developed suspected malignant hyperthermia. This hypermetabolic state posed a diagnostic challenge given the similar intraoperative presentation of carcinoid crisis and malignant hyperthermia. The patient's weight posed therapeutic challenges as massive doses and prolonged administration of dantrolene were required that quickly depleted the available supply. Current dantrolene dosing recommendations are based on actual body weight despite a paucity of literature in obese patients. We speculate that the prolonged need for dantrolene redosing was from the continuous release of the volatile anesthetic from the patient's adipose tissue.
... One of the most serious complications in anesthesiology is malignant hyperthermia (MH). Malignant hyperthermia is induced by all volatile inhalant anesthetics and depolarizing muscle relaxants, such as succinylcholine [2,3], which increase the rate of calcium release from the sarcoplasmic reticulum [4,5], resulting in abnormal and sustained muscle contraction in skeletal muscles and subsequently causing the destruction of skeletal muscles and the production of large amounts of heat [6,7]. ...
Article
Introduction A simple indicator of muscle damage is creatine kinase (CK). Although CK elevation is informative for malignant hyperthermia, no study has examined the relationship between the anesthetically awake state and CK in children. We aimed to prospectively examine the relationship between the awakening state and CK on the day after surgery in children who have undergone anesthesia with volatile inhalation anesthetics. Methods The study included 119 patients aged 0-15 years and scheduled to undergo general anesthesia for cleft lip and palate-related surgery. Emergence agitation (EA) was assessed after completion of general anesthesia using the five-point EA scale, and patients were divided into the following five groups according to the EA score: EA1, EA2, EA3, EA4, and EA5. The primary outcome was ΔCK (comparison of CK values one week prior to surgery to CK values on the day after surgery) in each EA group. The secondary outcome was ΔCK when the EA score was divided into the following two groups: EA ≤2 (EA score of 1 or 2) and EA ≥3 (EA score of 3, 4, or 5). Results The median ΔCK values in the EA1 to EA5 groups were 3 (quartile -19~9), 5 (-32~88), 99.5 (-18~190.5), 121 (29~219.5), and 144 (41~340.5), respectively, indicating a statistically significant difference overall. Statistically significant differences were also observed between the EA1 and EA4 groups and between the EA2 and EA4 groups. The median ΔCK values in the EA ≤2 and EA ≥3 groups were 3 (quartile -27~85) and 108 (23.5~206.7), respectively, indicating a statistically significant difference. Conclusion The results of this study revealed that a higher EA score at the time of anesthesia awakening is associated with a larger ΔCK, indicating that a high CK level on the day after surgery is highly related to the state of the patient upon awakening.
... 8,44 Severe hyperthermia could be misdiagnosed as MH. 45,46 Symptoms of confusion, agitation, and autonomic hyperactivity which result in tachycardia, hypertension, and hyperthermia might be misattributed to a "simple" emergence delirium in a patient with PTSD. [47][48][49][50] Management of SS in the perioperative period is challenging. ...
Article
Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction that may occur in patients treated with serotonin agonist medications. Medications responsible for serotonin syndrome include commonly prescribed antidepressants, anxiolytics, analgesics, and antiemetics. Veterans with post-traumatic stress disorder (PTSD) are at risk for polypharmacy with serotoninergic medications, given their psychological comorbidities and service-related musculoskeletal injuries. The perioperative period is a particularly vulnerable time owing to the use of high-dose anxiolytics and antiemetics frequently administered in this period, and places PTSD patients at higher risk of SS. Herein, we present the first case of SS in a young veteran with combat-related PTSD following an uncomplicated L5-S1 revision discectomy that highlights the unique set of clinical challenges and dilemmas faced when treating SS in a patient with severe postsurgical pain. As we are likely to encounter increasing numbers of veterans treated for PTSD who require multiple surgical procedures to treat their service-related injuries, health care providers need to be familiar with prevention, recognition, and the clinical challenges in the management of SS in the postoperative period.
... The real MH risk might actually be underestimated, since MH susceptibility is associated with many exome variants that could concern 1:2000 to 1:3000 of the French population [2,3]. Modern halogenated anaesthetic agents can induce unusual MH presentations, with incomplete or delayed manifestations, as in both cases we report [4]. However, early diagnosis and rapid dantrolene administration remain key points to decrease MH morbidity and mortality [5]. ...
... The time of onset of MH seems to be influenced by the type and dose of volatile anesthetic, whereas severity is also dependent on the duration of exposure. [18][19][20] Although our knowledge of factors influencing MH penetrance is limited, it is known that MH penetrance may depend on the additive effect of more than one genetic factor, 21 and allele-specific differences in RyR1 mRNA expression levels may explain the observed reduced penetrance and variations in MH phenotype among individuals. 22 Several studies 23-26 indicate higher incidence of MH in younger males, but the reason for that remains unclear. ...
Article
What we already know about this topic: Malignant hyperthermia is a rare life-threatening disorder triggered in genetically predisposed individuals by exposure to certain anestheticsThe ryanodine receptor 1 (RYR1) gene, which encodes the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is the major malignant hyperthermia-associated locusMalignant hyperthermia diagnostic mutations are more prevalent than the reported incidence of clinical malignant hyperthermia episodes because many mutation carriers are never exposed to anesthetic triggers and some may have several uneventful anesthetics before developing malignant hyperthermia reaction WHAT THIS ARTICLE TELLS US THAT IS NEW: In a multicenter case-control study of 229 genotype-positive subjects with previous recorded exposure to trigger anesthetics, there were 93 malignant hyperthermia cases, for an overall penetrance for the analyzed RYR1 mutations of 40.6%The probability of developing malignant hyperthermia on exposureto triggers was 0.25 among all RYR1 mutation carriers and 0.76 in survivors of malignant hyperthermia reactions (95% CI of the difference 0.41 to 0.59)Young age, male sex, and the use of succinylcholine were major nongenetic risk factors influencing expression of the RYR1 mutations conferring malignant hyperthermia susceptibility BACKGROUND:: Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. Methods: In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. Results: The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). Conclusions: Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.
... There was no significant difference found in MH symptoms comparing sevoflurane and desflurane. MH event may also occur after succinylcholine as the only trigger used [3,17]. ...
... MH onset time was shorter during sevoflurane anesthesia than during isoflurane or desflurane in the human cohort of MH cases. [15] Larach et al. observed cardiac dysfunction and level of consciousness change as the most common MH-related complications. [16] More the time period between the first clinical sign and dantrolene administration, higher complication rate was observed. ...
Article
Full-text available
Postoperative malignant hyperthermia (MH) is a very rare phenomena. It is generally observed within less than an hour after discontinuation of the anesthetic trigger. Present case describes rare delayed postoperative presentation of MH after off.pump coronary bypass surgery. Prompt recognition and immediate treatment with dantrolene can effectively treat the fatal syndrome. Family education and genetic counseling should be encouraged.
... However, MH symptoms in our Brody patient developed only postoperatively, which is not a common feature of a typical MH episode. While postoperative complications have been reported in some MH patients (Burkman et al. 2007;Larach et al. 2008), MH episode usually develops within the first few hours of exposure to inhalation anesthetics with signs of hypercarbia, tachycardia, and rapid increase in temperature (Burkman et al. 2007;Visoiu et al. 2014). Outside of the operating room, MH is diagnosed by muscle contracture tests (Larach 1989;Ording et al. 1997) that are highly sensitive to abnormal myoplasmic Ca 2+ regulation. ...
Article
Full-text available
Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.
... At least 50% of patients had previous anesthesia without any problems. The signs of malignant hyperthermia usually appear during surgery but can develop in the postoperative period and time for first signs could differ among anesthetic drugs (120). Rarely, attacks of malignant hyperthermia have been triggered by exercise, ingestion of caffeine, and stress. ...
Article
Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features, and possible underlying cellular mechanisms.
... Ergebnisse epidemiologischer Studien zeigten, dass die aktuell genutzten Anästhetika eine wesentlich geringere Triggerpotenz aufweisen als früher gebräuchliche Anästhetika, wie zum Beispiel Halothan [74,75]. Vor allem eine kombinierte Anwendung volatiler Anästhetika mit dem Muskelrelaxans Succinylcholin scheint eine hohe Triggerpotenz aufzuweisen [70] ...
... 16 The frequency of reported unique first signs in malignant hyperthermia cases is as follows: hypercarbia, 30.7%; masseter spasm, 24.8%; and sinus tachycardia, 21.1%. 17 In this case, hypercarbia was noted at 5:00 PM, sinus tachycardia was noted at 5:30 PM, and masseter spasm was noted at 5:45 PM (Figs 1, 2). So, as it is most commonly noted, the unexplained rise in the EtCO 2 level was the first sign noted to suggest malignant hyperthermia in this case. ...
Article
Malignant hyperthermia is a rare condition that occurs in susceptible patients exposed to triggering anesthetic agents. It is associated with a high mortality rate if not recognized immediately and treated appropriately. A 52-year-old man presented to our clinic 2 days after an assault for management of jaw pain. A minimally displaced right parasymphyseal fracture and moderately displaced left body fracture of the mandible were diagnosed. There were no known drug allergies. The patient reported no previous difficulty with anesthesia, as well as no known prior adverse reactions to anesthesia in any relatives. The planned surgical intervention was open reduction-internal fixation of bilateral mandibular fractures. The patient received succinylcholine and desflurane during the procedure. A full 70 minutes elapsed before initial signs of hypermetabolism were noted, namely a rise in end-tidal carbon dioxide level. The patient received dantrolene sodium approximately 120 minutes after induction of anesthesia. Signs of hypermetabolism began to abate within 45 minutes of commencement of the malignant hyperthermia treatment protocol. He was subsequently transferred to the surgical intensive care unit for continued management and had a favorable postoperative course. This case underscores the importance of awareness of malignant hyperthermia and its presentation. This condition carries a potential high risk of complications after exposure to triggering anesthetic agents. Taking a complete and detailed history may help to identify potential cases. In this case, it was subsequently discovered that the patient's biological sister had a nearly fatal reaction to general anesthesia several years before this incident. Intraoperative vigilance in the monitoring of vital signs cannot be overemphasized. An increase in end-tidal carbon dioxide values, in addition to other clinical signs that cannot be easily attributed to other causes, should increase the clinical index of suspicion for a diagnosis.
Chapter
The Side Effects of Drugs Annuals is a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions. This review covers publications made between July 2013 and December 2014 on General Anaesthetics and Therapeutic Gases. Specific agents reviewed in this issue are: etomidate, ketamine, thiopentone, methoxetamine, propofol, fospropofol, Dexmedetomidine, desflurane, isoflurane, methoxyflurane, sevoflurane and nitrous oxide.
Article
Maligne hyperthermie is een zeldzame farmacogenetische ‘aandoening’. Deze genetische afwijking heeft in het dagelijks leven geen relevantie en blijft daarom veelal verborgen. Door het gebruik van onder andere depolariserende spierverslappers en/of dampvormige anesthetica kan maligne hyperthermie getriggerd worden. Net als een alligator ligt maligne hyperthermie verborgen, totdat het’toeslaat. Vervolgens is het heel moeilijk om uit de kaken te ontsnappen.
Article
The Side Effects of Drugs Annuals form a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions. This review of the July 2013 to December 2014 publication on neuromuscular blocking agents and skeletal muscle relaxants covers the depolarizing neuromuscular blocking agent, succinylcholine (suxamethonium), non-depolarizing neuromuscular blocking agents, the rocuronium-reversing agent, sugammadex, as well as skeletal muscle relaxants such as baclofen, botulinum toxin, and carisoprodol.
Article
Recently, we analyzed data from the American Society of Anesthesiologist's (ASA) Anesthesia Quality Institute (AQI) to report the United States (U.S.) anesthesia workload by time of day and day of the week. The AQI data were reported using the Central Time zone. Times for the N = 613 calls to the Malignant Hyperthermia Association of the United States (MHAUS) Malignant Hyperthermia (MH) Hotline from August 1, 2012, through March 7, 2014, were adjusted similarly. The MH Hotline effectively provides at all times to each anesthesia group an additional board-certified anesthesiologist who has expertise in managing, diagnosing, and/or preventing MH crises. We compared the timing of calls with the MH Hotline consultants relative to times of most anesthesia workload nationally. The interval 6:30 AM to 6:30 PM Central Time on regular workdays accounted for most (P < 0.0001) calls to the MH Hotline (62.5% ± 2.0% [mean ± standard error]). However, the interval accounted for significantly less than the 82.2% of anesthesia minutes and 84.5% of general anesthesia minutes during that interval nationally (both P < 0.0001). Thus, most calls to the MH Hotline occurred when anesthesia groups nationwide were the busiest. Weekends accounted for 15.3% ± 1.5% of MH Hotline calls, significantly greater than the rates of 5.2% of anesthesia minutes and 4.3% of general anesthesia minutes during weekends nationally (both P < 0.0001). Thus, the MH Hotline was used proportionately more often when anesthesia providers have fewer colleagues present and available for consultation (all P < 0.0001). These findings may be expected of other (future) national support centers for anesthesia.
Article
Background Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene.Methods For this review a large litterature search was carried out and the Swedish MH database consisting of 436 probands who have undergone in vitro muscle contraction test (IVCT) during 1984–2014 was analyzed.ResultsTwelve different MH causative mutations have been found in Swedish patients so far. These mutations lead to a disturbed calcium balance in striated muscle tissue. A muscle biopsy for the IVCT or finding of an approved causative mutation are required for the diagnosis.ConclusionA Malignant Hyperthermia susceptible (MHS) patient should be anesthetized with trigger-free anesthesia. There are a few reports of MH-like reactions in patients unrelated to anesthesia. The outcome is dependent on early recognizing of the reaction and fast disconnection of the trigger agents and administration of dantrolene.
Chapter
Malignant hyperthermia (MH) syndrome is an unusual disorder. Much like an individual who has an allergy, the MH-susceptible patient is often unaware of his or her problem unless there is a family history of anesthesia-related problems that suggest MH or until exposed to the “triggering” agent. MH syndrome may not develop on all exposures. The resemblance to an allergy breaks down, however, on further analysis. MH is an inherited disorder [1]. Patients develop a hypermetabolic condition on exposure to drugs that are generally used to produce general anesthesia such as isoflurane, halothane, desflurane, and sevoflurane or skeletal muscle paralysis, namely, succinylcholine [2]. The pathophysiologic change in MH relates to an uncontrolled increase of intracellular calcium in skeletal muscle that leads to hypermetabolism, depletion of energy sources, acidosis, and membrane breakdown [1–3]. Untreated, MH syndrome is fatal in most cases. With prompt discontinuation of trigger agents and administration of the drug dantrolene [4], mortality may be close to zero [5]. This chapter discusses clinical presentation, pathophysiology, molecular genetics, diagnosis, treatment, and sources of information for this unusual cause of anesthetic morbidity and mortality.
Chapter
Malignant hyperthermia (MH) syndrome is an unusual disorder. Much like an individual who has an allergy, the MH-susceptible patient is often unaware of his or her problem unless there is a family history of anesthesia-related problems that suggest MH or until exposed to the “triggering” agent. MH syndrome may not develop on all exposures. The resemblance to an allergy breaks down, however, on further analysis. MH is an inherited disorder [1]. Patients develop a hypermetabolic condition on exposure to drugs that are generally used to produce general anesthesia such as isoflurane, halothane, desflurane, and sevoflurane or skeletal muscle paralysis, namely, succinylcholine [2]. The pathophysiologic change in MH relates to an uncontrolled increase of intracellular calcium in skeletal muscle that leads to hypermetabolism, depletion of energy sources, acidosis, and membrane breakdown [1–3]. Untreated, MH syndrome is fatal in most cases. With prompt discontinuation of trigger agents and administration of the drug dantrolene [4], mortality may be close to zero [5]. This chapter discusses clinical presentation, pathophysiology, molecular genetics, diagnosis, treatment, and sources of information for this unusual cause of anesthetic morbidity and mortality.
Chapter
The safe conduct of anesthesia requires a clear understanding of the child’s underlying medical conditions and their anesthetic implications. The child with a URTI is at increased risk for airway complications but such children should only be cancelled if he/she is wheezing, has rhonchi, is febrile or has behavioral changes. Obesity presents numerous physiological and pharmacological challenges that are discussed. Children with sickle cell disease may require preoperative transfusion to reduce risk (to Hb 10 g%), should be well hydrated, and receive oxygen in the perioperative period. Diabetic children should be scheduled as the first case of the day and managed according to their endocrinologist. Down syndrome presents several challenges including the airway and cardiac disease. Malignant hyperthermia is a potentially fatal crisis that requires careful planning and teamwork for successful management. Mitochondrial myopathies and the muscular dystrophies require careful preoperative assessment and an understanding of the anesthetic implications.
Article
Background: Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group. We hypothesized that there would be age-related differences in the clinical characteristics. Methods: A retrospective analysis of MH data collected in our database during 1960 to 2020 was performed to identify pediatric subjects (≤18 years) with a Clinical Grading Scale of ≥35, indicating "very likely" or "almost certain" MH. We compared clinical characteristics among the 0 to 24 month, 2 to 12 year, and 13 to 18 year (youngest, middle, and oldest, respectively) age groups. Results: Data were available for 187 patients: 15 in the youngest age group, 123 in the middle-aged group, and 49 in the oldest age group. Of these, 55 patients (29.4%) had undergone muscle biopsy and muscle contracture test. The mortality rates during the study period were 13.3%, 13.8%, 20.4%, and 15.5% in the youngest, middle, and oldest cohorts and overall, respectively. In contrast, the overall mortality rate from 2000 to 2020 was 8.8%. The most frequent initial symptoms of MH were elevated temperature (46.7%) and generalized muscular rigidity (26.7%) in the youngest cohort, masseter spasm (35.0%) and generalized muscular rigidity (19.5%) in the middle cohort, and elevated end-tidal carbon dioxide (26.5%) and tachycardia (22.4%) in the oldest cohort. Physical examination revealed that elevated temperature, sinus tachycardia, and respiratory acidosis occurred frequently in all groups. The middle cohort had high frequencies of masseter spasm (58.4%; P = .02) and dark urine (75.5%; P = .01) compared to those in the oldest groups, and had a higher peak creatine kinase level compared to those in the 3 groups. Skeletal muscle symptoms tended to be more common in patients administered succinylcholine (generalized muscular rigidity, P = .053; masseter spasm, P < .0001; dark urine, P < .0001). In particular, masseter spasm and dark urine were more common in the middle cohort when succinylcholine was administered (masseter spasm: versus youngest cohort, P = .06, versus oldest cohort, P = .027; dark urine: versus youngest cohort, P = .0072, versus oldest cohort, P = .0015). Conclusions: The clinical characteristics of pediatric patients with MH vary according to age group. The difference in initial symptoms of MH depending on age group is noteworthy information for the early diagnosis of MH.
Article
Malignant hyperthermia (MH) is a severe hypermetabolic disorder associated with dysregulation of calcium homeostasis and is triggered by inhalational anesthetics (isoflurane, sevoflurane, desflurane) and a depolarizing muscle relaxant (succinylcholine). We report the case of a 16-day-old infant undergoing laparoscopic surgery. The patient developed hyperthermia and hypercarbia with muscle rigidity. After the diagnosis of MH, dantrolene was administered with sufficient hydration. The patient was transferred to the pediatric intensive care unit for monitoring and treatment of acute renal injury due to myoglobinuria. Subsequently, two variants of the ryanodine receptor 1 (RYR1) gene were identified in the patient as the mutation point at c.1589G > A p.Arg530His and c.1841G > T p.Arg614Leu, which are known to be associated with MH. This was a rare case of MH in a 16-day-old infant that might be related to two RYR1 mutations inherited from the parents.
Article
Rhabdomyolysis, the release of myoglobin and other cellular breakdown products from necrotic muscle tissue, is seen in patients with crush injuries, drug overdose, malignant hyperthermia, muscular dystrophy, and with increasing frequency in obese patients undergoing routine procedures. For the perioperative clinician, managing the resultant shock, hyperkalemia, acidosis, and myoglobinuric acute kidney injury can present a significant challenge. Prompt recognition, hydration, and correction of metabolic disturbances may reduce or eliminate the need for long-term renal replacement therapy. This article reviews the pathophysiology and discusses key issues in the perioperative diagnosis, risk stratification, and management of rhabdomyolysis.
Article
Objective: Review current literature and guidelines for malignant hyperthermia in the context of neurotologic surgery. Patient: A case of malignant hyperthermia during vestibular schwannoma surgery, in a patient previously exposed to anesthesia. Interventions: Excision of vestibular schwannoma, acute management of malignant hyperthermia. Main outcome measures: Knowledge of the basic pathophysiology, clinical manifestations, and treatment protocols for malignant hyperthermia. Results: Rapid termination of the procedure and appropriate modifications in surgical technique permitted expeditious treatment of malignant hyperthermia and prevented its lethality. Conclusions: Malignant hyperthermia is a rare and lethal condition that may arise in neurotologic surgery, even in patients who have previously received general anesthesia. The neurotologic surgeon has a role in early recognition and expeditious termination of surgery to help reduce its mortality.
Chapter
Die maligne Hyperthermie (MH) ist eine metabolische Myopathie, die durch volatile Inhalationsanästhetika und depolarisierende Muskelrelaxanzien ausgelöst wird. Durch unkontrollierte intramuskuläre Kalziumfreisetzung kann sich innerhalb von Minuten bis Stunden eine lebensbedrohliche Stoffwechselentgleisung entwickeln (sog. MH-Krise). Anlageträger für eine maligne Hyperthermie sind im alltäglichen Leben nicht erkennbar. Frühzeitige Diagnose und Therapie einer MH-Krise entscheiden über das Schicksal des Patienten.
Article
Résumé Les myopathies sont des complications relativement communes des expositions aux agents environnants. Les plus fréquentes sont celles induites par les molécules médicamenteuses utilisées en pratique clinique. Certaines d’entre elles exercent des actions inattendues sur les tissus musculaires à l’origine d’un spectre très large de signes cliniques. Globalement, leurs effets sur les muscles squelettiques conduisent à des situations temporairement invalidantes (faiblesses musculaires et myalgies modérées) qui peuvent s’aggraver sous la forme d’un syndrome de rhabdomyolyse avec une élévation importante des créatine-kinases sériques (CK). Les lésions histopathologiques engendrées varient selon l’agent inducteur. Elles peuvent être nécrotiques (acide ɛ aminocaproïque et émétine), atrophiques (glucocorticoïdes), inflammatoires (d-pénicillamine) ou liées à des dysfonctionnements mitochondriaux (zidovudine) et lysosomaux (chloroquine). Plusieurs mécanismes d’action peuvent être déclenchés. Le muscle peut être une cible pour certains agents exogènes à travers des actions directes affectant les composants myocytaires (statines, glucocorticoïdes, antimitotiques, immunosuppresseurs, etc.) ou indirectes via des troubles fonctionnels. Ces derniers sont déclenchés par des interférences neuromusculaires (neuroleptiques, curares, etc.) et des dysfonctionnements du système endocrinien (glucocorticoïdes), immunitaire (d-pénicillamine) et hydroélectrolytique (diurétiques et laxatifs). Enfin, le nombre important et sans cesse croissant des médicaments supposés inducteurs de myopathies iatrogènes impose une vigilance particulière des praticiens et une prise en charge efficace des patients. L’algorithme décisionnel proposé portant sur la prévention, le diagnostic et le traitement de ces myopathies serait d’un grand apport dans l’amélioration du confort et de la qualité de vie des patients.
Article
Full-text available
What we already know about this topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. Methods: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. Results: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. Conclusions: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.
Article
Malignant hyperthermia (MH) can be fatal if the crisis is not appropriately treated. It is an inherited disease usually triggered by the administration of volatile inhalational anesthetics and/or succinylcholine, a muscle relaxant. In a patient with suspected MH, the mechanism of calcium release from storage in the sarcoplasmic reticulum in the skeletal muscle is abnormally accelerated. Unexplained hypercarbia representing >55 mmHg of end-tidal carbon dioxide, tachycardia, and muscle rigidity (including masseter muscle rigidity) are early signs of the initiation of MH, because the metabolism is accelerated. The body temperature can rise by >0.5 °C/15 min and may reach ≥40 °C. Respiratory and metabolic acidosis, arrhythmia, cola-colored urine, increased levels of serum potassium, and tented T-waves on electrocardiogram are common and can lead to cardiac arrest. MH should be treated by discontinuation of the triggering agents, administration of intravenous dantrolene (initially 1 mg/kg), and reduction of the body temperature. Early diagnosis and sufficient dantrolene with body temperature reduction are essential to relieve the patient’s MH crisis. This guideline in Japanese translation has been posted on the website: http://www.anesth.or.jp/guide/pdf/guideline_akuseikounetsu.pdf.
Article
A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association to either clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca(2+) homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
Article
Full-text available
We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.
Article
Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist.
Article
This paper considers the use of rank sums from a combined ranking of k independent samples in order to decide which populations differ. Such a procedure is suggested as a convenient alternative to making separate rankings for each pair of samples, and the two methods are compared. Asymptotic use of the normal tables is given and the treatment of ties is discussed. A numerical example is given.
Article
When a study uses an ordinal outcome measure with unknown differences in the anchors and a small range such as 4 or 7, use of the Wilcoxon rank sum test or the Wilcoxon signed rank test may be most appropriate. However, because nonparametric methods are at best indirect functions of standard measures of location such as means or medians, the choice of the most appropriate summary measure can be difficult. The issues underlying use of these tests are discussed. The Wilcoxon-Mann-Whitney odds directly reflects the quantity that the rank sum procedure actually tests, and thus it can be a superior summary measure. Unlike the means and medians, its value will have a one-to-one correspondence with the Wilcoxon rank sum test result. The companion article appearing in this issue of Anesthesia & Analgesia ("Aromatherapy as Treatment for Postoperative Nausea: A Randomized Trial") illustrates these issues and provides an example of a situation for which the medians imply no difference between 2 groups, even though the groups are, in fact, quite different. The trial cited also provides an example of a single sample that has a median of zero, yet there is a substantial shift for much of the nonzero data, and the Wilcoxon signed rank test is quite significant. These examples highlight the potential discordance between medians and Wilcoxon test results. Along with the issues surrounding the choice of a summary measure, there are considerations for the computation of sample size and power, confidence intervals, and multiple comparison adjustment. In addition, despite the increased robustness of the Wilcoxon procedures relative to parametric tests, some circumstances in which the Wilcoxon tests may perform poorly are noted, along with alternative versions of the procedures that correct for such limitations.
Article
Malignant hyperthermia (MH) is a potentially fatal complication of general anesthesia triggered by volatile anesthetics. In animal studies, sevoflurane has been reported to be a weak triggering agent. The aim of this study was to evaluate the clinical severity of sevoflurane-induced MH compared to isoflurane. From the Japanese MH database containing information for 520 MH cases since 1961, we analyzed 147 cases classified by the MH Clinical Grading Scale (CGS) as 'very likely' or 'almost certain', accumulated from 1990 to 2009. Sevoflurane without succinylcholine (S-SCh (-) group) was given to 48 cases, and isoflurane without succinylcholine (I-SCh (-) group) was given to 30. Variables studied were outcome, CGS score, CGS rank, the first MH sign, and time from induction to onset of MH (occurrence time). Clinical signs and maximum laboratory data from six processes of the CGS were also analyzed. Each of the Mann-Whitney U-test or the unpaired t-test was used for group comparisons. Mortality was 8.3% in the S-SCh (-) group and 10.0% in the I-SCh (-) group (P = 0.803). The CGS scores were 53.4 (SD, 12.2) and 52.3 (11.7) (P = 0.691), respectively. The five processes of the CGS did not differ between groups. Median occurrence times were 72.5 minutes (range, 36.3-127.5) and 65.0 minutes (30.0-131.3), respectively (P = 0.890). There were no clinically apparent differences between MH triggered by sevoflurane and isoflurane, and thus no evidence to support the postulate that sevoflurane is a weak or weaker MH triggering agent.
Article
Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown. De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes. Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM). The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.
Article
Over the past 50 yr, many drugs have been implicated as triggers of malignant hyperthermia (MH), a potentially fatal pharmacogenetic disorder of skeletal muscle calcium regulation. This review discusses the potent inhalation agents as the principal triggers and evidence that the modern agents, desflurane, sevoflurane, and isoflurane, can cause florid MH reactions in the same way as halothane but also are associated with reactions whose onset is delayed for several hours into anaesthesia. There is evidence that the triggering of MH by drugs is dose-dependent but the minimum dose that will trigger the condition is unknown. This has implications for the preparation of anaesthetic machines when used for known or suspected MH patients. While succinylcholine enhances the response of potent inhalation anaesthetics, its role as an inherent trigger of the condition is controversial. Non-depolarizing neuromuscular blocking drugs appear to protect against the development of MH and this may be by blocking excitation-coupled calcium entry-a recently described route of skeletal muscle calcium entry that may also explain the mechanism of the effect of succinylcholine in MH. Another mechanism for extracellular calcium influx, store-operated calcium entry, is activated in MH muscle and may explain how a triggered reaction is sustained. Finally, reports of drugs that have been implicated as additional triggers of MH over the past 10 yr are discussed.
Article
Malignant hyperthermia (MH) is a rare but life-threatening disease that occurs during general anesthesia. The actual prevalence of MH remains unclear, and the association between MH and various anesthetic drugs remains controversial because of a lack of universal reporting. Using the Japanese Diagnosis Procedure Combination database, we collected data of inpatients who had general anesthesia between July and December 2006-2008. Patients' age, gender, diagnoses, procedures, and the use of drugs during anesthesia, including volatile agents, muscle relaxants, and propofol, were investigated. Univariate comparisons were made to examine the relationship of each anesthetic drug or demographic factor with the occurrence of MH. Of 1,238,171 surgical patients undergoing general anesthesia, we identified 17 MH patients. Only one in-hospital death was identified. Men were significantly more likely to contract MH(odds ratio: 3.49; 95% CI 1.14 -10.7; P=0.029). No MH patient was found among 19,871 suxamethonium users. The prevalence of MH was relatively high in users of sevoflurane and rocuronium compared with nonusers but was not statistically significant [corrected].. No single drug was significantly associated with the occurrence of MH. Data should be continuously compiled, and further analyses with larger numbers of cases are necessary to identify possible causative agents.
Article
Malignant hyperthermia (MH), manifesting as MH crisis during and/or after general anesthesia, is a potentially fatal disorder in response to volatile anesthetics and depolarizing muscle relaxants. Though typical features of MH episode can provide clues for clinical diagnosis, MH susceptibility is confirmed by in vitro caffeine-halothane contracture test (CHCT) in western countries. It is traditionally thought that MH has less incidence and fewer typical characteristics in Chinese population than their western counterparts because of the different genetic background. In this study, we investigated the clinical features of MH in Chinese cases and applied the clinical grading scale and CHCT for diagnosis of MH. A cluster of three patients with MH, from January 2005 to December 2007, were included in the study. Common clinical presentations and the results of some lab examinations were reported in detail. The method of the clinical grading scale of diagnosis of MH was applied to estimate the qualitative likelihood of MH and predict MH susceptibility. Muscle fibers of femoral quadriceps of the patients were collected and CHCT was performed to confirm the diagnosis of MH. The clinical grading scales of diagnosis of the disease for these cases were all ranked grade D6, suggesting almost diagnosed ones. And the results of caffeine test were positive correspondingly, indicating that the patients should be diagnosed as MH susceptibility (MHS) according to diagnostic criteria of the North America MH group, which were already confirmed by clinical presentations and biochemical results. These Chinese cases manifest as MH crisis. The clinical grading scale of diagnosis of MH may provide clues for clinical diagnosis. CHCT can also be used in confirming diagnosis of MH in Chinese cases though they have different genetic background from their western counterparts.
Article
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder with an estimated mortality of less than 5%. The purpose of this study was to evaluate the current incidence of MH and the predictors associated with in-hospital mortality in the United States. The Nationwide Inpatient Sample, which is the largest all-payer inpatient database in the United States, was used to identify patients discharged with a diagnosis of MH during the years 2000-2005. The weighted exact Cochrane-Armitage test and multivariate logistic regression analyses were used to assess trends in the incidence and risk-adjusted mortality from MH, taking into account the complex survey design. From 2000 to 2005, the number of cases of MH increased from 372 to 521 per year. The occurrence of MH increased from 10.2 to 13.3 patients per million hospital discharges (P = 0.001). Mortality rates from MH ranged from 6.5% in 2005 to 16.9% in 2001 (P < 0.0001). The median age of patients with MH was 39 (interquartile range, 23-54 yr). Only 17.8% of the patients were children, who had lower mortality than adults (0.7% vs. 14.1%, P < 0.0001). Logistic regression analyses revealed that risk-adjusted in-hospital mortality was associated with increasing age, female sex, comorbidity burden, source of admission to hospital, and geographic region of the United States. The incidence of MH in the United States has increased in recent years. The in-hospital mortality from MH remains elevated and higher than previously reported. The results of this study should enable the identification of areas requiring increased focus in MH-related education.
Article
Mouth opening and the resistance to opening developed by the muscles of mastication were measured in 63 children anesthetized with halothane and relaxed with succinylcholine, pancuronium, or vecuronium. Measurement of mouth opening, induced by a constant test force, was made when each patient was deeply anesthetized, as judged by clinical parameters. Succinylcholine, vecuronium, or pancuronium was then administered. The mouth opening measurement was repeated immediately after the loss of limb muscle twitch response and 45 s following the loss of twitch response. For the 24 patients receiving succinylcholine, there was a significant reduction in mean mouth opening (P less than 0.0001) and a significant increase in jaw stiffness (P less than 0.0001) immediately after limb relaxation. Forty-five seconds after full limb relaxation was attained, the mean mouth opening was still reduced (P less than 0.0001) and the mean jaw stiffness was still increased (P less than 0.0003) in the succinylcholine group. Patients receiving either vecuronium or pancuronium did not show a significant change of mouth opening or jaw stiffness following limb relaxation. Three patients, who received succinylcholine, required several attempts at tracheal intubation due to increased resistance to mouth opening. Anesthesia and surgery proceeded in all patients. None of the patients developed malignant hyperthermia. In view of the fact that a reduction in mouth opening was a constant finding when succinylcholine was administered during halothane anesthesia, the assumption that isolated "masseter spasm" or jaw stiffness heralds malignant hyperthermia should be reconsidered.
Article
Questionnaires were sent to all anesthesia departments in Denmark to determine the total number of anesthetics given per year, and the distribution of different types of anesthesia. All cases of suspected malignant hyperthermia forwarded to the Danish Malignant Hyperthermia Register during a 6.5 yr period were reviewed and divided into subgroups according to clinical criteria. The incidence of suspected malignant hyperthermia in these subgroups was calculated in relation to type of anesthesia. The results are based on information about 386,250 anesthetics and 154 cases of suspected malignant hyperthermia. All cases of malignant hyperthermia occurred during general anesthesia, and more than 75% during anesthesia with a combination of potent inhalation agents and succinylcholine. The incidence of fulminant malignant hyperthermia was low: 1 in 250,000 total anesthetic procedures, but 1 in 62,000 anesthetic procedures with a combination of potent inhalation agents and succinylcholine. Masseter spasm occurred in 1 of 12,000 anesthetic procedures in which succinylcholine was administered. Suspicion of malignant hyperthermia was raised in 1 of 16,000 anesthetics total, but in 1 of 4,200 anesthetics with the above-mentioned combination of agents.
Article
The diagnosis of an acute malignant hyperthermia reaction by clinical criteria can be difficult because of the nonspecific nature and variable incidence of many of the clinical signs and laboratory findings. Development of a standardized means for estimating the qualitative likelihood of malignant hyperthermia in a given patient without the use of specialized diagnostic testing would be useful for patient management and would promote research into improved means for diagnosing this disease. Using the Delphi method and an international panel of 11 experts on malignant hyperthermia, a multifactor malignant hyperthermia clinical grading scale comprising standardized clinical diagnostic criteria was developed for classification of existing records and for application to new patients. This scale ranks the qualitative likelihood that an adverse anesthetic event represents malignant hyperthermia (malignant hyperthermia event rank) and that, with further investigation of family history, an individual patient will be diagnosed as malignant hyperthermia susceptible (malignant hyperthermia susceptibility rank). The assigned rank represents a lower bound on the likelihood of malignant hyperthermia. The clinical grading scale requires the anesthesiologist to judge whether specific clinical signs are appropriate for the patient's medical condition, anesthetic technique, and surgical procedure. The malignant hyperthermia clinical grading scale is recommended for use as an aid to the objective definition of this disease. It use may improve malignant hyperthermia research by allowing comparisons among well-defined groups of patients. This clinical grading system provides a new and comprehensive clinical case definition for the malignant hyperthermia syndrome.
Article
The agonist actions of succinylcholine (SCh) have recently come under study because of their involvement in the clinical problem of masseter muscle rigidity, and their possible involvement in malignant hyperthermia. The authors investigated factors affecting SCh-induced contractures in an animal preparation. Rats were anesthetized with either halothane (1-2%) or pentobarbital. Resting and twitch isometric tension were measured from the jaw muscles. Succinylcholine (500 or 750 micrograms/kg) was administered intravenously, producing increases in resting tension (i.e., contractures). Jaw muscle temperature was controlled by radiant heat. Succinylcholine increased jaw muscle tension for several seconds. These contractures exhibited tachyphylaxis, and were antagonized by vecuronium (0.8-1.5 mg/kg), indicating mediation by acetylcholine receptors (AChR). In the presence of 2% halothane, contractures were tenfold greater at a rectal temperature of 41 degrees C than at 37 degrees C. In contrast, under 50 mg/kg intraperitoneal pentobarbital anesthesia, contractures were not affected by rectal temperature. Neither the half-decay time of contracture nor twitch tension (0.2 Hz, preceding SCh) were increased in the presence of halothane at 41 degrees C. In a set of experiments in which rectal temperature was maintained at 37 degrees C but jaw temperature was varied between 36-41 degrees C, there was a significant regression of SCh-induced jaw contracture on temperature in the presence of halothane. In contrast, there was no significant relationship between jaw temperature and contracture in the presence of pentobarbital. These results in the rat demonstrate a temperature-dependent interaction between halothane and SCh that has not previously been described.
Article
Desflurane (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalational anesthetic currently under investigation for use in humans. Recently, the authors showed that desflurane is a trigger of malignant hyperthermia (MH) in susceptible swine. To date, there has been no in vivo comparison of the relative ability of inhalational anesthetics to trigger MH. The effects of desflurane, isoflurane, and halothane on six MH-susceptible purebred and six MH-susceptible mixed-bred Pietrain swine were examined. The animals were exposed to 1 MAC and 2 MAC (if MH was not triggered after 1 MAC hour) doses of each of the three volatile anesthetics in random sequence at 7-10-day intervals and changes in end-tidal CO2, arterial blood gases, serum lactate, core and muscle temperature, blood pressure, and heart rate were measured. There was a statistical difference between anesthetics in the time required to trigger MH; halothane exposure resulted in the fastest onset of an MH episode (20 +/- 5 min), compared with isoflurane (48 +/- 24 min) and desflurane (65 +/- 28 min), both of which required significantly longer exposures. There was no statistical difference between the MH purebred and mixed-bred swine in the time required to trigger MH (defined as a PaCO2 of 70 mmHg) with a given agent, and time to triggering was also independent of the order of exposure to the three anesthetics. Malignant hyperthermia susceptibility was confirmed in ten surviving animals, by both in vivo succinylcholine challenge and in vitro contracture testing. Although all three volatile anesthetics triggered MH, exposure to halothane resulted in significantly shorter times to MH triggering when compared with desflurane and isoflurane.
Article
A case of malignant hyperthermia (mh) in a 27-year-old man is described. In a first anaesthesia using isoflurane and succinylcholine, the end-tidal CO(2) rose from 39 to 49 mmHg 2.75 h post-intubation and the body temperature rose to 39.8 degrees C 14 h post-intubation but was normal again the next day. In a second anaesthesia using the same medication, the maximal end-tidal CO(2) was 44 mmHg and the body temperature rose to 39 degrees C after 9 h. After 4 days, the fever rose to 40 degrees C, and to 42 degrees C when death occurred 10 days after the second anaesthesia. Masseter spasms or muscle rigidity were never present. According to the death certificate, death was due to multi-organ failure from sepsis. At autopsy, the skeletal muscles were pale and oedematous. Histology demonstrated focal necroses in the skeletal muscles, shock kidneys with myoglobin excretion and myoglobin clots in small blood vessels of the lungs. Hence, the postmortem diagnosis "malignant hyperthermia" was established but accusations of medical maltreatment were rejected because of the atypical and protracted clinical course and because uncharacteristic signs of malignant hyperthermia were attributable to the clinically suspected sepsis.
Article
We investigated the transition of clinical signs of fulminant-type malignant hyperthermia (f-MH) by analyzing a database consisting of 383 cumulative cases of f-MH from 1961 to 2004. The cases were divided by time period into group 1 (1961-1984), group 2 (1985-1994), and group 3 (1995-2004). The variables considered were age, sex, type of agents used (succinylcholine and volatile anesthetics), dantrolene administration, clinical signs, laboratory data, and mortality. The level of statistical significance was considered to be less than 5%. Groups 1, 2, and 3 consisted of 196, 127, and 60 cases, respectively. In groups 1, 2, and 3, the rates of dantrolene administration were 18.4%, 93.6%, and 86.7%; the rates of occurrence of ventricular arrhythmia were: 75.2%, 55.6%, and 35.0%; and the rates of generalized muscle rigidity were 64.7%, 60.9%, and 23.9%, respectively. The mortality rate decreased over time, from 42.3% in group 1, to 15.0% in group 2 and group 3. We considered that this decrease occurred because of the increased use of dantrolene and the early diagnosis of malignant hyperthermia in the latter two groups.
Article
The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes. The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple comparisons. Of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death. The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr). Associated factors were muscular build (odds ratio, 18.7; P = 0.0016) and disseminated intravascular coagulation (odds ratio, 49.7; P < 0.0001). Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide (216 vs. 87 min; P = 0.003). Unrelated factors included patient or family history, anesthetic management, and the MH episode. Modern US anesthetic practice did not prevent MH-associated cardiac arrest and death in predominantly young, healthy patients undergoing low- to intermediate-risk surgical procedures.
Article
Mice with a malignant hyperthermia mutation (Y522S) in the ryanodine receptor (RyR1) display muscle contractures, rhabdomyolysis, and death in response to elevated environmental temperatures. We demonstrate that this mutation in RyR1 causes Ca(2+) leak, which drives increased generation of reactive nitrogen species (RNS). Subsequent S-nitrosylation of the mutant RyR1 increases its temperature sensitivity for activation, producing muscle contractures upon exposure to elevated temperatures. The Y522S mutation in humans is associated with central core disease. Many mitochondria in the muscle of heterozygous Y522S mice are swollen and misshapen. The mutant muscle displays decreased force production and increased mitochondrial lipid peroxidation with aging. Chronic treatment with N-acetylcysteine protects against mitochondrial oxidative damage and the decline in force generation. We propose a feed-forward cyclic mechanism that increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death. The cycle eventually produces a myopathy with damaged mitochondria.