The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®): A clinical part-randomised phase 1 study in healthy volunteers.

BACKGROUND: Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically. OBJECTIVES: Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation. DESIGN: Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings. SETTING: Single clinical centre in the UK, April to July 2021. PARTICIPANTS: Twenty-one healthy male and female individuals. INTERVENTIONS: Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas. MAIN OUTCOME MEASURES: Overall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. RESULTS: Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®. CONCLUSION: NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. TRIAL REGISTRATION: EudraCT Number: 2020-005719-35, MHRA approval.

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants.

Remimazolam is a novel general anesthetic and its safety in patients with malignant hyperthermia (MH) is unknown. We used myotubes derived from the skeletal muscle of patients with MH to examine the response to ryanodine receptor 1 (RYR1) agonist and remimazolam in MH-susceptible patients. Patients underwent muscle biopsy for the Ca2+-induced Ca2+ release (CICR) rate test, a diagnostic tool for MH in Japan. Ten patients had myotubes obtained from skeletal muscle cultures, and the genes associated with malignant hyperthermia in these patients were analyzed. The EC50 of caffeine, cresol, and remimazolam to induce intracellular calcium concentration change were compared between myotubes from CICR-negative genetic test patients and myotubes from other patients. Eight of the ten were CICR-positive, five of whom had RYR1 causative gene mutations or variants. Two patients had CICR-negative genetic tests, and as expected had the highest EC50 (the concentration of a drug that gives a half-maximal response) in response to caffeine, 4CmC and remimazolam. Three patients had a positive CICR but no known variants in RYR1 or CACNA1S (voltage-gated calcium channel subunit alpha1S). Myotubes in these patients had significantly lower EC50s for all agents than myotubes in CICR-negative patients. When myotubes from a patient who was CICR-negative and had no gene variant were used as a control, myotubes from CICR-positive patients were more hyper-responsive than controls to all stimulants used. The EC50 for remimazolam was lowest for myotubes from CICR-positive, RYR1-mutant patients, at 206 µM (corresponding to 123 µg/mL). The concentration was more than 80-times higher than the clinical concentration. RYR1 gene variants in R4645Q and W5020G were shown to be causative gene mutations for MH. Intracellular calcium in myotubes from MH patients are elevated at high concentrations of remimazolam but not at clinically used concentrations of remimazolam. Remimazolam appears to be safe to use in patients with MH.

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. The therapeutic effect of dantrolene is the result of a direct inhibitory action on the RyR1 channel, thus suppressing aberrant Ca2+ release from the sarcoplasmic reticulum. Despite the almost identical dantrolene-binding sequence exits in all three mammalian RyR isoforms, dantrolene appears to be an isoform-selective inhibitor. Whereas RyR1 and RyR3 channels are competent to bind dantrolene, the RyR2 channel, predominantly expressed in the heart, is unresponsive. However, a large body of evidence suggests that the RyR2 channel becomes sensitive to dantrolene-mediated inhibition under certain pathological conditions. Although a consistent picture of the dantrolene effect emerges from in vivo studies, in vitro results are often contradictory. Hence, our goal in this perspective is to provide the best possible clues to the molecular mechanism of dantrolene's action on RyR isoforms by identifying and discussing potential sources of conflicting results, mainly coming from cell-free experiments. Moreover, we propose that, specifically in the case of the RyR2 channel, its phosphorylation could be implicated in acquiring the channel responsiveness to dantrolene inhibition, interpreting functional findings in the structural context.

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia-Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability.

BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994-2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%-35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%-19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%-90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5-28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene ( RYR1 ) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3-30.9; P = .013). Dantrolene median dose was 50 (25-400) and 200 (25-400) mg·day -1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

Intravenous dantrolene in hypermetabolic syndromes: a survey of the U.S. Veterans Health Administration database.

BACKGROUND: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings. METHODS: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons. RESULTS: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene. CONCLUSIONS: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.

Donating Dantrolene: Development and Implementation of a Malignant Hyperthermia Program in a Scarce Resource Setting.

Intravenous dantrolene is the first-line treatment of malignant hyperthermia (MH), however, it is not always accessible in lower-middle income countries (LMICs). Facilities in the United States are in a transition period where dantrolene is being replaced with Ryanodex, therefore, there is an opportunity for excess dantrolene to be utilized in LMICs where neither dantrolene nor Ryanodex exist. Thirty-six vials of recently expired, unused dantrolene were obtained for a hospital in a LMIC and an MH program was developed in conjunction with the Lao Friends Hospital for Children (LFHC) anesthesia providers, LFHC liaison, LFHC leadership team, and an expert in the field of MH. Components of the MH program included developing a facility-specific protocol, treatment guidelines, supply list, and educational tools. A designated MH drawer was also created in preparation for an MH event. By procuring dantrolene and implementing an MH program in a facility where no MH protocol, treatment guidelines, supply list, or educational tools existed, LFHC is better equipped to handle a potentially lethal scenario.

Impact of a digital manual for guidance on malignant hyperthermia: patient education.

BACKGROUND: Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties due to a lack of knowledge about MH. As informational materials could increase knowledge and adherence to prevention/therapy, digital information about rare diseases validated for patients is needed. Our objective was to evaluate the following: (1) the impact of digital manuals on the knowledge/quality of life of MH patients and (2) access to MH services. MATERIALS AND METHODS: Fifty MH-susceptible patients filled out a virtual questionnaire twice (demographic/economic/clinical data, MH knowledge and impact on daily life, and SF-36 quality of life). Test groups 1 (n = 17) and 2 (n = 16) were evaluated 30 and 180 days after receiving a digital manual, and the control group (n = 17; without manual) was evaluated after 180 days. We collected the MH service data about the number of contacts. RESULTS: Twenty-four (48%) patients reported problems in personal/professional life, sports, clinical/surgical/dental treatments, and military service, in addition to concerns about emergency care and complaints of sequelae. The percentage of correct answers in the second MH knowledge questionnaire increased for test group 2 (62% vs. 74.1%; unpaired t test, p < 0.01), was significantly greater in test groups 1 (68.1%) and 2 (74.1%) than in the control group (56.5%; Kruskal-Wallis, p < 0.05), and correlated with more time studying the manual and reports of MH-related problems (multiple regression, p < 0.05). CONCLUSIONS: The digital manual improved patients' MH knowledge. Online contacts with the MH service increased, allowing greater information dissemination. As informational materials could increase knowledge/adherence to prevention/therapy, digital information about MH validated for patients should be implemented.

The effects of dantrolene in the presence or absence of ryanodine receptor type 1 variants in individuals predisposed to malignant hyperthermia.

Dantrolene is currently the only drug known to specifically treat malignant hyperthermia (MH) crises. Although dantrolene attenuates Ca2+ disorders by acting mainly on the ryanodine receptor type 1 (RYR1), some patients who manifest MH without RYR1 variants have also been successfully treated with dantrolene. Thus, dantrolene appears to have an inhibitory effect on patients with and without RYR1 variants. This study aimed to investigate whether the effects of dantrolene differed depending on the presence or absence of RYR1 variants using muscle cells from MH-predisposed individuals. The study participants were individuals diagnosed with MH predisposition by the Ca2+-induced Ca2+ release rate test. They were genetically tested and divided into two groups: with and without RYR1 variants. We investigated whether these two groups showed differences in the changes in the half-maximal effective concentration (EC50) for caffeine and the resting intracellular Ca2+ concentration ([Ca2+]i) before and after dantrolene administration. Dantrolene administration significantly increased the EC50 (P < 0.0001) and decreased the resting [Ca2+]i (P < 0.0001). The inhibitory effects of dantrolene and the presence of RYR1 variants showed no statistically significant interactions related to the EC50 (P = 0.59) and resting [Ca2+]i (P = 0.21). In conclusion, the presence or absence of RYR1 variants does not appear to influence the effect of dantrolene.

Treatment of Malignant Hyperthermia During Interfacility Transport of a Patient With Methamphetamine Toxicity.

Malignant hyperthermia (MH) is a rare disorder that leads to a hypermetabolic response; if unrecognized, it can quickly lead to serious morbidity and mortality. It is imperative that critical care transport providers are able to recognize and initiate treatment for MH. A 33-year-old man presented to the emergency department with seizures and altered mental status after ingesting methamphetamine. The patient was intubated in the emergency department with succinylcholine and propofol. After intubation, the patient became tetanic, hyperthermic, and hypercarbic. Given the concern for MH, the patient was treated with dantrolene and transported by helicopter air ambulance to the affiliated quaternary care center where he progressed to multiorgan failure and died. MH is a genetic disorder that manifests after exposure to certain stimuli, most notably inhaled anesthetics and succinylcholine. The hypermetabolic response is triggered by unregulated release of intracellular calcium secondary to a dysfunctional calcium channel. MH is often diagnosed clinically. Early clinical manifestations of MH include an increase in end-tidal carbon dioxide, tachycardia, muscle rigidity, and hyperthermia. For prehospital clinicians, the most likely offending agent is succinylcholine. The pharmacologic treatment of MH is dantrolene. Prompt recognition and treatment of MH can decrease morbidity and mortality.

[Therapeutic effects of novel type1 ryanodine receptor inhibitor on skeletal muscle diseases].

Type 1 ryanodine receptor (RyR1) plays a key role in Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling of skeletal muscle. Mutations in RyR1 hyperactivate the channel to cause malignant hyperthermia (MH). MH is a serious complication characterized by skeletal muscle rigidity and elevated body temperature in response to commonly used inhalational anesthetics. Thus far, more than 300 mutations in RyR1 gene have been reported in patients with MH. Some heat stroke triggered by exercise or environmental heat stress is also related to MH mutations in the RyR1 gene. The only drug approved for ameliorating the symptoms of MH is dantrolene, which has been first developed in 1960s as a muscle relaxant. However, dantrolene has several disadvantages for clinical use: poor water solubility which makes rapid preparation difficult in emergency situations and long plasma half-life, which causes long-lasting side effects such as muscle weakness. Here we show that a novel RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively rescues MH and heat stroke in new mouse model relevant to MH. Cpd1 has great advantages of higher water solubility and shorter plasma half-life compared to dantrolene. Our data suggest that Cpd1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations.

RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

Malignant Hyperthermia During Cardiac Surgery Successfully Treated by Deep Hypothermia Using Cardiopulmonary Bypass: A Case Report.

Malignant hyperthermia (MH) is a life-threatening hypermetabolic disorder triggered by volatile anesthetics and/or succinylcholine. We report a case of a 58-year-old patient with a type-A aortic dissection. After induction of general anesthesia, a hypermetabolic reaction was successfully treated by deep hypothermia using cardiopulmonary bypass. Dantrolene became available in theater after the hypermetabolism was already treated successfully by hypothermia. Because of a low suspicion of MH, dantrolene was not administered when it became available. The patient fully recovered, and MH susceptibility was confirmed. Cardiopulmonary bypass should be considered to treat MH in case dantrolene and conservative therapy are unavailable or insufficient.

A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.

Postoperative malignant hyperthermia confirmed by calcium-induced calcium release rate after breast cancer surgery, in which prompt recognition and immediate dantrolene administration were life-saving: a case report.

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.

Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists.

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Caso de hipertermia maligna en paciente intervenida de apendicectomía laparoscópica / Malignant Hyperthermia after a laparoscopic appendicectomy: Case report

Malignant hyperthermia is an hypermetabolic syndrome in which the intracellular calcium receptors are altered. Patients who present compatible symptoms with this symdrome are genetically predisposed. Many of the cases have been described in the surgical area, due to the use of anesthesic drugs and neuromuscular blockers. However, there are some cases with an unknown trigger. The prevalence of the syndrome is very difficult to estimate. The diagnosis and early treatment are pronostic factors predicting the evolution of the syndrome.

La hipertermia maligna es conocida como un síndrome de estimulación masiva del metabolismo, debido a la alteración en la liberación de calcio intracelular. Muchos pacientes que presentan clínica compatible con este síndrome están genéticamente predispuestos. La mayoría de los casos se describen en el ámbito quirúrgico, con el empleo de fármacos anestésicos y determinados relajantes neuromusculares, aunque también existen casos en los que no se halla desencadenante. De prevalencia difícil de estimar, la sospecha diagnóstica y el tratamiento precoz marcan el pronóstico evolutivo de estos pacientes.

Síndrome de hipertermia maligna: una patología infrecuente / Malignant hyperthermia syndrome: A rare entity

Resumen Introducción: El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

Abstract Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Malignant hyperthermia syndrome: A rare entity.

Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Background: Introducción">El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines.

Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.