Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study

Abstract Introduction Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. Objective To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. Methods We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). Results Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). Conclusions Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

Fatigue, depression, and physical activity in patients with malignant hyperthermia: a cross-sectional observational study

Abstract Background Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered by halogenated anesthesia agents/succinylcholine and characterized by hypermetabolism crisis during anesthesia, but also by day-to-day symptoms, such as exercise intolerance, that may alert the health professional. Objective The study aimed to analyze the incidence of fatigue in MH susceptible patients and the variables that can impact perception of fatigue, such as the level of routine physical activity and depression. Methods A cross-sectional observational study was carried out with three groups - 22 patients susceptible to MH (positive in vitro muscle contracture test), 13 non-susceptible to MH (negative in vitro muscle contracture test) and 22 controls (no history of MH). Groups were assessed by a demographic/clinical questionnaire, a fatigue severity scale (intensity, specific situations, psychological consequences, rest/sleep response), and the Beck depression scale. Subgroups were re-assessed with the Baecke habitual physical exercise questionnaire (occupational physical activity, leisure physical exercise, leisure/locomotion physical activity). Results There were no significant differences among the three groups regarding fatigue intensity, fatigue related to specific situations, psychological consequences of fatigue, fatigue response to resting/sleeping, depression, number of active/sedentary participants, and the mean time and characteristics of habitual physical activity. Nevertheless, unlike the control sub-group, the physically active MH-susceptible subgroup had a higher fatigue response to resting/sleeping than the sedentary MH susceptible subgroup (respectively, 5.9 ± 1.9 vs. 3.9 ± 2, t-test unpaired, p< 0.05). Conclusion We did not detect subjective fatigue in MH susceptible patients, although we reported protracted recovery after physical activity, which may alert us to further investigation requirements.

Patient suspected susceptibility to malignant hyperthermia: impact of the disease

Abstract Introduction Malignant Hyperthermia (MH) is an inherited hypermetabolic syndrome triggered by exposure to halogenated anesthetics/succinylcholine. The lack of knowledge regarding this condition might be associated with the rare occurrence of MH reaction and symptoms. Methods This observational study evaluated 68 patients from 48 families with confirmed or suspected MH susceptibility due to medical history of MH reaction or idiopathic increase of creatine kinase or MH-related myopathies. Participants were assessed by a standardized questionnaire and submitted to physical/neurological examination to assess the characteristics of patients with MH, their knowledge about the disease, and the impact suspected MH had on their daily lives. Results Suspected MH impacted the daily life of 50% of patients, creating difficulties in performing surgical/clinical/dental treatment and problems related to their family life/working/practicing sports. The questionnaire on MH revealed a correct answer score of 62.1 ± 20.8 (mean ± standard deviation) on a scale 0 to 100. Abnormal physical/neurological examination findings were detected in 92.6% of susceptible patients. Conclusions Suspected MH had impacted the daily lives of most patients, with patients reporting problems even before MH investigation with IVCT. Patients showed a moderate level of knowledge about MH, suggesting the need to implement continuing education programs. MH susceptible patients require regular follow-up by a health team to detect abnormalities during physical and neurological examination.

Hipertermia maligna / Malignant huperthermia

Carriers of malignant hyperthermia (MH), a subclinical metabolic myopathy, respond differently to the general population in response to triggering agents, such as volatile anesthetics and succinylcholine. Its incidence ranges from 1:10,000 to 1:250,000 anesthesias. Using etiological treatment, the current mortality rate is around 5%. The biochemical, metabolic, and physiological deterioration generally associated with MH is a direct result of a sudden and progressive increase in intracellular calcium in striated muscle cells. This generates a hypermetabolic state, with a rapid increase in body temperature that can lead to a fatal outcome if not diagnosed and treated in time. The genetic factors that determine susceptibility to MH are complex, with the participation of more than one gene. Its clinical symptoms are highly variable, from mild or moderate to fulminant attacks with severe muscle hypermetabolism and rhabdomyolysis. Capnography and pulse oximetry have great clinical diagnostic value. Other early symptoms of an MH attack may include sinus tachycardia, supraventricular or ventricular arrhythmia, and isolated masterean spasm or generalized muscle stiffness. The rise in temperature is a late sign. After an attack, or in possibly susceptible patients, the laboratory diagnosis is made with the in vitro contracture test, in which the contraction of muscle fibers, obtained through a skeletal muscle biopsy, is studied in the presence of halothane or caffeine. In patients known to be susceptible to MH, neuraxial and regional techniques should be preferred if surgery allows it; otherwise, trigger-free anesthetic methods (TIVA) should be available. Management of the MH crisis is based on three main actions: 1) stopping the administration of halogenates; 2) hyperventilation with 100% oxygen, and 3) administration of intravenous dantrolene.

La hipertermia maligna (HM) es una miopatía metabólica subclínica, cuyos portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante: anestésicos volátiles y succinilcolina. Su incidencia tiene rangos entre 1:10.000 a 1:250.000 anestesias. Su mortalidad actual usando tratamiento etiológico es de 5%. El deterioro bioquímico, metabólico y fisiológico asociado clásicamente al cuadro de HM es el resultado directo de un aumento súbito y progresivo del calcio intracelular de las células musculares estriadas, que genera un estado hipermetabólico, calor y un rápido aumento de la temperatura corporal, que puede llevar a un desenlace fatal si no se diagnostica y se trata a tiempo. Su herencia es complicada: se trata de una transmisión multigénica, en que la susceptibilidad a la HM depende de más de un gen. Los síntomas clínicos son muy variables, desde leves o moderados hasta crisis fulminantes con hipermetabolismo muscular severo y rabdomiólisis. La capnografía y la oximetría tiene un gran valor diagnóstico clínico. Otros síntomas tempranos de una crisis de HM pueden incluir taquicardia sinusal, arritmia supraventricular o ventricular y espasmo de maséteros aislado o rigidez muscular generalizada; el aumento de la temperatura es un signo tardío. Después de la crisis o en los pacientes posiblemente susceptibles, el diagnóstico de laboratorio se hace con el test de contractura , basado en la contracción de fibras musculares tomadas a partir de una biopsia de músculo estriado en presencia de halotano o cafeína. En los pacientes conocidamente susceptibles a HM se debe preferir las técnicas neuroaxiales y regionales si la cirugía lo permite; en caso contrario, debe disponerse de métodos anestésicos libres de agentes desencadenantes (TIVA). El manejo de la crisis de HM está basado en tres medidas principales: 1) la detención de la administración de halogenados; 2) la hiperventilación con oxígeno al 100% y 3) la administración de dantrolene endovenoso.

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.

Acute postoperative sepsis mimicking symptomology suspicious for malignant hyperthermia: case report / Sepse aguda pós-operatória simulando sintomatologia suspeita para hipertermia maligna: relato de caso

Abstract Background: Sepsis is a life-threatening organ dysfunction with non-specific clinical features that can mimic other clinical conditions with hyper metabolic state such as malignant hyperthermia. Perioperatively anesthesia providers come across such scenarios, which are extremely challenging with the need for urgent intervention. Objective: To illustrate the need for early intervention and consultation for added assistance to approach and rule out malignant hyperthermia and other possible causes during such a scenario. Case report: A 63-year-old male underwent an uneventful elective flexible cystoscopy and transrectal ultrasound-guided prostate biopsy. Postoperatively he developed symptoms raising suspicion for malignant hyperthermia. Immediately malignant hyperthermia protocol was initiated that included administration of dantrolene and consultation of malignant hyperthermia association hotline along with other diagnostic and interventional management aimed at patient optimization. While early administration of dantrolene helped in hemodynamically stabilizing the patient, the consultation with other providers and malignant hyperthermia association hotline along with repeated examinations and lab works helped in ruling out malignant hyperthermia as the possible diagnosis. The patient later recovered in the intensive care unit where he was treated for the bacteremia that grew in his blood cultures. Conclusions: Sepsis shares clinical symptoms that mimic malignant hyperthermia. While sepsis rapidly progresses to secondary injuries, malignant hyperthermia is life threatening. Providing ideal care requires good clinical judgment and a high level of suspicion where timely and appropriate care such as early administration of dantrolene and consultation of malignant hyperthermia association hotline for added assistance can influence positive outcomes.

Resumo Justificativa: A sepse é uma disfunção orgânica fatal com características clínicas inespecíficas que podem imitar outras condições clínicas com quadro hipermetabólico, como a hipertermia maligna. Os cenários são extremamente desafiadores para a anestesia perioperatória e requerem intervenção urgente. Objetivo: Ilustrar a necessidade de intervenção e consulta precoces para uma assistência adicional na abordagem e exclusão de hipertermia maligna e outras possíveis causas durante tal cenário. Relato de caso: Paciente do sexo masculino, 63 anos, submetido à cistoscopia eletiva com cistoscópio flexível e biópsia transretal da próstata guiada por ultrassom sem intercorrências. No pós-operatório, o paciente desenvolveu sintomas que levantaram a suspeita de hipertermia maligna. O protocolo de hipertermia maligna foi imediatamente iniciado, inclusive a administração de dantrolene e uma consulta pela linha direta da associação de hipertermia maligna, juntamente com outros diagnósticos e manejos intervencionistas com vistas ao aprimoramento do paciente. Enquanto a administração precoce de dantrolene ajudou na estabilização hemodinâmica do paciente, a consulta com outros anestesistas e com a Associação de Hipertermia Maligna, juntamente com repetidos exames físicos e laboratoriais, ajudou a excluir a hipertermia maligna como o possível diagnóstico. O paciente recuperou-se mais tarde na unidade de terapia intensiva, onde recebeu tratamento para a bacteremia detectada em suas hemoculturas. Conclusões: A sepse compartilha sintomas clínicos que mimetizam a hipertermia maligna. Enquanto a sepse progride rapidamente para lesões secundárias, a hipertermia maligna é uma ameaça à vida. Proporcionar o tratamento ideal requer um bom julgamento clínico e um alto nível de suspeita quanto aos cuidados oportunos e apropriados, como a administração precoce de dantrolene e a consulta pela linha direta da Associação de Hipertermia Maligna para assistência adicional, que podem resultar em desfechos positivos.

Diagnóstico de hipertermia maligna: reporte de caso / Diagnostic of malignant hyperthermia: a case presentation

Antecedentes: La Hipertermia maligna, desorden farmacogenético autosómico dominante, se presenta en pacientes susceptibles a gases anestésicos; estimándose predisposición genética en 1:3000 individuos generada por las variantes de los genes RYR1, CACNA1, STAC3, que explican la susceptibilidad del 77%-86% de la población caucásica europea. Se reporta incidencia en-tre 1:5000-100000 procedimientos de anestesia. Se induce por liberación excesiva sin recaptación adecuada de calcio citoplásmico desde el retículo sarcoplásmico, generando rigidez muscular, alto gasto de energía como ATP, hipermetabolismo, aumento secundario de CO2, calor, rabdomiólisis, hiperpotasemia, mioglobinuria y aumento de CPK. Descripción delcaso clínico: Paciente masculino 18 años sometido a cirugía con anestesia general por apendicitis aguda, durante la cirugía presentó rigidez muscular, inestabilidad hemodinámica, hipertermia (40°C), taquicardia (Frecuencia cardiaca: 120 lpm) e hipotensión (Presión Arterial 50/20), sin esfuerzo res-piratorio y pérdida de relejos osteotendinosos. Se diagnosticó hipertermia maligna y se inició manejo, sin embargo, paciente fallece poco menos de dos horas después de haber iniciado el cuadro. Conclusiones: La Hipertermia maligna, es una condición que genera un evento en respuesta a la exposición a agentes anestésicos durante una cirugía, cuadro difícil de prevenir. El manejo requiere cele-ridad y preparación exhaustiva que debe seguir las recomendaciones de manejo europeas y estadounidenses. Este es el primer caso reportado a nivel nacional y se acompaña con una revisión que permite determinar que, aunque no se disponga del fármaco clave en el sistema nacional para mejorar el pronóstico, la protocolización preventiva y terapéutica, así como el entrenamiento en simulación del personal de quirófano podrían inluir en la supervivencia...(AU)

Anesthesia for muscle biopsy to test susceptibility to malignant hyperthermia / Anestesia durante biópsia muscular para teste de suscetibilidade à hipertermia maligna

Abstract Introduction Malignant hyperthermia is an autosomal dominant pharmacogenetic disorder, characterized by hypermetabolic crisis triggered by halogenated anesthetics and/or succinylcholine. The standard method for diagnosing malignant hyperthermia susceptibility is the in vitro muscle contracture test in response to halothane-caffeine, which requires muscle biopsy under anesthesia. We describe a series of anesthetic procedures without triggering agents in malignant hyperthermia, comparing peripheral nerve block and subarachnoid anesthesia. Method We assessed the anesthetic record charts of 69 patients suspected of malignant hyperthermia susceptibility who underwent muscle biopsy for in vitro muscle contracture in the period of 7 years. Demographic data, indication for malignant hyperthermia investigation, in vitro muscle contracture test results, and surgery/anesthesia/recovery data were analyzed. Results Sample with 34 ± 13.7 years, 60.9% women, 65.2% of in vitro muscle contracture test positive. Techniques used: peripheral nerve blocks — lateral femoral and femoral cutaneous, latency 65 ± 41 min — (47.8%); subarachnoid anesthesia (49.3%), and total venous anesthesia (1.4%). There was 39.4% failure of peripheral nerve block and 11.8% of subarachnoid anesthesia. Adverse events (8.7%) occurred only with subarachnoid blockade (bradycardia, nausea, and transient neurological syndrome). All patients remained in the post-anesthesia care unit until discharge. Age and weight were significantly higher in patients with blockade failure (ROC cut-off point of 23.5 years and 59.5 kg) and blockade failure was more frequent in the presence of increased idiopathic creatine kinase. Conclusion Anesthesia with non-triggering agents has been shown to be safe in patients with malignant hyperthermia susceptibility. Variables such as age, weight, and history of increased idiopathic creatine kinase may be useful in selecting the anesthetic technique for this group of patients.

Resumo Introdução Hipertermia maligna é uma doença farmacogenética autossômica dominante, caracterizada por crise hipermetabólica desencadeada por anestésicos halogenados e/ou succinilcolina. O padrão para diagnóstico da suscetibilidade à hipertermia maligna é o teste de contratura muscular in vitro em resposta ao halotano-cafeína, para o qual é necessária biopsia muscular sob anestesia. Descrevemos uma série de anestesias sem agentes desencadeantes na hipertermia maligna e comparamos bloqueios de nervo periférico e anestesias subaracnóideas. Método Foram analisados os prontuários/fichas anestésicas de 69 pacientes suspeitos de susceptibilidade à hipertermia maligna, submetidos à biópsia muscular para teste de contratura muscular in vitro durante sete anos. Analisamos dados demográficos, indicação para investigação de hipertermia maligna, resultado do teste de contratura muscular in vitro e dados da cirurgia/anestesia/recuperação. Resultados Amostra com 34 ± 13,7 anos, 60,9% mulheres, 65,2% de teste de contratura muscular in vitro positivos. Técnicas empregadas: 47,8% bloqueios de nervo periférico (femoral e cutâneo femoral lateral, latência 65 ± 41 minutos), 49,3% anestesias subaracnóideas e 1,4% anestesia venosa total. Falha em 39,4% dos bloqueios de nervo periférico e 11,8% das anestesias subaracnóideas. Eventos adversos (8,7%) como bradicardia, náuseas e síndrome neurológica transitória só ocorreram com bloqueio subaracnóideo. Todos os pacientes permaneceram na sala de recuperação pós-anestésica até liberação. Idade e peso foram significativamente maiores nos pacientes com falha no bloqueio (ponto de corte da curva ROC de 23,5 anos e 59,5 Kg) e esta foi mais frequente na presença de aumento idiopático de creatinoquinase. Conclusão Anestesia com agentes não desencadeantes mostrou-se segura em pacientes suscetíveis à hipertermia maligna. Variáveis como idade, peso e antecedente de aumento idiopático de creatinoquinase podem ser úteis para selecionar a técnica anestésica nesse grupo.

Profile of malignant hyperthermia susceptibility reports confirmed with muscular contracture test in Brazil / Perfil dos relatos de suscetibilidade à hipertermia maligna confirmados com teste de contratura muscular no Brasil

Abstract Background and objectives: Malignant hyperthermia is an autosomal dominant hypermetabolic pharmacogenetic syndrome, with a mortality rate of 10%-20%, which is triggered by the use of halogenated inhaled anesthetics or muscle relaxant succinylcholine. The gold standard for suspected susceptibility to malignant hyperthermia is the in vitro muscle contracture test in response to halothane and caffeine. The determination of susceptibility in suspected families allows the planning of safe anesthesia without triggering agents for patients with known susceptibility to malignant hyperthermia by positive in vitro muscle contracture test. Moreover, the patient whose suspicion of malignant hyperthermia was excluded by the in vitro negative muscle contracture test may undergo standard anesthesia. Susceptibility to malignant hyperthermia has a variable manifestation ranging from an asymptomatic subject presenting a crisis of malignant hyperthermia during anesthesia with triggering agents to a patient with atrophy and muscle weakness due to central core myopathy. The aim of this study is to analyze the profile of reports of susceptibility to malignant hyperthermia confirmed with in vitro muscle contracture test. Method: Analysis of the medical records of patients with personal/family suspicion of malignant hyperthermia investigated with in vitro muscle contracture test, after given written informed consent, between 1997 and 2010. Results: Of the 50 events that motivated the suspicion of malignant hyperthermia and family investigation (sample aged 27 ± 18 years, 52% men, 76% white), 64% were investigated for an anesthetic malignant hyperthermia crisis, with mortality rate of 25%. The most common signs of a malignant hyperthermia crisis were hyperthermia, tachycardia, and muscle stiffness. Susceptibility to malignant hyperthermia was confirmed in 79.4% of the 92 relatives investigated with the in vitro muscle contracture test. Conclusion: The crises of malignant hyperthermia resembled those described in other countries, but with frequency lower than that estimated in the country.

Resumo Justificativa e objetivo: Hipertermia maligna é uma síndrome farmacogenética hipermetabólica, autossômica dominante, com mortalidade entre 10%-20%, desencadeada por uso de anestésico inalatório halogenado ou relaxante muscular succinilcolina. O padrão-ouro para pesquisa de suscetibilidade à hipertermia maligna é o teste de contratura muscular in vitro em resposta ao halotano e à cafeína. A determinação da suscetibilidade nas famílias suspeitas permite planejar anestesias seguras sem agentes desencadeantes para os pacientes confirmados como suscetíveis à hipertermia maligna pelo teste de contratura muscular in vitro positivo. Além disso, o paciente no qual a suspeita de hipertermia maligna foi excluída pelo teste de contratura muscular in vitro negativo pode ser anestesiado de forma convencional. Suscetibilidade à hipertermia maligna tem manifestação variável, desde indivíduo assintomático que apresenta crise de hipertermia maligna durante anestesia com agentes desencadeantes, até paciente com atrofia e fraqueza muscular por miopatia central core disease. O objetivo deste trabalho é analisar o perfil dos relatos de suscetibilidade à hipertermia maligna confirmados com teste de contratura muscular in vitro. Método: Análise das fichas de notificação dos pacientes com suspeita pessoal/familiar de hipertermia maligna investigados com teste de contratura muscular in vitro, após assinatura do termo de consentimento, entre 1997-2010. Resultados: Dos 50 eventos que motivaram a suspeita de hipertermia maligna e a investigação familiar (amostra com 27 ± 18 anos, 52% homens, 76% brancos), 64% foram investigados por crise de hipertermia maligna anestésica, com mortalidade de 25%. Sinais mais comuns da crise de hipertermia maligna foram hipertermia, taquicardia e rigidez muscular. Suscetibilidade à hipertermia maligna foi confirmada em 79,4% dos 92 parentes investigados com teste de contratura muscular in vitro. Conclusão: Crises de hipertermia maligna assemelharam-se às descritas em outros países, porém com frequência inferior à estimada no país.

Hipertermia maligna: reporte de un caso clínico / Malignant hyperthermia: report of a clinical case / Hipertermia maligna: relatório de um caso clínico

Resumen: La Hipertermia Maligna (HM), es un síndrome clínico que ocurre en pacientes susceptibles tras la exposición a un agente anestésico desencadenante. La mortalidad desciende con tratamiento específico, por lo que es fundamental su diagnóstico y tratamiento precoz. Se presenta el caso clínico de una niña de 3 años y 10 meses, en estudio por hemiparesia derecha de 3 meses de evolución. Se plantea probable enfermedad desmielinizante. Se le realizaron dos resonancias magnéticas (RNM) previas con anestesia sin incidentes. Por mala evolución de su enfermedad, se realiza nueva RNM con anestesia. A las 5 horas presenta episodio de distonías, acidosis, CPK elevada. Se interpreta como HM, se inicia tratamiento para la misma con mejoría del cuadro clínico. Presentamos este caso con el objetivo de exponer un enfoque diagnóstico y terapéutico de esta patología.

Summary: Malignant Hyperthermia (MH)is a clinical syndrome that occurs in susceptible patients after exposure to a triggering anesthetic agent. Associated mortality decreases with specific treatment, which is why its diagnosis and early treatment is essential. We present the case of a 3-year and 10-month-old girl, who presented a right hemiparesis. Possible demyelinating disease was suspected. Two previous magnetic resonance imaging (MRI) were performed under general anesthesia without complications. Due to poor evolution of his disease, new MRI is performed with anesthesia. After the procedure, she presented an episode of dystonias, acidosis, elevated CPK. It was interpreted as MH, and specific treatment was initiated instated. We present this case with the objective of exposing a diagnostic and therapeutic approach to this pathology.

Resumo: A hipertermia maligna (HM), è uma sindrome clinica que ocorre em pacientes sucetíveis devido a exposição a um agente anestésico desencadeante. A mortalidade diminui com tratamento específico, para o qual é fundamental diagnostico e tratamento precoce. Apresenta-se um caso clínico de uma criança de 3 anos e 10 meses de idade, em estudo por hemiparesia direita de 3 meses de evolução. Questiona-se provável doença desmielinizante. Foram realizadas duas ressonância magnéticas (RNM) previas, sob anestesia, sem incidentes. Devido à má evolução de sua doença, realizuo-se nova RNM sob anestesia. Cinco horas após apresentou episódios de rigidez muscular, acidose e CPK elevada. Interpretou-se como HM, iniciando-se tratamento específico, obtém-se melhoria do quadro clínico. Apresentamos este caso clínico com o objetivo de expor um enfoque diagnóstico e terapêutico desta patologia.

Hipertermia maligna: ¿cómo estar preparados? / Malignant hyperthermia: how to be prepared?

Malignant hyperthermia is an autosomal dominant genetic disease that affects the skeletal muscle. Specifically corresponds to a hypermetabolic response against triggering agents such as halogenated gases and the muscle relaxant succinylcholine. Because MH is a potentially fatal disease and ocurrs unexpectedly during a surgery, it is important to stablish how should be the perioperative management of these patients. The aim of this review is to present the current knowledge about the incidence, pathophysiology and triggers of malignant hyperthermia in addition to concepts for the safe management of these patients.

La hipertermia maligna es una enfermedad genética autosómica dominante que afecta al músculo esquelético. Específicamente corresponde a una respuesta hipermetabólica frente a agentes gatillantes como los gases halogenados y el relajante muscular succinilcolina. Debido a que la HM es una enfermedad potencialmente letal e inesperada, que ocurre durante una cirugía, es importante establecer claramente como debe ser el manejo perioperatorio de estos pacientes. El objetivo de esta revisión es presentar los conocimientos actuales sobre la incidencia, fisiopatología y factores desencadenantes de la hipertermia maligna, además de conceptos para el manejo seguro de estos pacientes.

Hipertermia maligna: aspectos moleculares e clínicos / Malignant hyperthermia: clinical and molecular aspects / Hipertermia maligna: aspectos moleculares y clínicos

CONTEÚDO: A hipertermia maligna (HM) é uma doença farmacogenética potencialmente letal que acomete indivíduos geneticamente predispostos. Manifesta-se em indivíduos susceptíveis em resposta à exposição a anestésicos inalatórios, relaxantes musculares despolarizantes ou atividade física extrema em ambientes quentes. Durante a exposição a esses agentes desencadeadores, há um aumento rápido e sustentado da concentração de cálcio mioplasmático (Ca2+) induzido pela hiperativação dos receptores de rianodina (RYR1) do músculo esquelético, causando uma alteração profunda na homeostase de Ca2+, caracterizando um estado hipermetabólico. RYR1, canais de libertação de Ca2+ do retículo sarcoplasmático, é o principal local de susceptibilidade à HM. Várias mutações no gene que codifica a proteína RYR1 foram identificadas, mas outros genes podem estar envolvidos. Atualmente, o método padrão para o diagnóstico de sensibilidade à HM é o teste de contratura muscular para exposição ao halotano-cafeína (CHCT) e o único tratamento é o uso de dantroleno. No entanto, com os avanços no campo da genética molecular, um pleno entendimento da etiologia da doença pode ser fornecido, favorecendo o desenvolvimento de um diagnóstico preciso, menos invasivo, com o teste de ADN, e também proporcionar o desenvolvimento de novas estratégias terapêuticas para o tratamento da HM. Logo, esta breve revisão tem como objetivo integrar os aspectos clínicos e moleculares da HM, reunindo informações para uma melhor compreensão desta canalopatia.

CONTENT: Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder that affects genetically predisposed individuals. It manifests in susceptible individuals in response to exposure to Inhalant anesthetics, depolarizing muscle relaxants or extreme physical activity in hot environments. During exposure to these triggering agents, there is a rapid and sustained increase of myoplasmic calcium (Ca2+) concentration induced by hyperactivation of ryanodine receptor of skeletal muscle (RyR1), causing a profound change in Ca2+ homeostasis, featuring a hypermetabolic state. RyR1, Ca2+ release channels of sarcoplasmic reticulum, is the primary locus for MH susceptibility. Several mutations in the gene encoding the protein RyR1 have been identified; however, other genes may be involved. Actually, the standard method for diagnosing MH susceptibility is the muscle contracture test for exposure to halothane-caffeine (CHCT) and the only treatment is the use of dantrolene. However, with advances in molecular genetics, a full understanding of the disease etiology may be provided, favoring the development of an accurate diagnosis, less invasive, with DNA test, and also will provide the development of new therapeutic strategies for treatment of MH. Thus, this brief review aims to integrate molecular and clinical aspects of MH, gathering input for a better understanding of this channelopathy.

CONTENIDO: La hipertermia maligna (HM) es una enfermedad farmacogenética potencialmente letal que afecta a individuos genéticamente predispuestos. Se manifiesta en los individuos susceptibles en respuesta a la exposición a los anestésicos inhalatorios, relajantes musculares despolarizantes o actividad física extrema en ambientes calientes. Durante la exposición a esos agentes desencadenantes, existe un aumento rápido y constante de la concentración de calcio mioplasmático (Ca2+) inducido por la hiperactivación de los receptores de rianodina (RYR1) del músculo esquelético, causando una alteración profunda en la homeostasa de Ca2+, y caracterizando un estado hipermetabólico. RYR1, canales de liberación de Ca2+ del retículo sarcoplasmático, es la principal región de susceptibilidad a la HM. Varias mutaciones en el gen que codifica la proteína RYR1 han sido identificadas, pero otros genes pueden estar involucrados también. Actualmente, el método estándar para el diagnóstico de la sensibilidad a la HM es el test de contractura muscular para la exposición al halotano-cafeína (CHCT) y el único tratamiento es el uso de dantroleno. Sin embargo, con los avances en el campo de la genética molecular, un pleno entendimiento de la etiología de la enfermedad puede ser suministrado, favoreciendo así el desarrollo de un diagnóstico preciso, menos invasivo, con el test de ADN, y también proporcionar el desarrollo de nuevas estrategias terapéuticas para el tratamiento de la HM. Por eso, esta breve revisión intenta integrar los aspectos clínicos y moleculares de la HM, reuniendo informaciones para lograr una mejor comprensión de esa canalopatía.

Hipertermia maligna / Malignant hypertermia

La hipertermia maligna es un trastorno muscular hereditario que se manifiesta como un estado hipermetabólico desencadenado después de que individuos susceptibles reciben anestésicos volátiles y/o relajantes musculares depolarizantes. La susceptibilidad se basa en una alteración en la regulación del calcio dentro de la fibra del músculo esquelético causada por un defecto en canales de calcio en el retículo sarcoplásmico. Una vez que la crisis de hipertermia maligna se desencadena, se inicia una liberación anormalmente alta de calcio en el retículo sarcoplásmico, dando lugar a un estado hipermetabólico, con signos clínicos típicos tales como taquicardia, rigidez muscular, hipercapnia e hipertermia. Debido a que la hipertermia maligna es potencialmente letal, es relevante establecer los conceptos de manejo de cuidados perioperatorios durante la crisis inesperada y en los pacientes susceptibles que se someten a cirugía. El objetivo de esta revisión es presentar los conocimientos actuales sobre la fisiopatología y los factores desencadenantes de la hipertermia maligna, así como conceptos para el manejo seguro de la anestesia de estos pacientes.

Malignant hyperthermia is an inherited muscle disorder characterized by hypermetabolism and is usually triggered after susceptible individuals are given volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility is based on an altered regulation of calcium within the skeletal muscle fibre caused by a defective calcium release channel at the sarcoplasmic reticulum. Once malignant hyperthermia is triggered an abnormally high release of calcium from the sarcoplasmic reticulum is initiated resulting in a hypermetabolic state, leading to typicalclinical signs, such as tachycardia, muscle rigidity, hypercapnia as well as hyperthermia. Because malignant hyperthermia is potentially lethal, it is relevant to establish management concepts for perioperative care during unexpected crisis and susceptible patients who require surgery. The aim of this review is to present current knowledge about pathophysiology and triggers of malignant hyperthermia as well as concepts for safe anaesthesiological management of these patients.

Escobar syndrome in three male patients of same family.

We describe three male individuals from a consanguineous south Indian family affected with the multiple pterygium syndrome (Escobar syndrome). Common clinical features included short stature, multiple pterygium, skeletal anomalies, and normal intelligence. The first report of this condition was made in 1902 from this same place (Pondicherry) and the disease received its present popular name Escobar syndrome in 1982. The genetic defect for this condition was identified in 2006 as mutation in the fetal acetylcholine receptor.

Use of the caffeine-halothane contracture test for the diagnosis of malignant hyperthermia in Brazil

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine. Deaths due to MH have been reported in Brazil. The first Malignant Hyperthermia Diagnostic and Research Center in Latin America was inaugurated in 1993 at the Federal University of Rio de Janeiro, Brazil. The center followed the diagnostic protocols of the North America MH Group, in which the contractures of biopsies from the vastus lateralis muscle are analyzed after exposure to caffeine and halothane (CHCT). CHCT was performed in individuals who survived, their relatives and those with signs/symptoms somewhat related to MH susceptibility (MHS). Here, we report data from 194 patients collected over 16 years. The Southeast (N = 110) and South (N = 71) represented the majority of patients. Median age was 25 (4-70) years, with similar numbers of males (104) and females (90). MHS was found in 90 patients and 104 patients were normal. Abnormal responses to both caffeine and halothane were observed in 59 patients and to caffeine or halothane in 20 and 11 patients, respectively. The contracture of biopsies from MHS exposed to caffeine and halothane was 1.027 ± 0.075 g (N = 285) and 4.021 ± 0.255 g (N = 226), respectively. MHS was found in patients with either low or high blood creatine kinase and also, with a low score on the clinical grading scale. Thus, these parameters cannot be used with certainty to predict MHS. We conclude that the CHCT protocol described by the North America MH Group contributed to identification of MHS in suspected individuals at an MH center in Brazil with 100 percent sensitivity and 65.7 percent specificity.

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered in susceptible individuals by the administration of volatile halogenated anesthetics and/or succinylcholine, leading to the development of a hypermetabolic crisis, which is caused by abnormal release of Ca2+ from the sarcoplasmic reticulum, through the Ca2+ release channel ryanodine receptor 1 (RyR1). Mutations in the RYR1 gene are associated with MH in the majority of susceptible families. Genetic screening of a 5-generation Brazilian family with a history of MH-related deaths and a previous MH diagnosis by the caffeine halothane contracture test (CHCT) in some individuals was performed using restriction and sequencing analysis. A novel missense mutation, Gly4935Ser, was found in an important functional and conserved locus of this gene, the transmembrane region of RyR1. In this family, 2 MH-susceptible individuals previously diagnosed with CHCT carry this novel mutation and another 24 not previously diagnosed members also carry it. However, this same mutation was not found in another MH-susceptible individual whose CHCT was positive to the test with caffeine but not to the test with halothane. None of the 5 MH normal individuals of the family, previously diagnosed by CHCT, carry this mutation, nor do 100 controls from control Brazilian and USA populations. The Gly4932Ser variant is a candidate mutation for MH, based on its co-segregation with disease phenotype, absence among controls and its location within the protein.

Farmacología y aplicaciones clínicas del dantrolene / Dantrolene: pharmacology and clinical uses

El dantrolene (DNL) es el fármaco de elección para prevenir y revertir los síntomas de la hipertermia maligna (HM); es un derivado liposoluble de la hidantoína que relaja y paraliza totalmente al músculo esquelético. La HM es un síndrome que produce estragos fisiológicos. La identificación de los pacientes sensibles a hipertermia maligna (SHM) puede prevenir el desencadenamiento de este síndrome evitando el uso de agentes anestésicos y relajantes que lo inducen. El dantrolene ejerce su efecto miorrelajante disminuyendo la frecuencia de reapertura de los canales de calcio del retículo sarcoplásmico a través del receptor de ryanodina (RYI), disminuyendo el calcio en el sarcoplasma y de este modo la exitación-contracción, con un efecto agonista dopaminérgico. El dantrolene se metaboliza en el hígado y aunque atraviesa la barrera placentaria, no se han reportado efectos adversos en neonatos. La mortalidad de la HM, sin la administración del dantrolene era del 95 por ciento y solo se podía hacer un tratamiento sintomático. La aplicación de este medicamento, sumado a un diagnóstico precoz y un tratamiento específico, ha reducido la mortalidad a un 3 por ciento. El síndrome de hipertermia maligna (SHM) se presenta con: taquicardia, aumento de CO2, taquipnea, rigidez muscular, arritmias cardíacas, acidosis respiratoria y metabólica, aumento de la temperatura corporal, tensión arterial inestable, cianosis, mioglobinuria, oliguria y rigidez del músculo masetero (RMM). También puede ocurrir como un síndrome serotoninérgico, o ser causado por intoxicación por IMAO, anfetaminas, cocaína o CO. Se adjuntan tres casos clínicos donde se utilizó con éxito el DNL.

Dantrolene (DNL) is the medication of choice to prevent and to revert the symptoms of the malignant hyperthermia(HM), it is a liposoluble derivative of the hydantoine that relaxes and paraIyzes totally the skeletal muscle. HM is a syndrome that produces physiological devastations. The identification of the sensitive patients to hyperthermia malignant (SHM) can anticipate the triggering of these cases avoiding the use of anaesthesic and relaxing agents who induce it. The miorelaxing effect diminishes the frequency of reopening of the calcium channels of the reticulum sarcoplasmatic across the ryanodine receptor (RYI), diminishing the calcium in the sarcoplasma and hereby it reduce the excitation-contraction, resulting in agonist dopaminergic effect. DNL is metabolized in the liver. It crosses the placental barrier; nevertheless adverse effects have not been reported in neonates. The mortality in the HM without the specific drug was 95 percent, it was possible to do only symptomatic treatment. The application of this medicine, added to an early diagnosis and a specific treatment, has reduced the mortality to 3 percent. The syndrome of hyperthermia malignant (SHM) appears with: tachycardia, increase of CO2, taquipnea, muscular inflexibility, cardiac arrhythmias, respiratory and metabolic acidosis, increase of the corporal temperature, arterial unstable tension, cyanosis, mioglobinuria, oliguria and inflexibility of the masseter muscle (RMM). Also it can happen as a serotoninergic syndrome, poisoning for IMAO, anfetamines, cocaine and poisoning from CO. Three clinical cases are included where the DNL was in use successfully.

O dantrolene (DNL)‚ é o fármaco de escolha para a prevençao e reversao dos sintomas da hipertermia maligna (HM); e um derivado lipossolúvel da hidantoína que relaxa e paralisa totalmente o músculo esquelético. A HM é uma síndrome que causa enormes danos fisiológicos; a identificaçao dos pacientes sensíveis à hipertermia maligna (SHM) pode prevenir o desencadeamento dessa síndrome evitando o uso de agentes anestésicos e relaxantes que a induzem. O daxtrolene exerce seu efeito miorrelaxante diminuindo a freqüência de reabertura dos canais de cálcio do reticulo sarcoplásmico através do receptor da ryanodina (RYI) e reduzindo o cálcio no sarcoplasma, e, conseqüentemente, também a excitaçao-contraçao, com efeito agonista dopaminérgico. E metabolizado pelo fígado, e apesar de atravessar a barreira placentária, nao se informaram efeitos adversos em neonatos. A mortalidade da HM sem a administraçao de dantrolene era de 95 por cento, e apenas era possivel o tratamento sintomático. A aplicaçao deste medicamento, junto a um diagnóstico precoce e tratamento específico, tem diminuída a mortalidade a 3 por cento. A síndrome de hipertermia maligna (SHM) associa-se a: taquicardia, aumento do CO2, taquipnéia, rigidez muscular, arritmias cardíacas, acidose respiratória e metabólica, aumento da temperatura corporal, tensao arterial instável, cianose, mioglobinúria, oligúria e rigidez do músculo masseter (RMM). Também pode-se apresentar como síndrome serotoninérgica, intoxicaçao por IMAO, anfetaminas, cocaína e intoxicaçao por CO. Sao informados três casos clínicos nos quais se utilizou o DNL.