Análise do teste de contratura muscular para diagnóstico de hipertermia maligna: comparação dos critérios do grupo europeu e norte-americano
Data
2021
Autores
Mello, Jean Marcel 
Orientadores
Silva, Helga Cristina Almeida
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A Hipertermia Maligna (HM) anestésica é uma síndrome farmacogenética, hereditária e autossômica dominante, com mutações em genes ligados à dinâmica intracelular do cálcio do músculo esquelético. É desencadeada por agentes anestésicos halogenados ou o relaxante muscular despolarizante succinilcolina. A HM está associada a alta mortalidade. Objetivos: 1. Comparar os critérios diagnósticos do teste de contratura do grupo Europeu (teste de contratura in vitro - TCIV) e do grupo Norte-americano (teste de contratura halotano cafeína - TCHC), usando a base de dados do Centro de Estudo, Diagnóstico e Investigação de Hipertermia Maligna da Universidade Federal de São Paulo; 2. verificar que variáveis influem no resultado do teste; e 3. analisar fatores que influenciam concordância e discordância diagnóstica entre TCIV e TCHC. Métodos: Foram selecionados aleatoriamente gráficos do TCIV de 128 pacientes realizados no período de 2004 a 2019. Foram incluídos no estudo pacientes com contração máxima inicial ≥1 g ou contratura após 32 mM de cafeína ≥5 g em pelo menos um dos fragmentos expostos à cafeína, contração máxima inicial ≥1 g em pelo menos um dos fragmentos expostos ao halotano e disponibilidade do teste de Bolus de halotano a 3%. Cinco foram eliminados por terem dados insuficientes e mais nove foram eliminados por não terem o teste de Bolus de Halotano a 3%, sendo mantidos 114 pacientes aptos para compor a amostra do estudo. Desses pacientes, foram coletados os seguintes dados: idade no momento da biópsia, sexo, motivo do encaminhamento, presença de fraqueza muscular no exame neurológico, presença de miopatia com cores no estudo anatomopatológico muscular, resultado final do teste de contratura segundo protocolo europeu e Norte-americano, presença de mutações nos genes do receptor rianodina tipo 1 (RYR1) / diidropridina (CACNA1S) e parâmetros do TCIV. Resultado: De acordo com o critério do TCIV, 58,7% dos pacientes foram suscetíveis à hipertermia maligna (MHS), contra 42% do TCHC. Houve 21 discordantes com resultado negativo no TCHC e positivo no TCIV (resposta apenas ao halotano) e apenas um paciente positivo no TCHC e negativo no TCIV. Significativamente mais pacientes do sexo masculino tiveram resultado positivo no TCIV. Grupos que reagiram somente a halotano (MHSh), somente à cafeína (MHSc), ou às duas substâncias (MHShc), tiveram diferenças nos parâmetros clínicos e contráteis do TCIV, tais como no grupo discordante, por resposta ao halotano no TCIV, havia significativamente mais homens que no grupo concordante e menor frequência de variantes nos genes RYR1/CACNA1S. Além disso, no grupo discordante os fragmentos musculares, após exposição à cafeína, mostraram significativamente maior contração após estímulo tetânico a 100 Hz (TF), menor contratura em reação a 32 mM de cafeína (TQ), e menor contratura a 2 mM. Após exposição ao halotano, fragmentos desse mesmo grupo necessitaram de significativamente maior concentração de halotano para atingir 0,2 g de contratura. Conclusão: Critérios diagnósticos do teste de contratura do grupo Europeu e Norte-americano são equivalentes em amostra brasileira. O sexo do paciente influencia resultado do teste de contratura. Há heterogeneidade clínica-laboratorial entre subgrupos diagnósticos dos pacientes positivos no teste de contratura, o que fala a favor de mecanismos subjacentes/variantes genéticas diversos. Pacientes discordantes entre dois protocolos apresentam-se como grupo com particularidades não explicadas.
Introduction: Anesthetic Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome, with mutations in genes linked to the intracellular dynamics of skeletal muscle calcium. It is triggered by halogenated anesthetic agents or the depolarizing muscle relaxant succinylcholine. MH is associated with high mortality. Objectives: 1. Compare the diagnostic criteria of the European group contracture test (in vitro contracture test - IVCT) and the North American group (caffeine halothane contracture test - CHCT), using the study center database, Diagnosis and Malignant Hyperthermia Investigation at the Federal University of São Paulo; 2. check which variables influence the test result; and 3. analyze factors that influence diagnostic agreement and disagreement between IVCT and CHCT. Methods: IVCT graphics of 128 patients performed from 2004 to 2019 were randomly selected. Patients with initial maximum contraction ≥1 g or contracture after 32 mM caffeine ≥5 g in at least one of the fragments exposed to caffeine were included in the study, contraction initial maximum ≥1 g in at least one of the fragments exposed to halothane and availability of the 3% halothane Bolus test. Five were eliminated for having insufficient data and nine more were eliminated for not having the 3% Halothane Bolus test, with 114 patients being kept fit to compose the study sample. From these patients, the following data were collected: age at the time of biopsy, sex, reason for referral, presence of muscle weakness in the neurological examination, presence of myopathy with Cores in the muscular anatomopathological study, final result of the contracture test according to European and North American protocols, presence of mutations in the ryanodine receptor type 1 (RYR1)/dihydropridine (CACNA1S) genes and IVCT parameters. Result: According to the IVCT criteria, 58.7% of the patients were susceptible to malignant hyperthermia (MHS), against 42% for CHCT. There were 21 discordant patients with a negative result on the CHCT and positive on the IVCT (response only to halothane) and only one patient positive on the CHCT and negative on the IVCT. Significantly more male patients tested positive on the IVCT. Groups that reacted only to halothane (MHSh), only to caffeine (MHSc), or to both substances (MHShc), had differences in clinical and contractile parameters of the IVCT, such as in the discordant group, by response to halothane in the IVCT, there were significantly more men than in the concordant group and lower frequency of variants in the RYR1/CACNA1S genes. Furthermore, in the discordant group, muscle fragments, after exposure to caffeine, showed significantly greater contraction after tetanus stimulation at 100 Hz (TF), less contracture in response to 32 mM of caffeine (TQ), and less contracture at 2 mM. After exposure to halothane, fragments from this same group required a significantly higher concentration of halothane to reach 0.2 g of contracture. Conclusion: Diagnostic criteria of the contracture test of the European and North American group are equivalent in a Brazilian sample. The patient's gender influences the result of the contracture test. There is clinical and laboratory heterogeneity between diagnostic subgroups of patients who are positive in the contracture test, which speaks in favor of different underlying mechanisms/genetic variants. Discordant patients between two protocols present themselves as a group with unexplained particularities.
Introduction: Anesthetic Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome, with mutations in genes linked to the intracellular dynamics of skeletal muscle calcium. It is triggered by halogenated anesthetic agents or the depolarizing muscle relaxant succinylcholine. MH is associated with high mortality. Objectives: 1. Compare the diagnostic criteria of the European group contracture test (in vitro contracture test - IVCT) and the North American group (caffeine halothane contracture test - CHCT), using the study center database, Diagnosis and Malignant Hyperthermia Investigation at the Federal University of São Paulo; 2. check which variables influence the test result; and 3. analyze factors that influence diagnostic agreement and disagreement between IVCT and CHCT. Methods: IVCT graphics of 128 patients performed from 2004 to 2019 were randomly selected. Patients with initial maximum contraction ≥1 g or contracture after 32 mM caffeine ≥5 g in at least one of the fragments exposed to caffeine were included in the study, contraction initial maximum ≥1 g in at least one of the fragments exposed to halothane and availability of the 3% halothane Bolus test. Five were eliminated for having insufficient data and nine more were eliminated for not having the 3% Halothane Bolus test, with 114 patients being kept fit to compose the study sample. From these patients, the following data were collected: age at the time of biopsy, sex, reason for referral, presence of muscle weakness in the neurological examination, presence of myopathy with Cores in the muscular anatomopathological study, final result of the contracture test according to European and North American protocols, presence of mutations in the ryanodine receptor type 1 (RYR1)/dihydropridine (CACNA1S) genes and IVCT parameters. Result: According to the IVCT criteria, 58.7% of the patients were susceptible to malignant hyperthermia (MHS), against 42% for CHCT. There were 21 discordant patients with a negative result on the CHCT and positive on the IVCT (response only to halothane) and only one patient positive on the CHCT and negative on the IVCT. Significantly more male patients tested positive on the IVCT. Groups that reacted only to halothane (MHSh), only to caffeine (MHSc), or to both substances (MHShc), had differences in clinical and contractile parameters of the IVCT, such as in the discordant group, by response to halothane in the IVCT, there were significantly more men than in the concordant group and lower frequency of variants in the RYR1/CACNA1S genes. Furthermore, in the discordant group, muscle fragments, after exposure to caffeine, showed significantly greater contraction after tetanus stimulation at 100 Hz (TF), less contracture in response to 32 mM of caffeine (TQ), and less contracture at 2 mM. After exposure to halothane, fragments from this same group required a significantly higher concentration of halothane to reach 0.2 g of contracture. Conclusion: Diagnostic criteria of the contracture test of the European and North American group are equivalent in a Brazilian sample. The patient's gender influences the result of the contracture test. There is clinical and laboratory heterogeneity between diagnostic subgroups of patients who are positive in the contracture test, which speaks in favor of different underlying mechanisms/genetic variants. Discordant patients between two protocols present themselves as a group with unexplained particularities.