FISIOPATOLOGÍA DE
NUEVAS EVIDENCIAS
Este es el título de la conferencia que gustosamente el Dr. José Rafael López Padrino, dictó en las instalaciones el SAHCM, a petición de
Geneticamente se asocia a mutaciones del receptor RYR1. En las fibras musculares de animales y sujetos susceptibles a
.- Aumento de la liberación de Calcio
.- Disminución del transporte de calcio
.- Aumento de la entrada de calcio extracelular
.- Aumento en la salida pasiva de calcio de retículo sarcoplásmico
.- Historia Familiar
.- Hipertrofia muscular
.- Hernias (sobre todo en niños)
.- Intolerancia al ejercicio
.- Estrabismo
.- Mioglobinuria
.- Aumento de CPK
.- Electromiograma Normal
.- Estudios Morfológicos y bioquímicos normales
.- Estudios genéticos (RYR1 y DHPR)
.- Halogenados
.- Succinilcolina
.- Stress (¿?)
.-Cambios de temperatura (¿?)
.- Actividad física (¿?)
.- Episodio de HM:
Taquicardia, Hipercapnia, Aumento del consumo de oxígeno Hipertermia, Aumento del tono muscular, Cianosis, Acidosis metabólica/respiratoria Aumento de CPK, Calcio, Potasio, Mioglobinuria, Muerte
.- Suspender agentes desencadenantes
.- Administrar Dantrolene 2,5 μg/kg
.- Cambiar sistemas anestésicos
.- Abortar procedimiento quirúrgico
.- Medidas de enfriamiento
.- Corregir Acidosis
.- Aumentar la diuresis
.- Continuar Dantrolene 1 μg/kg cada 4 horas por
.- Observación por 36 horas
Desalojar vaporizadores. Preparar la máquina de anestesia, administrando alto flujo de oxígeno: 10 lt por minuto por 20 minutos.
Considerar uso de dantrolene:
·- Vía oral: 2 μg/kg cada 6 horas
·- IV: 2,5 μg/kg 30 minutos antes de intervención quirúrgica
Uso de drogas seguras: relajantes musculares no despolarizantes y agentes anestésicos no halogenados. Esta pequeña reseña, no pretende ser una guía para el manejo y tratamiento de
Comentarios: Dr. Miguel A. Silva B.
Nota: Hacer Click en Jose R. Lopez para ver resúmenes y artículos originales.
Hypersensitivity of Malignant Hyperthermia+usceptible Swine Skeletal Muscle to Caffeine Is Mediated by High Resting Myophsrnic 2+ Ka I Anesthesiology 2000; 92: 1799 - 806 Jose R. Lopez, M. D., Ph. D.,* Jaime Contreras, M. D., t Nancy Linares, B.S.,$ Paul D. Allen, M. D., Ph. D.5
Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible
(MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility.
Methods: We studied the effects of caffeine on myoplasmicfree calcium concentration ([Ca2+],) in MHN and MHS swine muscle fibers by means of Caz+-selective microelectrodes before and after K+-induced partial depolarization.
Results: [CaZC]i,n untreated MHN fibers was
When either MHN or MHS, muscle fibers were incubated in 10 mh! K+ [Ca*+], transiently increased to
m~ K+, [Ca2+]r, eturned to control levels in all fibers, and the effect of 2 m~ caffeine on resting [Ca'+], returned to control, despite continued partial membrane depolarization.
Conclusions: These results suggest that the increased "sensitivity'! to caffeine of MHS swine muscle fibers is a nonspecific response related, at least in part, to the high resting [Ca'+], and not an increased caffeine sensitivity of the sarcoplasmic reticulum CaZ+ release channel per se. (Key words: Hyperpyrexia; potassium xanthine.)
CELLULAR METABOLISM
Elevated resting [Ca2+]i in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive
calcium leak from the SR.
Tianzhong Yang,1 Eric Esteve,1 Isaac N. Pessah,2 Tadeusz F. Molinski,3 Paul D. Allen,1 and José R. López1
Am J Physiol Cell Physiol 292:1591-1598, 2007. First published Dec 20, 2006;
1Department of Anesthesiology, Perioperative and Pain Medicine, Brigham
and Women's Hospital, Boston, Massachusetts; 2Department of Molecular
Biosciences, School of Veterinary Medicine, University of California, Davis,
California; and 3Department of Chemistry and Biochemistry and Skaggs
School of Pharmacy and Pharmaceutical Sciences, University of California,
San Diego,
Submitted 23 March 2006 ; accepted in final form 15 December 2006
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal
muscle triggered in susceptible individuals by inhalation anesthetics and
depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% of cases studied to date. Using double-barreled Ca2+ microelectrodes in myotubes
expressing wild-type RyR1 (WTRyR1) or RyR1 with one of four common MH mutations (MHRyR1), we measured resting intracellular Ca2+ concentration ([Ca2+]i). Changes in resting [Ca2+]i produced by several drugs known to
modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the MH RyR1s had a 2.0- to 3.7-fold higher resting [Ca2+]i than those expressing WT RyR1. Exposure of myotubes expressing
MH RyR1s to ryanodine (500 μM) or (2,6-dichloro-4-aminophenyl)isopropylamine (FLA 365; 20 μM) had no effects on their resting [Ca2+]i. However, when myotubes were exposed to bastadin 5 alone or to a combination of ryanodine and bastadin 5,
the resting [Ca2+]i was significantly reduced (P <>
Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2]i
Am J Physiol Cell Physiol 288: C606–C612, 2005.
First published November 10, 2004; doi:10.1152/ajpcell.00297.2004.
José R. López,1,2 Nancy Linares,1 Isaac N. Pessah,3 and Paul D. Allen2
1Centro de Biofı´sica y Bioquı´mica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela;2Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and 3Department of Molecular Biosciences, University of California, Davis, California Submitted 23 June 2004; accepted in final form 8 October 2004 López, José R., Nancy Linares, Isaac N. Pessah, and Paul D. Allen.
Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2]i. Am J Physiol Cell Physiol 288: C606–C612, 2005. First published November 10, 2004; doi:10.1152/ajpcell. 00297.2004.—Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic syndrome caused by exposure to halogenated volatile anesthetics and/or depolarizing muscle relaxants. We have measured intracellular Ca2 concentration ([Ca2]i) using double-barreled, Ca2-selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca2]i was approximately twofold in MHS compared with MHN quiescent myoballs (232 [1] 35 vs. 112 [1] 11nM). Treatment of myoballs with caffeine or 4-chloro-m-cresol (4-CmC) produced an elevation in [Ca2]i in both groups; however, the concentration required to cause a rise in [Ca2]i elevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca2 buffer BAPTA reduced [Ca2]i, raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca2]i, and reduced the amount of Ca2 release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC may be mediated at least in part by the chronic high resting [Ca2]i levels inthese cells. calcium homeostasis; 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid
