Department of Physiology and Biophysics, Rush University Medical Centre, Chicago, IL, USA.
Malignant Hyperthermia Unit, Department of Anaesthesiology and Pain Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
Br J Anaesth. 2023 Jul;131(1):47-55. doi: 10.1016/j.bja.2023.01.008. Epub 2023 Feb 13.
Most patients with malignant hyperthermia susceptibility diagnosed by the in vitro caffeine-halothane contracture test (CHCT) develop excessive force in response to halothane but not caffeine (halothane-hypersensitive). Hallmarks of halothane-hypersensitive patients include high incidence of musculoskeletal symptoms at rest and abnormal calcium events in muscle. By measuring sensitivity to halothane of myotubes and extending clinical observations and cell-level studies to a large group of patients, we reach new insights into the pathological mechanism of malignant hyperthermia susceptibility.
Patients with malignant hyperthermia susceptibility were classified into subgroups HH and HS (positive to halothane only and positive to both caffeine and halothane). The effects on [Ca] of halothane concentrations between 0.5 and 3 % were measured in myotubes and compared with CHCT responses of muscle. A clinical index that summarises patient symptoms was determined for 67 patients, together with a calcium index summarising resting [Ca] and spontaneous and electrically evoked Ca events in their primary myotubes.
Halothane-hypersensitive myotubes showed a higher response to halothane 0.5% than the caffeine-halothane hypersensitive myotubes (P<0.001), but a lower response to higher concentrations, comparable with that used in the CHCT (P=0.055). The HH group had a higher calcium index (P<0.001), but their clinical index was not significantly elevated vs the HS. Principal component analysis identified electrically evoked Ca spikes and resting [Ca] as the strongest variables for separation of subgroups.
Enhanced sensitivity to depolarisation and to halothane appear to be the primary, mutually reinforcing and phenotype-defining defects of halothane-hypersensitive patients with malignant hyperthermia susceptibility.
大多数通过体外咖啡因-氟烷收缩试验（CHCT）诊断为恶性高热易感性的患者在氟烷作用下会产生过度的收缩力，但对咖啡因无反应（氟烷敏感型）。氟烷敏感型患者的特征包括在休息时肌肉骨骼症状的发生率高，以及肌肉中钙事件异常。通过测量肌管对氟烷的敏感性，并将临床观察和细胞水平的研究扩展到一大群患者，我们对恶性高热易感性的病理机制有了新的认识。
将恶性高热易感性患者分为 HH 和 HS 亚组（仅对氟烷敏感和对咖啡因和氟烷均敏感）。测量氟烷浓度在 0.5%至 3%之间对肌管中[Ca]的影响，并与肌肉的 CHCT 反应进行比较。为 67 名患者确定了一个综合患者症状的临床指数，以及一个综合其原代肌管静息[Ca]和自发及电诱发 Ca 事件的钙指数。
氟烷敏感型肌管对氟烷 0.5%的反应高于咖啡因-氟烷敏感型肌管（P<0.001），但对较高浓度的反应较低，与 CHCT 中使用的浓度相当（P=0.055）。HH 组的钙指数较高（P<0.001），但与 HS 组相比，其临床指数没有显著升高。主成分分析确定电诱发 Ca 峰和静息[Ca]是区分亚组的最强变量。
对去极化和氟烷的敏感性增强似乎是恶性高热易感性氟烷敏感型患者的主要、相互增强和表型定义缺陷。
