米達諾引起門診直腸鏡手術病人相關認知功能缺損與贊安諾治療之恢復效果

Abstract

研究背景與目的：米達諾為內視鏡手術中常用之苯環類麻醉劑，贊安諾為其拮抗劑，可恢復米達諾之藥物效果。本研究欲瞭解米達諾相關之認知功能受損型態、贊安諾對其之恢復效果及劑量-效應關係，並探討使用個體內比較統計方式之可行性。方法：為前瞻、雙盲、隨機分派之研究。研究一納入三十位接受內視鏡手術且同意麻醉的病人與二十五位無麻醉無接受手術之健康成人，對其進行三次神經心理測驗，分別於施打米達諾前、施打後15分鐘及120分鐘，測量的認知功能面向包括定向感、持續性注意力、心理運作速度、記憶、工作記憶、及執行功能。在研究二分別有14、18、19 位病人接受三種隨機分派的藥物操弄：（一）米達諾；（二）米達諾與0.1毫克贊安諾；（三）米達諾與0.4毫克贊安諾，另有控制組同研究一共25人，分別在施打米達諾前與施打後15分鐘進行兩次神經心理測驗，所測面向包含心理運作速度與記憶功能。結果：米達諾影響持續性注意力（11%）、心理運作速度（48%）、記憶（達37%）、及工作記憶（17%），但對定向感及執行功能較無影響，大多數米達諾引起的認知功能缺損可在兩小時內自動緩解，但有10%的病人的記憶表現仍較麻醉前差。贊安諾可大幅改善米達諾引起的心理運作速度與記憶功能缺損，但對前者的恢復效果較佳，高劑量贊安諾可完全恢復心理運作速度的異常，低劑量則否；無論高低劑量的贊安諾皆無法完全恢復記憶功能，但高劑量效果較佳。結論：米達諾對認知功能有選擇性的影響，包括注意、心理運作、記憶、及工作記憶功能，其效果大致於兩小時自動緩解，贊安諾之恢復效果有劑量-效應關係且選擇性地對心理運作速度較佳，其對認知功能的恢復程度應與劑量有關。個體內比較之統計方式較為敏感，可避免個體間表現差異於整組中互相抵銷而低估藥物副作用，其優點與限制在文中討論。

BACKGROUND AND AIMS: Midazolam is a widely used benzodiazepine sedative agent in endoscopy. Flumazenil is a benzodiazepine antagonist capable of reversing midazolam-induced state. The present study aimed to investigate the midazolam-induced cognitive vulnerability profile, the reversal effects and dose-dependent effect of flumazenil, and statistical feasibility of intrapersonal analysis adopting modified Reliable Change Index procedure. METHOD: Prospective, double-blinded and randomized studies were conducted. In study one, thirty patients undergoing sedative colonoscopy and twenty-five non-sedative, non-operated controls were recruited. A battery of neuropsychological tests was given at the entry of study, 15 and 120 minutes after midazolam infusion. Orientation, sustained attention, psychomotor speed, memory, working memory, and executive functions were assessed. In study two, 14, 18, and 19 patients were randomly assigned to receive three different amounts of flumazenil as follows: (i) midazolam only; (ii) midazolam and 0.1mg flumazenil; (iii) midazolam and 0.4mg flumazenil. Control group was the same as in study 1. Psychomotor speed and memory function were assessed before treatment and 15 minutes after drug infusion. RESULTS: Our results revealed that midazolam affected sustained attention (11%), psychomotor speed (48%), memory functions (up to 37%), and working memory (17%), whilst there was no effect on orientation and executive function. Midazolam-induced cognitive impairments generally spontaneously recovered in 2 hours, whereas residual memory impairments were still evident in 10% of the patients. Flumazenil largely reversed psychomotor and memory impairments, particularly the former at 15 minutes. High- rather than low- dosed flumazenil reversed psychomotor function completely. However, flumazenil regardless of the dose level failed to fully reversed memory impairments, but low dose seemed to act better in partially reversing memory impairment. CONCLUSIONS: Midazolam selectively affected sustained attention, psychomotor, and memory functions but these effects generally subsided in 2 hours. Flumazenil improved impaired performance on psychomotor better than memory functions. These reversal effects were dose-dependent, thereby degree of reversal seemed to depend on dosage. Intrapersonal analysis was more sensitive to drug-induced cognitive impairments since individuals’ cognitive changes were liable to be obscured by group mean data analysis. Strength and limitation of this procedure are discussed.