Doi Matsuyuki, Takahashi Naoki, Nojiri Rumi, Hiraoka Takehiko, Kishimoto Yusuke, Inoue Shinichi, Oya Nobuyo
Department of Anesthesiology and Intensive Care Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
Clinical Development Department, Maruishi Pharmaceutical Co., Ltd., 2-2-18 Imazu-Naka, Tsurumi-Ku, Osaka, 538-0042, Japan.
J Intensive Care. 2023 Nov 13;11(1):51. doi: 10.1186/s40560-023-00698-9.
The aims of this study were to evaluate the efficacy, safety, and pharmacokinetics (PK) of continuous intravenous administration of remifentanil in mechanically ventilated patients in the intensive care unit (ICU).
This was a multicenter, randomized, double-blinded, fentanyl-controlled, non-inferiority phase 3 study. Patients aged ≥ 20 years requiring 6 h to 10 days mechanical ventilation in an ICU and requiring pain relief were randomly assigned in a 1:1 ratio to receive either remifentanil (n = 98) or fentanyl (n = 98). Dose was titrated from an infusion rate of 1 mL/h (remifentanil: 0.025 µg/kg/min, fentanyl: 0.1 µg/kg/h) until the target level of analgesia (behavioral pain scale [BPS] ≤ 5 or numerical rating score [NRS] ≤ 3) was achieved by escalating the dose in 1 mL/h increasing. Administration was then adjusted to maintain the target level of analgesia until weaning from the ventilator. The primary endpoint was the proportion of patients who did not require rescue fentanyl. Safety was assessed according to standard procedures. PK of remifentanil in the arterial blood was assessed in 24 patients.
The proportion of patients achieving the primary endpoint in the remifentanil and fentanyl groups was 100% (92/92) and 97.8% (88/90), respectively. The difference between the groups was 2.2% (95% confidence interval, - 0.8-5.3) and non-inferiority of remifentanil to fentanyl was verified (p < 0.0001). The incidences of any adverse events in the remifentanil and fentanyl groups was 34 of 92 patients (37.0%) and 34 of 90 patients (37.8%), respectively. Adverse drug reactions was 12 in 92 patients (13.0%) and 15 in 90 patients (16.7%), respectively. In the PK analysis, blood remifentanil concentration decreased within 10 min to almost 50% of the end of administration, suggesting rapid offset of action following discontinuation of remifentanil.
Remifentanil can be used safely for pain management in mechanically ventilated Japanese patients in the ICU.
Japan Registry of Clinical Trials, jRCT2080224954. Registered 20 November 2019, https://jrct.niph.go.jp/latest-detail/jRCT2080224954 .
本研究旨在评估在重症监护病房（ICU）中机械通气患者持续静脉输注瑞芬太尼的疗效、安全性及药代动力学（PK）。
这是一项多中心、随机、双盲、以芬太尼为对照的非劣效性3期研究。年龄≥20岁、在ICU需要进行6小时至10天机械通气且需要镇痛的患者按1:1比例随机分配，分别接受瑞芬太尼（n = 98）或芬太尼（n = 98）治疗。剂量从1 mL/h的输注速率开始滴定（瑞芬太尼：0.025 μg/kg/min，芬太尼：0.1 μg/kg/h），直至通过每小时增加1 mL来提高剂量，达到目标镇痛水平（行为疼痛量表[BPS]≤5或数字评分量表[NRS]≤3）。然后调整给药以维持目标镇痛水平，直至脱机。主要终点是不需要补救性芬太尼的患者比例。根据标准程序评估安全性。在24例患者中评估动脉血中瑞芬太尼的PK。
瑞芬太尼组和芬太尼组达到主要终点的患者比例分别为100%（92/92）和97.8%（88/90）。两组之间的差异为2.2%（95%置信区间，-0.8 - 5.3），证实瑞芬太尼不劣于芬太尼（p < 0.0001）。瑞芬太尼组和芬太尼组任何不良事件的发生率分别为92例患者中的34例（37.0%）和90例患者中的34例（37.8%）。药物不良反应分别为92例患者中的12例（13.0%）和90例患者中的15例（16.7%）。在PK分析中，动脉血中瑞芬太尼浓度在10分钟内降至给药结束时的近50%，表明瑞芬太尼停药后作用迅速消失。
瑞芬太尼可安全用于ICU中机械通气的日本患者的疼痛管理。
日本临床试验注册中心，jRCT2080224954。于2019年11月20日注册，https://jrct.niph.go.jp/latest-detail/jRCT2080224954 。
