背景:严重创伤性脑损伤后的靶向β受体阻滞剂可能通过减弱交感肾上腺反应来减少继发性脑损伤。艾司洛尔的潜在作用和最佳剂量,一个选择性的,短效,可滴定β-1β受体阻滞剂,作为一个保险箱,尚未评估严重创伤性脑损伤后的推定早期治疗。
方法:我们进行了单中心,使用基于自适应模型的设计的开放标签剂量发现研究。患有严重创伤性脑损伤和颅内压监测的成年人(18岁或以上)在受伤后24小时内接受艾司洛尔治疗,以使他们的心率从前4小时的基线降低15%,同时确保脑灌注压保持在60mmHg以上。在三人一组中,在无剂量限制性毒性的情况下,起始剂量和剂量增量按照预设的计划递增.剂量限制性毒性定义为不能维持脑灌注压,触发停止输注艾司洛尔。主要结果是艾司洛尔的最大耐受剂量方案,定义为剂量限制性毒性的概率小于10%。次要结果包括6个月死亡率和6个月延长的格拉斯哥预后量表评分。
结果:16例患者(6例[37.5%]女性患者;平均年龄36岁[标准差13岁])格拉斯哥昏迷评分中位数为6.5分(四分位距5-7分)接受艾司洛尔治疗。艾司洛尔的最佳起始剂量为10μg/kg/min,每30分钟递增5μg/kg/min,因为它是最高剂量,剂量限制性毒性估计概率小于10%(7%)。6个月时的全因死亡率为12.5%(相当于0.63的标准化死亡率)。观察到一个剂量限制性毒性事件和严重的不良血流动力学影响。
结论:艾司洛尔给药,滴定至心率降低15%,在重型颅脑损伤的24小时内是可行的。当使用优化的方案时,需要停用艾司洛尔的剂量限制性毒性的可能性较低。试用注册我SRCTN,ISRCTN11038397,追溯注册2021年1月7日(https://www.isrctn.com/ISRCTN11038397).
BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed.
METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score.
RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 μg/kg/min, with increments every 30 min of 5 μg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen.
CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).