术前应用乌司他丁对择期下肢关节置换术患者血清炎性因子和术后谵妄的影响

Effects of preoperative ulinastatin treatment on serum cytokines and post-operative delirium in elderly patients receiving lower limb joint replacement

目的 探讨术前应用乌司他丁（ulinastatin, UTI）对下肢关节置换术患者血清炎性因子和术后谵妄（postoperative delirium, POD）的影响。 方法 采用前瞻性、双盲、随机对照研究设计。选择65-85岁，ASA分级Ⅰ-Ⅲ级，择期行下肢关节置换术的老年患者80例，采用随机数字表法分为UTI组和对照组（每组40例）。UTI组于手术开始前将30万单位UTI加入100 ml生理盐水中，30 min内静脉滴注；对照组予以等量生理盐水30 min内静脉滴注。气管插管全身麻醉下完成手术，术后行髂筋膜间隙阻滞。术前1 d行简易智能精神状态检查量表（minimum mental state examination， MMSE）评分，术后24 h（T2）、48 h（T3）、72 h（T4）用意识混乱评估法（confusion assessment method， CAM）进行谵妄评分。记录患者一般情况、术中指标（麻醉时间、手术时间、术中出血及输血量等）及术后指标（VAS评分、术后住院时间及副作用等）。术前（T0）、术毕即刻（T1）、T2、T3分别采集外周静脉血3 ml，离心后批量检测血清促炎细胞因子TNF？蛳α、IL-1β、IL-6及S100β蛋白的含量。 结果 T2和T3时点CAM评分UTI组［（12.8±2.1）、（13.1±2.9）分］均显著低于对照组［（14.0±2.5）、（14.7±3.1）分］（P〈0.05）；T2、T3和T4时点两组POD发生率比较，差异无统计学意义（P＞0.05）。两组患者血清S100β蛋白浓度在T1时达高峰（P〈0.05），与对照组比较，UTI组T1时血清S100β蛋白浓度升高水平显著降低［（304±142） ng/L比（396±208） ng/L］（P〈0.05）。两组患者血清IL-1β和IL-6浓度在T1、T2时点呈上升趋势，T2时达高峰（P〈0.05）；与对照组相比，UTI组T1、T2时血清IL-1β［（70.4±7.3） ng/L比（81.6±8.5） ng/L，（99.6±7.7） ng/L比（105.7±8.0） ng/L）］和IL-6浓度［（55±8） ng/L比（62±8） ng/L，（88±8） ng/L比（99±11） ng/L）］升高水平显著降低（P〈0.05）。 结论 术前应用UTI可降低择期下肢关节置换术老年患者术后48 h CAM评分，改善术后认知功能，其机制可能与抑制炎性因子活化通路有关。

Objective To investigated the effects of preoperative application of ulinastatin（UTI） on serum inflammatory factors and postoperative delirium in elderly patients receiving elective lower limb arthroplasty. Methods A prospective, double-blind, randomized controlled study was conducted. A total of 80 elderly patients（65-85 y old） with ASA grades of Ⅰ-Ⅲ were enrolled in elective lower limb arthroplasty. They were randomly and evenly assigned into ulinastatin treated- （UTI） and non-treated- （control） groups （n=40）. Before surgery, 300 thousand units of UTI was added into 100 ml normal saline and was intravenously infused in 30 min in UTI group, while 100 ml normal saline was intravenously administered in control group in 30 min. All patients received tracheal intubation under general anesthesia during the operation and were subjected to iliac fascia space block guided by ultrasound. We measured minimum mental state examination（MMSE） scores 1 day before operation and assessed the existence of delirium with confusion assessment method（CAM） at postoperative 24 h（T2）, 48 h（T3）, and 72 h（T4）. We collected peri- and post-operative information from the patients, including demographic information, intraoperative parameters （such as, duration of anesthesia and operation, volume of intraoperative bleeding and blood transfusion, dosage of anesthetics, etc.） and postoperative indices（VAS, postoperative recovery and adverse effects, etc.）. We also collected 3 ml peripheral blood from patients before operation（T0） and at post-operative time points （T1, T2 and T3） to detect the serum proinflammatory cytokines, such as, TNF-α, IL-1β, IL-6, and S100β. Results The CAM scores in UTI group[（12.8±2.1）, （13.1±2.9）] were significantly lower than those of control group[（14.0±2.5）, （14.7±3.1）] at T2 and T3（P〈0.05）, respectively. The prevalence of postoperative delirium was not significantly different at T2 through T4 between two groups（P〉0.05）. S100β reached peak at T1 in both UTI and control groups. Compared with the control group, S100β in serum was significantly lower at T1 in UTI group[（304±142） ng/L vs （396±208） ng/L]（P〈0.05）. In two groups of patients, IL-1β and IL-6 in serum at T0-T2 showed upward trends and reached peaks at T2. Compared with the control group, IL-1β and IL-6 in UTI group decreased significantly at T1 [IL-1β： （70.4±7.3） ng/L vs （81.6±8.5） ng/L, IL-6： （55±8） ng/L vs （62±8） ng/L] and T2 [IL-1β： （99.6±7.7） ng/L vs （105.7±8.0） ng/L, IL-6： （88±8） ng/L vs （99±11） ng/L]（P〈0.05）. Conclusions Preoperative treatment with UTI can improve post-operative CAM scores and cognitive function in elderly patients receiving elective lower limb joint replacement. The effects of UTI may be related to its inhibition of inflammatory cytokines.