Abstract
目的
术后谵妄(postoperative delirium，POD)和术后认知功能障碍(postoperative cognitive dysfunction，POCD)是围手术期常见的神经认知障碍，给患者、家庭和社会带来了沉重的负担，因此寻找合适的预防药物非常关键。既往研究证实，围手术期使用右美托咪定可降低POD和早期POCD的发生率，但在肝叶切除术老年患者中的作用及其机制尚不明确。本研究旨在观察术中使用不同剂量右美托咪定对老年肝叶切除术患者POD和早期POCD的预防效果及对促炎与抗炎失衡的影响。
方法
本研究为单中心、前瞻性、随机对照试验，纳入于2019年1月至2020年12月拟择期行肝叶切除术的患者120例，年龄60~80岁，美国麻醉医师协会(American Society of Anesthesiologists，ASA)II~III级。根据随机数字表将纳入的患者分为3组(n=40)：对照组(C组)、右美托咪定1组(Dex1组)和右美托咪定2组(Dex2组)。Dex1组于麻醉诱导后以0.3 μg/(kg·h)的速率泵注右美托咪定；Dex2组于麻醉诱导后以0.6 μg/(kg·h)的速率泵注右美托咪定；C组则泵注等体积的生理盐水。比较3组低血压和心动过缓的发生情况。于麻醉诱导前(T0)、术后第1天(T1)、术后第3天(T2)、术后第5天(T3)和术后第7天(T4)，根据意识模糊评估表(Confusion Assessment Method，CAM)和简易精神状态评价量表(Mini Mental Status Examination，MMSE)评估POD及POCD的发生情况；抽取静脉血，检测神经元特异性烯醇化酶(neuron-specific enolase，NSE)、TNF-α、IL-1β及IL-10的水平。
结果
Dex1组和Dex2组心动过缓发生率均明显高于C组(均P<0.05)，低血压发生率与C组差异无统计学意义(均P>0.05)。C组、Dex1组和Dex2组的POD发生率分别为22.5%、5.0%和7.5%。与C组相比，Dex1组和Dex2组的POD发生率均显著降低(P<0.05)。Dex1组与Dex2组的POD发生率差异无统计学意义(P>0.05)。C组、Dex1组和Dex2组的POCD发生率分别为30.0%、12.5%和10.0%。与C组相比，Dex1和Dex2的POCD发生率均显著降低(P<0.05)。Dex1组与Dex2组的POCD发生率差异无统计学意义(P>0.05)。与C组相比，在T1~T4时间点Dex1组和Dex2组TNF-α和IL-1β显著降低，IL-10水平显著升高(均P<0.05)。与Dex1组相比，Dex2组患者T2时间点IL-1β水平、T1~T3时间点IL-10水平升高(均P<0.05)。与T0相比，C组T1~T4时间点、Dex1组和Dex2组患者T1~T3时间点的NSE水平均升高(均P<0.05)。与C组相比，Dex1组和Dex2组患者的NSE水平在T1~T4时间点均显著降低(均P<0.05)。
结论
术中使用右美托咪定能降低肝叶切除术老年患者POD和POCD的发生率，其机制可能与右美托咪定下调TNF-α、IL-1β和上调IL-10水平，从而调节促炎与抗炎平衡有关。
Keywords: 右美托咪定, 老年患者, 肝叶切除术, 术后谵妄, 术后认知功能障碍
Abstract
Objective
Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are common operative neurocognitive disorders, which places a heavy burden on patients, families and society. Therefore, it is very important to search for preventive drugs. Previous studies have demonstrated that perioperative use of dexmedetomidine resulted in a decrease the incidence of POD and POCD. But the specific effect of dexmedetomidine on elderly patients undergoing hepatic lobectomy and its potential mechanism are not clear. This study aims to evaluate the efficacy of intraoperative use of dexmedetomidine on preventing POD and POCD in elderly patients undergoing hepatic lobectomy and the influence on the balance between proinflammation and anti-inflammation.
Methods
This trial was designed as a single-center, prospective, randomized, controlled study. One hundred and twenty hospitalized patients from January 2019 to December 2020, aged 60-80 years old with American Society of Anesthesiologists (ASA) II-III and scheduled for hepatic lobectomy, were randomly allocated into 3 groups (n=40) using a random number table: A C group, a Dex1 group, and a Dex2 group. After anesthesia induction, saline in the C group, dexmedetomidine [0.3 μg/(kg·h)] in the Dex1 group, and dexmedetomidine [0.6 μg/(kg·h)] in the Dex2 group were infused until the end of operation. The incidences of hypotension and bradycardia were compared among the 3 groups. Confusion Assessment Method (CAM) for assessing POD and Mini Mental State Examination (MMSE) for evaluating POCD were recorded and venous blood samples were obtained for the determination of neuron specific enolase (NSE), TNF-α, IL-1β, and IL-10 at the different time below: the time before anesthesia (T0), and the first day (T1), the third day (T2), the fifth day (T3), and the seventh day (T4) after operation.
Results
Compared with the C group, the incidences of bradycardia in the Dex1 group or the Dex2 group increased (both P<0.05) and there was no difference in hypotension in the Dex1 group or the Dex2 group (both P>0.05). The incidences of POD in the C group, the Dex1 group, and the Dex2 group were 22.5%, 5.0%, and 7.5%, respectively. The incidences of POD in the Dex1 group or the Dex2 group declined significantly as compared to the C group (both P<0.05). However, there is no difference in the incidence of POD between the Dex1 group and the Dex2 group (P>0.05). The incidences of POCD in the C group, the Dex1 group, and the Dex2 group were 30.0%, 12.5%, and 10.0%, respectively. The incidences of POCD in the Dex1 group and the Dex2 group declined significantly as compared to the C group (both P<0.05). And no obvious difference was seen in the incidence of POCD in the Dex1 group and the Dex2 group (P>0.05). Compared with the C group, the level of TNF-α and IL-1β decreased and the level of IL-10 increased at each time points (from T1 to T4) in the Dex1 group and the Dex2 group (all P<0.05). Compared with the Dex1 group, the level of IL-1β at T2 and IL-10 from T1 to T3 elevated in the Dex2 group (all P<0.05). Compared with the T0, the concentrations of NSE in C group at each time points (from T1 to T4) and in the Dex1 group and the Dex2 group from T1 to T3 increased (all P<0.05). Compared with the C group, the level of NSE decreased from T1 to T4 in the Dex1 group and the Dex2 group (all P<0.05).
Conclusion
Intraoperative dexmedetomidine infusion can reduce the incidence of POCD and POD in elderly patients undergoing hepatic lobectomy, and the protective mechanism appears to involve the down-regulation of TNF-α and IL-1β and upregulation of IL-10 expression, which lead to rebalance between proinflammation and anti-inflammation.
Keywords: dexmedetomidine, elderly patients, hepatic lobectomy, postoperative delirium, postoperative cognitive dysfunction
围手术期认知障碍常表现为术后谵妄(postoperative delirium，POD)和术后认知功能(postoperative cognitive dysfunction，POCD)[1]。POD和POCD是围手术期严重的并发症，可能进一步发展为轻度认知障碍甚至痴呆，给患者、家庭和社会带来沉重的负担[1]。因此，寻找合适的预防或治疗药物非常关键。右美托咪定是一种高选择性α2肾上腺素能受体激动剂，具有中枢性抗交感、镇痛、镇静和稳定血流动力学的作用[2]。既往研究[3-4]报道：右美托咪定可降低非心脏手术患者POCD和POD的发生率，但在老年肝叶切除患者中的作用尚不明确。本研究旨在研究术中输注不同剂量的右美托咪定对老年肝叶切除术患者POD和早期POCD的影响，为麻醉医师选择临床药物提供参考，并探讨促炎与抗炎平衡在其中的作用。
1. 对象与方法
1.1. 对象和分组
本研究为2019年1月至2020年12月于湖南省人民医院(湖南师范大学附属第一医院)天心阁院区进行的单中心、前瞻性、随机对照试验，并通过湖南省人民医院(湖南师范大学附属第一医院)医学伦理委员会同意(审批号：2019科研伦审第02号)，术前与患者或患者家属签署知情同意书。
纳入择期行肝叶切除的患者120例，年龄60~80岁，美国麻醉医师协会(American Society of Anesthesiologists，ASA)分级II~III级。排除标准：术前定期使用阿片类药物或镇静药、抗抑郁药或抗焦虑药；术前无法正常沟通交流；术前简易精神状态评价量表(Mini Mental Status Examination，MMSE)测定小于26分；既往存在脑损伤或神经外科手术病史；严重肝功能障碍(Child-Pugh C级)；需要进行透析治疗的严重肾功能不全；术前心脏彩色多普勒超声检查示左室射血分数(ejection fraction，EF)<50%或II度II型以上房室传导阻滞；病态窦房结综合征。根据随机数字表将患者分为对照组(C组)、右美托咪定1组(Dex1组)、右美托咪定2组(Dex2组)，每组40例。
1.2. 方法
患者在进入手术室前禁食8 h，禁饮4 h。进入手术室后，按常规方法开放静脉通路，行心电监护并监测脑电双频指数。麻醉诱导：咪达唑仑(江苏恩华药业有限公司)0.04 mg/kg、1%的丙泊酚注射液(北京费森尤斯卡比医药有限公司)1 mg/kg，舒芬太尼(宜昌人福药业责任有限公司)0.4 μg/kg，顺苯磺酸阿曲库胺(江苏恒瑞医药股份有限公司)0.2 mg/kg。气管插管后，行右桡动脉动脉穿刺置管监测动脉压，右侧颈内静脉置管监测中心静脉压。麻醉维持：1%~2%七氟烷(江苏恒瑞医药股份有限公司)吸入、瑞芬太尼(宜昌人福药业责任有限公司)0.1~0.2 μg/(kg·h)泵注、1%丙泊酚注射液1~4 mg/(kg·h)泵注，根据术中需要间断补充顺苯磺酸阿曲库胺和舒芬太尼。将脑电双频指数维持在40~60之间。Dex1组于麻醉诱导后 10 min开始以0.3 μg/(kg·h)的速率泵注右美托咪定，直至手术完成；Dex2组于麻醉诱导后10 min开始以0.6 μg/(kg·h)的速率泵注右美托咪定，直至手术完成；C组则泵注等体积的生理盐水。术中出现收缩压相对术前值下降>30%和/或收缩压<90 mmHg(1 mmHg=0.133 kPa)时定义为低血压。心率<50 min-1时定义为窦性心动过缓。
1.3. 监测指标
收集患者年龄、性别、ASA分级、BMI、手术时间等一般情况；比较3组术中低血压、心动过缓发生情况。
认知功能评估：于麻醉诱导前(T0)、术后第1天(T1)、术后第3天(T2)、术后第5天(T3)和术后第7天(T4)下午3至6点由不参与麻醉实施的研究人员根据意识模糊评估量表(Confusion Assessment Method，CAM)和简易精神状态量表(Mini-mental State Examination，MMSE)评估患者POCD和POD的发生情况[5]。计算纳入患者T0时MMSE得分的标准差，若患者术后各时间点MMSE评分与T0时间点MMSE评分之差等于或大于1个标准差，则诊断为POCD[6]。计算观察期内患者POCD和POD的发生率。
于T0~T4时间点抽取4 mL中心静脉血，使用ELISA法检测血清中神经元特异性烯醇化酶(neuron-specific enolase，NSE)、TNF-α、IL-1β、IL-10的水平。
1.4. 统计学处理
本研究为随机对照试验，三组样本量比值为1꞉1꞉1。根据既往报道[7-8]，围手术期POCD和POD发生率分别为26%和38%，使用右美托咪定干预后可分别降至6%和2%，设双侧α=0.05，把握度为90%。失访以及拒访的情况以10%计算，得出分别需要20例(POD)和49例(POCD)。使用SPSS 23.0进行数据分析。计量资料以均数±标准差( ±s)表示，使用单因素方差分析或重复测量方差分析(事后分析使用LSD-t检验)；计数资料采用卡方检验或Fisher确切概率法(两两比较使用卡方分割)，P<0.05为差异有统计学意义。
2. 结 果
2.1. 一般资料
3组患者的年龄、性别构成、ASA分级比例、BMI、手术时间差异均无统计学意义(均P>0.05，表1)。
表1.
3组一般临床资料比较(n=40)
Table 1 Comparison of general clinical data among the 3 groups (n=40)
| 组别 | 年龄/岁 | 男/女 | BMI/(kg·m-2) | 手术时间/min | ASA分级/例 | |
|---|---|---|---|---|---|---|
| II | III | |||||
| C组 | 68.71±6.64 | 21/19 | 21.19±6.55 | 169.78±24.78 | 25 | 15 |
| Dex1组 | 66.27±7.16 | 26/14 | 22.84±5.42 | 152.16±27.29 | 12 | 28 |
| Dex2组 | 69.67±6.87 | 18/22 | 21.95±3.25 | 151.35±19.54 | 20 | 20 |
| χ2 /F | 2.586 | 3.29 | 0.99 | 2.81 | 8.62 | |
| P | 0.08 | 0.19 | 0.38 | 0.06 | 0.13 | |
2.2. 循环不良事件发生情况
Dex1组和Dex2组心动过缓发生率均明显高于C组(P=0.005)，低血压发生率与C组差异无统计学意义(P=0.21，表2)。
表2.
3组循环不良事件、POCD和POD的发生率比较(n=40)
Table 2 Comparison of incidence of circulatory adverse events, POCD, and POD among the 3 groups (n=40)
| 组别 | 低血压/[例(%)] | 心动过缓/[例(%)] | POCD/ [例(%)] | POD/ [例(%)] |
|---|---|---|---|---|
| C组 | 8(20.0) | 7(17.5) | 12(30.0) | 9(22.5) |
| Dex1组 | 13(32.5) | 10(25.0)* | 5(12.5)* | 2(5.0)* |
| Dex2组 | 15(37.5) | 15(37.5)* | 4(10.0)* | 3(7.5)* |
| χ2 | 3.10 | 10.73 | 5.99 | 6.11 |
| P | 0.21 | 0.005 | <0.05 | <0.05 |
POCD：术后认知功能障碍；POD：术后谵妄。与C组比较，*P<0.05。
2.3. POD和POCD发生情况
C组、Dex1和Dex组的POD发生率分别为22.5%、5.0%和7.5%。Dex1和Dex2的POD发生率低于C组，差异具有统计学意义(P<0.05)。Dex1组与Dex2组的POD发生率差异无统计学意义(P>0.05，表2)。
C组、Dex1组和Dex2组的POCD发生率分别为30.0%、12.5%和10.0%。Dex1和Dex2的POCD发生率低于C组，差异具有统计学意义(P<0.05)。Dex1组与Dex2组的POCD发生率差异无统计学意义(P>0.05，表2)。
2.4. TNF-α、IL-1β、IL-10与NSE水平
3组患者术前TNF-α、IL-1β、IL-10水平差异均无统计学意义(均P>0.05)。与T0相比，3组患者T1~T4的TNF-α、IL-1β和IL-10水平均显著升高(均 P<0.05)。与C组相比，在T1~T4，Dex1组和Dex2组TNF-α和IL-1β降低，IL-10水平升高(均P<0.05)。与Dex1组相比，Dex2组患者血清中IL-1β水平(T2)降低，IL-10(T1~T3)水平升高(均P<0.05)。3组患者术前NSE水平差异无统计学意义(P>0.05)。与T0相比，C组T1~T4、Dex1组和Dex2组患者T1~T3的NSE水平均升高，差异均有统计学意义(均P<0.05)。Dex1组和Dex2组患者的NSE水平在T1~T4均显著低于C组(P<0.05，表3)。
表3.
3组不同时间点TNF-α、IL-1β、IL-10和NSE的比较(n=40， ±s)
Table 3 Comparison of TNF-α, IL-1β, IL-10, and NSE at each time point in the 3 groups (n=40, ±s)
| 分组 | 时间点 | TNF-α/(ng·L-1) | IL-1β/(ng·L-1) | IL-10/(ng·L-1) | NSE/(μg·L-1) |
|---|---|---|---|---|---|
| C组 | T0 | 11.46±2.01 | 46.17±7.42 | 7.83±2.59 | 13.68±4.55 |
| T1 | 48.17±6.13* | 222.24±31.68* | 38.20 ±8.92* | 22.68±2.10* | |
| T2 | 24.29±5.67* | 204.54±35.17* | 28.12 ±8.11* | 19.72±4.52* | |
| T3 | 21.55±3.15* | 175.54±23.95* | 17.12 ±7.73* | 19.22±2.62* | |
| T4 | 17.42±3.22* | 121.42±37.19* | 11.51 ±2.65* | 16.11±2.51* | |
| Dex1组 | T0 | 10.10±1.29 | 41.23±6.20 | 6.93±3.18 | 12.33±3.75 |
| T1 | 38.44±5.84*† | 200.87±37.16*† | 46.79 ±9.10*† | 18.33±1.61*† | |
| T2 | 16.42±8.92*† | 165.51±26.72*† | 34.53±6.18*† | 16.23±3.61*† | |
| T3 | 17.16±4.29*† | 127.15±34.19*† | 22.83±5.37*† | 17.33±4.06*† | |
| T4 | 13.19±4.57*† | 100.19±30.17*† | 15.83±2.11*† | 14.26±2.76† | |
| Dex2组 | T0 | 9.88±1.43 | 48.89±5.18 | 7.13±1.68 | 12.91±4.48 |
| T1 | 36.23±7.23*† | 192.23±29.23*† | 52.16 ±6.19*†‡ | 15.14±2.35*†‡ | |
| T2 | 18.64±7.61*† | 175.54±33.54*†‡ | 40.28±9.55*†‡ | 17.05±5.17*† | |
| T3 | 16.22±4.29*† | 116.15±29.28*† | 28.45±7.27*†‡ | 15.11±3.29*†‡ | |
| T4 | 14.47±3.19*† | 89.47±24.18*† | 14.37±4.17*† | 13.15±2.23† |
NSE：神经元特异性烯醇化酶；TNF-α：肿瘤坏死因子-α；IL-1β：白细胞介素-1β；IL-10：白细胞介素-10。与T0时比较，*P<0.05；与C组比较，†P<0.05；与Dex1组比较，‡P<0.05。
3. 讨 论
肝叶切除术有创伤大、手术时间较长、出血较多、术中常用低中心静脉压技术导致循环波动大等特点，患者术后也常经历疼痛、多种引流管留置、睡眠障碍等导致的不适，而且高龄是POCD及POD的独立危险因素，因此肝叶切除术的老年患者围手术期POD和POCD发生率较高[9-10]。目前临床上常用MMSE来评估患者的认知功能状态，而NSE作为脑损伤的标志，与POCD有相关性。CAM是目前最广泛使用的POD筛查工具。研究[11-12]表明右美托咪定可预防或减轻老年患者POD和POCD的发生，但临床上使用的剂量多种多样，最合适的给药剂量也尚不明确。根据药品说明书推荐的给药方法，负荷剂量为1 μg/kg，10 min之内静脉泵注；维持剂量为0.2~0.7 μg/(kg·h)，患者常出现心动过缓、低血压、心律不齐等循环不良事件，在老年患者中更甚[13]。本研究的结果显示：两种剂量的右美托咪定均能降低POD和POCD的发生率，改善脑损伤，而且低血压的发生率与对照组无明显差异。此研究结果为老年肝叶切除患者围手术期使用右美托咪定提供了用药依据，具有较大的临床价值。
目前围手术期神经认知障碍的机制不明。既往研究[14]显示围手术期手术创伤等因素引起的炎症反应是POD和POCD发生的重要机制之一。麻醉和手术刺激可引发全身炎症反应，炎症因子表达增多，炎症细胞活化并迁移至脑组织，其中TNF-α和IL-1β作为全身炎症的启动因子，具有广泛的生物学活性，可直接或间接穿透血脑屏障，引起神经元水肿，影响突触功能，改变神经递质的传递，导致中枢神经系统炎症[15]。在中枢神经系统炎症阶段，TNF-α和IL-1β可易化外周炎症因子迁移，促进兴奋性神经毒性损伤，扩大中枢神经系统炎症反应，参与POCD与POD的发生[15-16]。IL-10是体内维持促炎与抗炎平衡的重要细胞因子，它通过减少促炎因子(TNF-α、IL-1β和IL-6)的产生发挥限制炎症反应强度、终止炎症反应的作用[17]。本研究结果显示：右美托咪定可促进抗炎因子IL-10的分泌，抑制TNF-α和IL-1β的产生，调整全身促炎与抗炎的平衡，可能的机制如下：1)右美托咪定作用于中枢及外周神经系统α2肾上腺受体，抑制交感活性，减轻应激反应，并激活胆碱能抗炎通路，从而降低全身炎症反应强度[18-19]；2)右美托咪定通过抑制TLR4/NF-κB、JAK2-STAT3和NF-κB/COX-2途径下调NF-κB通路活性，从而降低炎症因子的表达[19-20]。
本研究存在不足之处：1)虽然比较了2种剂量的右美托咪定对围手术期神经认知障碍的影响，但没有观察对肝组织的影响；2)未能对纳入研究的患者进行长期认知功能的观察。上述不足将在进一步的研究中探讨。
综上，右美托咪定可降低老年肝叶切除术患者早期POCD和POD的发生风险，该作用可能与右美托咪定调整炎症与抗炎失衡有关。
基金资助
湖南省自然科学基金(2018JJ3296)；长沙市科技局项目(kq1901056)。
This work was supported by the Natural Science Foundation of Hunan Province (2018JJ3296) and the Project of Changsha Science and Technology Bureau (kq1901056), China.
利益冲突声明
作者声称无任何利益冲突。
作者贡献
唐轶珣 ELISA实验操作、患者术后认知功能评估、文章撰写与修订；王永胜 临床病例收集；孔高茵 指导论文修改；赵媛 临床病例收集；魏来 临床病例收集及统计学方法指导；刘际童 实验设计及临床指导、指导论文修改。
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202202219.pdf
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