Preliminary Communication | February 19, 2019

Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial

Balachundhar Subramaniam, Puja Shankar, Shahzad Shaefi, et al

JAMA. 2019;321(7):686-696. doi:10.1001/jama.2019.0234

Abstract

Importance 背景

Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative.

心脏手术后谵妄非常普遍，可能受到麻醉药物及镇静药物选择的影响。

Objective 目的

To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery.

评价术后静脉(IV)对乙酰氨基酚与安慰剂联合IV异丙酚与右美托咪定对老年患者心脏手术后谵妄的影响。

Design, Setting, and Participants 设计，场景及研究人群

Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2018.

美国一个中心进行的随机、安慰剂对照、析因设计临床试验，纳入60岁及以上接受体外循环冠脉搭桥手术(CABG)或CABG联合瓣膜手术的患者。2015年9月至2018年4月入选患者，随访截止于2018年4月。

Interventions 干预措施

Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30).

患者被随机分至4组中的1组，术后分别接受IV对乙酰氨基酚或安慰剂（每6小时给药，疗程48小时）镇痛，从关胸开始至术后使用右美托咪定或异丙酚镇静，持续不超过6小时（对乙酰氨基酚和右美托咪定：n = 29；安慰剂和右美托咪定：n = 30；对乙酰氨基酚和异丙酚：n = 31；安慰剂和异丙酚：n = 30）。

Main Outcomes and Measures 主要预后指标

The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay.

主要预后指标为根据CAM法评估的术后住院期间谵妄发生率。次要预后指标包括谵妄持续时间，认知下降，最初48小时内突破性镇痛药物使用，ICU住院日及总住院日。

Results 结果

Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, −18% [95% CI, −32% to −5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, −4% [95% CI, −18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, −1 [95% CI, −2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, −16.7 [95% CI, −20.3 to −0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, −83 [95% CI, −154 to −14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, −69 [95% CI, −155 to −4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension.

总共121名患者接受随机分组（中位年龄69岁；19名女性患者[15.8%]），120名完成试验。接受IV对乙酰氨基酚治疗的患者谵妄发生率显著降低（10% vs 安慰剂28%；差异，−18% [95% CI, −32% to −5%]；P = .01；HR，2.8 [95% CI, 1.1-7.8]）。接受右美托咪定或异丙酚的患者谵妄发生率无显著差异（17% vs 21%；差异，−4% [95% CI, −18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]）。对于3项预先确定的次要预后指标而言，与安慰剂对照相比，对乙酰氨基酚并无显著差异：谵妄持续时间（中位数1 vs 2 天；差异，−1 [95% CI, −2 to 0]），ICU住院日（中位数 29.5 vs 46.7 小时；差异，−16.7 [95% CI, −20.3 to −0.8]），突破性镇痛药物使用（中位数，322.5 vs 405.3 µg 吗啡等效剂量；差异，−83 [95% CI, −154 to −14]）。右美托咪定与异丙酚相比，仅有突破性镇痛药物使用存在显著差异（中位数，328.8 vs 397.5 µg；差异，−69 [95% CI, −155 to −4]; P = .04）。安慰剂-右美托咪定组(46%)及对乙酰氨基酚-异丙酚组(45%)各有14名患者及对乙酰氨基酚-右美托咪定组(24%)和安慰剂-异丙酚组(23%)各有7名患者发生低血压。

Conclusions and Relevance 结论与意义

Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted.

对于接受心脏手术的老年患者，与安慰剂对照相比，术后计划性使用IV对乙酰氨基酚，联合IV异丙酚或右美托咪定，能够减少住院期间谵妄发生。需要进一步研究包括比较IV与口服对乙酰氨基酚和其他非阿片类镇痛药物对术后谵妄的影响。

Trial Registration 研究注册

ClinicalTrials.gov Identifier: NCT02546765