Duncan Dallas, Sankar Ashwin, Beattie W Scott, Wijeysundera Duminda N
Department of Anesthesia, University of Toronto, 123 Edward Street, 12th Floor, Toronto, ON, Canada, M5G 1E2.
Cochrane Database Syst Rev. 2018 Mar 6;3(3):CD004126. doi: 10.1002/14651858.CD004126.pub3.
The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications.
To determine the efficacy and safety of α-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery.
We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles.
We included randomized controlled trials that compared α-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-α-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of α-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia).
Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI).
We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The α-2 adrenergic agonist studied was clonidine in 21 trials, dexmedetomidine in 24 trials and mivazerol in two trials.In non-cardiac surgery, there was high quality evidence that α-2 adrenergic agonists led to a similar risk of all-cause mortality compared with control groups (1.3% with α-2 adrenergic agonists versus 1.7% with control; RR 0.80, 95% CI 0.61 to 1.04; participants = 14,081; studies = 16). Additionally, the risk of cardiac mortality was similar between treatment groups (0.8% with α-2 adrenergic agonists versus 1.0% with control; RR 0.86, 95% CI 0.60 to 1.23; participants = 12,525; studies = 5, high quality evidence). The risk of myocardial infarction was probably similar between treatment groups (RR 0.94, 95% CI 0.69 to 1.27; participants = 13,907; studies = 12, moderate quality evidence). There was no associated effect on the risk of stroke (RR 0.93, 95% CI 0.55 to 1.56; participants = 11,542; studies = 7; high quality evidence). Conversely, α-2 adrenergic agonists probably increase the risks of clinically significant bradycardia (RR 1.59, 95% CI 1.18 to 2.13; participants = 14,035; studies = 16) and hypotension (RR 1.24, 95% CI 1.03 to 1.48; participants = 13,738; studies = 15), based on moderate quality evidence.There was insufficient evidence to determine the effect of α-2 adrenergic agonists on all-cause mortality in cardiac surgery (RR 0.52, 95% CI 0.26 to 1.04; participants = 1947; studies = 16) and myocardial infarction (RR 1.01, 95% CI 0.43 to 2.40; participants = 782; studies = 8), based on moderate quality evidence. There was one cardiac death in the clonidine arm of a study of 22 participants. Based on very limited data, α-2 adrenergic agonists may have reduced the risk of stroke (RR 0.37, 95% CI 0.15 to 0.93; participants = 1175; studies = 7; outcome events = 18; low quality evidence). Conversely, α-2 adrenergic agonists increased the risk of bradycardia from 6.4% to 12.0% (RR 1.88, 95% CI 1.35 to 2.62; participants = 1477; studies = 10; moderate quality evidence), but their effect on hypotension was uncertain (RR 1.19, 95% CI 0.87 to 1.64; participants = 1413; studies = 9; low quality evidence).These results were qualitatively unchanged in subgroup analyses and sensitivity analyses.
AUTHORS' CONCLUSIONS: Our review concludes that prophylactic α-2 adrenergic agonists generally do not prevent perioperative death or major cardiac complications. For non-cardiac surgery, there is moderate-to-high quality evidence that these agents do not prevent death, myocardial infarction or stroke. Conversely, there is moderate quality evidence that these agents have important adverse effects, namely increased risks of hypotension and bradycardia. For cardiac surgery, there is moderate quality evidence that α-2 adrenergic agonists have no effect on the risk of mortality or myocardial infarction, and that they increase the risk of bradycardia. The quality of evidence was inadequate to draw conclusions regarding the effects of alpha-2 agonists on stroke or hypotension during cardiac surgery.
手术应激反应在围手术期心脏并发症的发病机制中起重要作用。α-2肾上腺素能激动剂可减轻这种反应，并可能有助于预防术后心脏并发症。
确定α-2肾上腺素能激动剂在降低接受心脏手术和非心脏手术的成人死亡率和心脏并发症方面的疗效和安全性。
我们检索了Cochrane系统评价数据库（2017年第4期）、MEDLINE（1950年至2017年4月第4周）、Embase（1980年至2017年5月）、科学引文索引、临床试验注册库以及纳入文章的参考文献列表。
我们纳入了将α-2肾上腺素能激动剂（即可乐定、右美托咪定或米伐唑醇）与安慰剂或非α-2肾上腺素能激动剂进行比较的随机对照试验。纳入的试验必须评估α-2肾上腺素能激动剂预防围手术期死亡或心脏并发症（或两者）的疗效和安全性，或测量一个或多个相关结局（即死亡、心肌梗死、心力衰竭、急性中风、室上性快速心律失常和心肌缺血）。
两位作者独立评估试验质量、提取数据并独立进行抽象数据的计算机录入。我们联系研究作者以获取更多信息。不良事件数据来自试验。我们使用Cochrane“偏倚风险”工具评估纳入的研究，并使用GRADE方法评估汇总治疗效果的证据质量。鉴于心脏手术和非心脏手术之间的临床异质性，我们分别分析了这些亚组。我们将治疗效果表示为具有95%置信区间（CI）的汇总风险比（RR）。
我们纳入了47项试验，共17039名参与者。在这些研究中，24项试验仅纳入接受心脏手术的参与者，23项仅纳入接受非心脏手术的参与者，8项仅纳入接受血管手术的参与者。所研究的α-2肾上腺素能激动剂在21项试验中为可乐定，24项试验中为右美托咪定，2项试验中为米伐唑醇。在非心脏手术中，有高质量证据表明，与对照组相比，α-2肾上腺素能激动剂导致全因死亡风险相似（α-2肾上腺素能激动剂组为1.3%，对照组为1.7%；RR 0.80，95%CI 0.61至1.04；参与者 = 14081；研究 = 16）。此外，治疗组之间的心脏死亡风险相似（α-2肾上腺素能激动剂组为0.8%，对照组为1.0%；RR 0.86，95%CI 0.60至1.23；参与者 = 12525；研究 = 5，高质量证据）。治疗组之间心肌梗死风险可能相似（RR 0.94，95%CI 0.69至1.27；参与者 = 13907；研究 = 12，中等质量证据）。对中风风险无相关影响（RR 0.93，95%CI 0.55至1.56；参与者 = 11542；研究 = 7；高质量证据）。相反，基于中等质量证据，α-2肾上腺素能激动剂可能增加临床上显著心动过缓（RR 1.59，95%CI 1.18至2.13；参与者 = 14035；研究 = 16）和低血压（RR 1.24，95%CI 1.03至1.48；参与者 = 13738；研究 = 15）的风险。基于中等质量证据，没有足够的证据来确定α-2肾上腺素能激动剂对心脏手术中全因死亡（RR 0.52，95%CI 0.26至1.04；参与者 = 1947；研究 = 16）和心肌梗死（RR 1.01，95%CI 0.43至2.40；参与者 = 782；研究 = 8）的影响有一项涉及22名参与者的研究中，可乐定组有1例心脏死亡。基于非常有限的数据，α-2肾上腺素能激动剂可能降低了中风风险（RR 0.37，95%CI 0.15至0.93；参与者 = 1175；研究 = 总事件 = 18；低质量证据）。相反，α-2肾上腺素能激动剂使心动过缓风险从6.4%增加到12.0%（RR 1.88，95%CI 1.35至2.62；参与者 = 1477；研究 = 10；中等质量证据），但其对低血压的影响不确定（RR 1.19，95%CI 0.87至1.64；参与者 = 1413；研究 = 9；低质量证据）。这些结果在亚组分析和敏感性分析中在质量上没有变化。
我们的综述得出结论，预防性使用α-2肾上腺素能激动剂通常不能预防围手术期死亡或主要心脏并发症。对于非心脏手术，有中等到高质量的证据表明这些药物不能预防死亡、心肌梗死或中风。相反，有中等质量的证据表明这些药物有重要的不良反应，即低血压和心动过缓风险增加。对于心脏手术，有中等质量的证据表明α-2肾上腺素能激动剂对死亡风险或心肌梗死没有影响，并且会增加心动过缓的风险。证据质量不足以就α-2激动剂对心脏手术期间中风或低血压影响得出结论。
