Weibel Stephanie, Jelting Yvonne, Afshari Arash, Pace Nathan Leon, Eberhart Leopold Hj, Jokinen Johanna, Artmann Thorsten, Kranke Peter
Department of Anaesthesia and Critical Care, University of Würzburg, Oberduerrbacher Str. 6, Würzburg, Germany.
Juliane Marie Centre - Anaesthesia and Surgical Clinic Department 4013, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Cochrane Database Syst Rev. 2017 Apr 13;4(4):CD011989. doi: 10.1002/14651858.CD011989.pub2.
BACKGROUND: Multiple analgesic strategies for pain relief during labour are available. Recently remifentanil, a short-acting opioid, has recently been used as an alternative analgesic due to its unique pharmacological properties. OBJECTIVES: To systematically assess the effectiveness of remifentanil intravenous patient-controlled analgesia (PCA) for labour pain, along with any potential harms to the mother and the newborn. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (9 December 2015), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), handsearched congress abstracts (November 2015), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster-randomised trials comparing remifentanil (PCA) with another opioid (intravenous (IV)/intramuscular (IM)), or with another opioid (PCA), or with epidural analgesia, or with remifentanil (continuous IV), or with remifentanil (PCA, different regimen), or with inhalational analgesia, or with placebo/no treatment in all women in labour including high-risk groups with planned vaginal delivery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data, and appraised study quality.We contacted study authors for additional information other than incomplete outcome data. We performed random-effects meta-analysis.To reduce the risk of random error in meta-analysis we performed trial sequential analysis. We included total zero event trials and used a constant continuity correction of 0.01 (ccc 0.01) for meta-analysis. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: Twenty RCTs with 3569 women were included. Of those, 10 trials (2983 participants) compared remifentanil (PCA) to an epidural, four trials (216 participants) to another opioid (IV/IM), three trials (215 participants) to another opioid (PCA), two trials (135 participants) to remifentanil (continuous IV), and one trial (20 participants) to remifentanil (PCA, different regimen). No trials were identified for the remaining comparisons.Methodological quality of studies was moderate to poor. We assessed risk of bias as high for blinding issues and incomplete outcome data in 65% and 45% of the included studies, respectively.There is evidence of effect that women in the remifentanil (PCA) group were more satisfied with pain relief than women in the other opioids (IV/IM) group (standardised mean difference (SMD) 2.11, 95% confidence interval (CI) 0.72 to 3.49, four trials, very low-quality evidence), and that women were less satisfied compared to women in the epidural group (SMD -0.22, 95% CI -0.40 to -0.04, seven trials, very low-quality evidence).There is evidence of effect that remifentanil (PCA) provided stronger pain relief at one hour than other opioids administered IV/IM (SMD -1.58, 95% CI -2.69 to -0.48, three trials, very low-quality evidence) or via PCA (SMD -0.51, 95% CI -1.01 to -0.00, three trials, very low-quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (SMD 0.57, 95% CI 0.31 to 0.84, six trials, low-quality evidence).Data were limited on safety aspects for both the women and the newborns. Only one study analysed maternal apnoea in a comparison of remifentanil (PCA) versus epidural and reported that half of the women in the remifentanil and none in the epidural group had an apnoea (very low-quality evidence). There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for maternal respiratory depression when compared to epidural analgesia (RR 0.91, 95% CI 0.51 to 1.62, ccc 0.01, three trials, low-quality evidence) and no reliable conclusion might be reached compared to remifentanil (continuous IV) (all study arms included zero events, two trials, low-quality evidence). In one trial of remifentanil (PCA) versus another opioid (IM) three out of 18 women in the remifentanil and none out of 18 in the control group had a respiratory depression (very low-quality evidence).There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for newborns with Apgar scores less than seven at five minutes compared to epidural analgesia (RR 1.26, 95% CI 0.62 to 2.57, ccc 0.01, five trials, low-quality evidence) and no reliable conclusion might be reached compared to another opioid (IV) and compared to remifentanil (PCA, different regimen) both with zero events in all study arms (one trial, very-low quality evidence). In one trial of remifentanil (PCA) versus another opioid (PCA) none out of nine newborns in the remifentanil and three out of eight in the opioid (PCA) group had Apgar scores less than seven (very-low quality evidence).There is evidence that remifentanil (PCA) was associated with a lower risk for the requirement of additional analgesia when compared to other opioids (IV/IM) (RR 0.57, 95% CI 0.40 to 0.81, three trials, moderate-quality evidence) and that it was associated with a higher risk compared to epidural analgesia (RR 9.27, 95% CI 3.73 to 23.03, ccc 0.01, six trials, moderate-quality evidence). There is no evidence of effect that remifentanil (PCA) reduced the requirement for additional analgesia compared to other opioids (PCA) (RR 0.76, 95% CI 0.45 to 1.28, three trials, low-quality evidence).There is evidence that there was no difference in the risk for caesarean delivery between remifentanil (PCA) and other opioids (IV/IM) (RR 0.63, 95% CI 0.30 to 1.32, ccc 0.01, four trials, low-quality evidence) and epidural analgesia (RR 1.0, 95% CI 0.82 to 1.22, ccc 0.01, nine trials, moderate-quality evidence), respectively. Pooled meta-analysis revealed an increased risk for caesarean section under remifentanil (PCA) compared to other opioids (PCA) (RR 2.78, 95% CI 0.99 to 7.82, two trials, very low-quality evidence). However, a wide range of clinically relevant and non-relevant treatment effects is compatible with this result. AUTHORS' CONCLUSIONS: Based on the current systematic review, there is mostly low-quality evidence to inform practice and future research may significantly alter the current situation. The quality of evidence is mainly limited by poor quality of the studies, inconsistency, and imprecision. More research is needed on maternal and neonatal safety outcomes (maternal apnoea and respiratory depression, Apgar score) and on the optimal mode and regimen of remifentanil administration to provide highest efficacy with reasonable adverse effects for mothers and their newborns.
背景：分娩期间有多种镇痛策略可供选择。最近，瑞芬太尼作为一种短效阿片类药物，因其独特的药理特性，已被用作替代镇痛药。 目的：系统评价瑞芬太尼静脉自控镇痛（PCA）用于分娩镇痛的有效性，以及对母亲和新生儿的任何潜在危害。 检索方法：我们检索了Cochrane妊娠与分娩组试验注册库（2015年12月9日）、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台（ICTRP），手工检索了会议摘要（2015年11月），并检索了纳入研究的参考文献列表。 选择标准：随机对照试验（RCT）和整群随机试验，比较瑞芬太尼（PCA）与另一种阿片类药物（静脉注射（IV）/肌肉注射（IM）），或与另一种阿片类药物（PCA），或与硬膜外镇痛，或与瑞芬太尼（持续静脉注射），或与瑞芬太尼（PCA，不同方案），或与吸入性镇痛，或与安慰剂/未治疗，纳入所有分娩妇女，包括计划阴道分娩的高危组。 数据收集与分析：两位综述作者独立评估试验是否纳入，提取数据，并评估研究质量。我们联系研究作者以获取除不完整结局数据之外的其他信息。我们进行随机效应荟萃分析。为降低荟萃分析中随机误差的风险，我们进行了试验序贯分析。我们纳入了所有零事件试验，并在荟萃分析中使用了0.01的恒定连续性校正（ccc 0.01）。我们应用推荐分级、评估、制定和评价（GRADE）方法来评估证据质量。 主要结果：纳入了20项RCT，共3569名妇女。其中，10项试验（2983名参与者）比较了瑞芬太尼（PCA）与硬膜外镇痛，4项试验（216名参与者）比较了瑞芬太尼（PCA）与另一种阿片类药物（IV/IM），3项试验（215名参与者）比较了瑞芬太尼（PCA）与另一种阿片类药物（PCA），2项试验（135名参与者）比较了瑞芬太尼（持续静脉注射）与瑞芬太尼（PCA），1项试验（20名参与者）比较了瑞芬太尼（PCA，不同方案）与瑞芬太尼（PCA）。未发现其余比较的试验。研究的方法学质量为中等至较差。我们评估纳入研究中65%和45%的研究因盲法问题和不完整结局数据导致的偏倚风险较高。有证据表明，瑞芬太尼（PCA）组的妇女比其他阿片类药物（IV/IM）组的妇女对疼痛缓解更满意（标准化均值差（SMD）2.11，95%置信区间（CI）0.72至3.49，4项试验，极低质量证据），且与硬膜外组的妇女相比满意度较低（SMD -0.22，95% CI -0.40至-0.04，7项试验，极低质量证据）。有证据表明，瑞芬太尼（PCA）在1小时时比静脉注射/肌肉注射的其他阿片类药物（SMD -1.58，95% CI -2.69至-0.48，3项试验，极低质量证据）或通过PCA给药的其他阿片类药物（SMD -0.51，95% CI -1.01至-0.00，3项试验，极低质量证据）提供更强的疼痛缓解。与硬膜外组相比，瑞芬太尼（PCA）组的疼痛强度更高（SMD 0.57，95% CI 0.31至0.84，6项试验，低质量证据）。关于母亲和新生儿的安全方面的数据有限。只有一项研究在比较瑞芬太尼（PCA）与硬膜外镇痛时分析了母亲呼吸暂停，报告瑞芬太尼组一半的妇女出现呼吸暂停，而硬膜外组无一人出现呼吸暂停（极低质量证据）。没有证据表明与硬膜外镇痛相比，瑞芬太尼（PCA）与母亲呼吸抑制风险增加有关（风险比（RR）0.91，95% CI 0.51至1.62，ccc 0.01，3项试验，低质量证据），与瑞芬太尼（持续静脉注射）相比也无法得出可靠结论（所有研究组均为零事件，2项试验，低质量证据）。在一项瑞芬太尼（PCA）与另一种阿片类药物（IM）的试验中，瑞芬太尼组18名妇女中有3人出现呼吸抑制，而对照组18名妇女中无人出现呼吸抑制（极低质量证据）。没有证据表明与硬膜外镇痛相比，瑞芬太尼（PCA）与5分钟时阿氏评分低于7分的新生儿风险增加有关（RR 1.26，95% CI 0.62至2.57，ccc 0.01，5项试验，低质量证据），与另一种阿片类药物（IV）相比以及与瑞芬太尼（PCA，不同方案）相比也无法得出可靠结论，所有研究组均为零事件（1项试验，极低质量证据）。在一项瑞芬太尼（PCA）与另一种阿片类药物（PCA）的试验中，瑞芬太尼组9名新生儿中无人阿氏评分低于7分，而阿片类药物（PCA）组8名新生儿中有3人阿氏评分低于7分（极低质量证据）。有证据表明，与其他阿片类药物（IV/IM）相比，瑞芬太尼（PCA）与额外镇痛需求风险较低有关（RR 0.57，95% CI 0.40至0.81，3项试验，中等质量证据），与硬膜外镇痛相比风险较高（RR 9.27，95% CI 3.73至23.03，ccc 0.01，6项试验，中等质量证据）。没有证据表明与其他阿片类药物（PCA）相比，瑞芬太尼（PCA）降低了额外镇痛的需求（RR 0.76，95% CI 0.45至1.28，3项试验，低质量证据）。有证据表明，瑞芬太尼（PCA）与其他阿片类药物（IV/IM）之间剖宫产风险无差异（RR 0.63，95% CI 0.30至1.32，ccc 0.01，4项试验，低质量证据），与硬膜外镇痛之间也无差异（RR 1.0，95% CI 0.82至1.22，ccc 0.01，9项试验，中等质量证据）。汇总的荟萃分析显示，与其他阿片类药物（PCA）相比，瑞芬太尼（PCA）下剖宫产风险增加（RR 2.78，95% CI 0.99至7.82，2项试验，极低质量证据）。然而，广泛的临床相关和不相关治疗效果与该结果相符。 作者结论：基于当前的系统评价，大多是低质量证据来指导实践，未来的研究可能会显著改变当前状况。证据质量主要受研究质量差、不一致性和不精确性的限制。需要更多关于母婴安全结局（母亲呼吸暂停和呼吸抑制、阿氏评分）以及瑞芬太尼给药的最佳模式和方案的研究，以提供对母亲及其新生儿疗效最高且不良反应合理的效果。
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