Shah Vibhuti S, Ohlsson Arne, Halliday Henry L, Dunn Michael
Department of Paediatrics and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, ON, Canada, M5G 1X5.
Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, ON, Canada, M5G 1X5.
Cochrane Database Syst Rev. 2017 Jan 4;1(1):CD001969. doi: 10.1002/14651858.CD001969.pub4.
Chronic lung disease (CLD) remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short- and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects.
To determine the impact of inhaled corticosteroids administered to preterm infants with birth weight up to 1500 grams (VLBW) beginning in the first two weeks after birth for the prevention of CLD as reflected by the requirement for supplemental oxygen at 36 weeks' postmenstrual age (PMA).
Randomised and quasi-randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 5 January 2016), MEDLINE (1966 to 5 January 2016), Embase (1980 to 5 January 2016), CINAHL (1982 to 5 January 2016), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 to May 2016).
We included in this review randomised controlled trials of inhaled corticosteroid therapy initiated within the first two weeks of life in VLBW preterm infants.
We evaluated data regarding clinical outcomes, including: CLD at 28 days or 36 weeks' PMA; mortality; combined outcome of death or CLD at 28 days of age and at 36 weeks' PMA; the need for systemic corticosteroids; failure to extubate within 14 days; and adverse effects of corticosteroids. All data were analysed using Review Manager (RevMan) 5. Meta-analyses were performed using relative risk (RR) and risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat for an additional beneficial outcome (NNTB) was calculated. We used the GRADE approach to assess the quality of evidence.
According to GRADE the quality of the studies was moderate. Three additional trials are included in this update. The present review includes data analyses based on 10 qualifying trials that enrolled 1644 neonates. There was no significant difference in the incidence of CLD at 36 weeks' PMA in the inhaled steroid versus the placebo group (5 trials, 429 neonates) among all randomised (typical RR 0.97, 95% CI 0.62 to 1.52; typical RD -0.00, 95% CI -0.07 to 0.06). There was no heterogeneity for this outcome (typical RR I² = 11%; typical RD I² = 0%). There was a significant reduction in the incidence of CLD at 36 weeks' PMA among survivors (6 trials, 1088 neonates) (typical RR 0.76, 95% CI 0.63 to 0.93; typical RD -0.07, 95% CI -0.13 to -0.02; NNTB 14, 95% CI 8 to 50). There was a significant reduction in the combined outcome of death or CLD at 36 weeks' PMA among all randomised neonates (6 trials, 1285 neonates) (typical RR 0.86, 95% CI 0.75 to 0.99; typical RD -0.06, 95% CI -0.11 to -0.00) (P = 0.04); NNTB 17, 95% CI 9 to infinity). There was no significant heterogeneity for any of these analyses (I² = 0%). A lower rate of reintubation was noted in the inhaled steroid group compared with the control group in one study. There were no statistically significant differences in short-term complications between groups and no differences in adverse events at long-term follow-up reported. Long-term follow-up of infants enrolled in the study by Bassler 2015 is ongoing.
AUTHORS' CONCLUSIONS: Based on this updated review, there is increasing evidence from the trials reviewed that early administration of inhaled steroids to VLBW neonates is effective in reducing the incidence of death or CLD at 36 weeks' PMA among either all randomised infants or among survivors. Even though there is statistical significance, the clinical relevance is of question as the upper CI limit for the outcome of death or CLD at 36 weeks' PMA is infinity. The long-term follow-up results of the Bassler 2015 study may affect the conclusions of this review. Further studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short- and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.
慢性肺部疾病（CLD）仍是早产儿常见的并发症。越来越多的证据表明，炎症在CLD的发病机制中起重要作用。由于其强大的抗炎特性，皮质类固醇是一种有吸引力的干预策略。然而，人们越来越关注全身使用皮质类固醇的短期和长期影响。理论上，吸入皮质类固醇给药可能对肺部系统产生有益作用，同时降低出现不良全身副作用的风险。
确定出生体重达1500克的极低出生体重（VLBW）早产儿在出生后前两周开始吸入皮质类固醇对预防CLD的影响，以孕龄（PMA）36周时补充氧气的需求来反映。
通过检索Cochrane图书馆中的Cochrane对照试验中心注册库（CENTRAL；2015年第12期）（检索时间为2016年1月5日）、MEDLINE（1966年至2016年1月5日）、Embase（1980年至2016年1月5日）、CINAHL（1982年至2016年1月5日）、已发表试验的参考文献列表以及发表在《儿科研究》上或在儿科学术协会网站上以电子方式发表的摘要（1990年至2016年5月）来识别随机和半随机试验。
我们纳入了本综述中关于出生后前两周内开始对VLBW早产儿进行吸入皮质类固醇治疗的随机对照试验。
我们评估了关于临床结局的数据，包括：孕龄28天或36周时的CLD；死亡率；28天龄和孕龄36周时死亡或CLD的综合结局；全身使用皮质类固醇的需求；14天内未能拔管；以及皮质类固醇的不良反应。所有数据均使用Review Manager（RevMan）5进行分析。使用相对风险（RR）和风险差（RD）及其95%置信区间（CI）进行荟萃分析。如果RD显著，则计算为获得额外有益结局所需治疗的人数（NNTB）。我们使用GRADE方法评估证据质量。
根据GRADE，研究质量为中等。本次更新纳入了三项额外试验。本综述包括基于10项符合条件的试验的数据分析，这些试验共纳入1644名新生儿。在所有随机分组中（5项试验，429名新生儿），吸入类固醇组与安慰剂组在孕龄36周时CLD的发生率无显著差异（典型RR 0.97，95%CI 0.62至1.52；典型RD -0.00，95%CI -0.07至0.06）。该结局无异质性（典型RR I² = 11%；典型RD I² = 0%）。幸存者中孕龄36周时CLD的发生率显著降低（6项试验，1088名新生儿）（典型RR 0.76，95%CI 0.63至0.93；典型RD -0.07，95%CI -0.13至-0.02；NNTB 14，95%CI 8至50）。所有随机分组新生儿中孕龄36周时死亡或CLD的综合结局显著降低（6项试验，1285名新生儿）（典型RR 0.86，95%CI 0.75至0.99；典型RD -0.06，95%CI -0.11至-0.00）（P = 0.04）；NNTB 17，95%CI 9至无穷大）。这些分析中的任何一项均无显著异质性（I² = 0%）。一项研究中，吸入类固醇组与对照组相比，再次插管率较低。两组之间短期并发症无统计学显著差异，长期随访中报道的不良事件也无差异。Bassler 2015年研究中纳入的婴儿的长期随访正在进行。
基于本次更新的综述，从所审查的试验中越来越多的证据表明，对VLBW新生儿早期给予吸入类固醇在降低所有随机分组婴儿或幸存者中孕龄36周时死亡或CLD的发生率方面是有效的。尽管具有统计学显著性，但由于孕龄36周时死亡或CLD结局的置信区间上限为无穷大，其临床相关性存在疑问。Bassler 2015年研究的长期随访结果可能会影响本综述的结论。需要进一步研究来确定这些药物不同给药技术和给药方案的风险/效益比。研究需要关注吸入类固醇的短期和长期益处及不良反应，尤其要关注神经发育结局。
