Gebistorf Fabienne, Karam Oliver, Wetterslev Jørn, Afshari Arash
Pediatric Intensive Care Unit, Geneva University Hospital, 6 rue Willy Donzé, Geneva, Switzerland, 1205.
Cochrane Database Syst Rev. 2016 Jun 27;2016(6):CD002787. doi: 10.1002/14651858.CD002787.pub3.
Acute hypoxaemic respiratory failure (AHRF) and mostly acute respiratory distress syndrome (ARDS) are critical conditions. AHRF results from several systemic conditions and is associated with high mortality and morbidity in individuals of all ages. Inhaled nitric oxide (INO) has been used to improve oxygenation, but its role remains controversial. This Cochrane review was originally published in 2003, and has been updated in 2010 and 2016.
The primary objective was to examine the effects of administration of inhaled nitric oxide on mortality in adults and children with ARDS. Secondary objectives were to examine secondary outcomes such as pulmonary bleeding events, duration of mechanical ventilation, length of stay, etc. We conducted subgroup and sensitivity analyses, examined the role of bias and applied trial sequential analyses (TSAs) to examine the level of evidence.
In this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015 Issue 11); MEDLINE (Ovid SP, to 18 November 2015), EMBASE (Ovid SP, to 18 November 2015), CAB, BIOSIS and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We handsearched the reference lists of the newest reviews and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception until 18 November 2015.
We included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data.
Two review authors independently extracted data and resolved disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effects of INO in adults and children and on various clinical and physiological outcomes. We presented pooled estimates of the effects of interventions as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias through assessment of trial methodological components and risk of random error through trial sequential analysis.
Our primary objective was to assess effects of INO on mortality. We found no statistically significant effects of INO on longest follow-up mortality: 250/654 deaths (38.2%) in the INO group compared with 221/589 deaths (37.5%) in the control group (RR 1.04, 95% CI 0.9 to 1.19; I² statistic = 0%; moderate quality of evidence). We found no statistically significant effects of INO on mortality at 28 days: 202/587 deaths (34.4%) in the INO group compared with 166/518 deaths (32.0%) in the control group (RR 1.08, 95% CI 0.92 to 1.27; I² statistic = 0%; moderate quality of evidence). In children, there was no statistically significant effects of INO on mortality: 25/89 deaths (28.1%) in the INO group compared with 34/96 deaths (35.4%) in the control group (RR 0.78, 95% CI 0.51 to 1.18; I² statistic = 22%; moderate quality of evidence).Our secondary objective was to assess the benefits and harms of INO. For partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), we found significant improvement at 24 hours (mean difference (MD) 15.91, 95% CI 8.25 to 23.56; I² statistic = 25%; 11 trials, 614 participants; moderate quality of evidence). For the oxygenation index, we noted significant improvement at 24 hours (MD -2.31, 95% CI -2.73 to -1.89; I² statistic = 0%; five trials, 368 participants; moderate quality of evidence). For ventilator-free days, the difference was not statistically significant (MD -0.57, 95% CI -1.82 to 0.69; I² statistic = 0%; five trials, 804 participants; high quality of evidence). There was a statistically significant increase in renal failure in the INO groups (RR 1.59, 95% CI 1.17 to 2.16; I² statistic = 0%; high quality of evidence).
AUTHORS' CONCLUSIONS: Evidence is insufficient to support INO in any category of critically ill patients with AHRF. Inhaled nitric oxide results in a transient improvement in oxygenation but does not reduce mortality and may be harmful, as it seems to increase renal impairment.
急性低氧性呼吸衰竭（AHRF），主要是急性呼吸窘迫综合征（ARDS），是危急病症。AHRF由多种全身性疾病引起，在各年龄段人群中均与高死亡率和高发病率相关。吸入一氧化氮（INO）已被用于改善氧合，但它的作用仍存在争议。本Cochrane系统评价最初发表于2003年，并于2010年和2016年进行了更新。
主要目的是研究吸入一氧化氮对成人和儿童ARDS患者死亡率的影响。次要目的是研究诸如肺出血事件、机械通气时间、住院时间等次要结局。我们进行了亚组分析和敏感性分析，检查了偏倚的作用，并应用试验序贯分析（TSA）来检查证据水平。
在本次更新中，我们检索了Cochrane对照试验中心注册库（CENTRAL；2015年第11期）；MEDLINE（Ovid SP，截至2015年11月18日）、EMBASE（Ovid SP，截至2015年11月18日）、CAB、BIOSIS以及护理学与健康相关文献累积索引（CINAHL）。我们手工检索了最新综述的参考文献列表，并与我们对MEDLINE的检索结果进行交叉核对。我们联系了纳入研究的主要作者，以询问是否有遗漏、未报告或正在进行的研究。检索从起始日期至2015年11月18日进行。
我们纳入了所有随机对照试验（RCT），无论其发表状态、发表日期、盲法状态、已发表的结局或语言如何。我们联系了试验研究者和研究作者以获取相关和缺失的数据。
两位综述作者独立提取数据，并通过讨论解决分歧。我们的主要结局指标是全因死亡率。我们进行了多项亚组分析和敏感性分析，以评估INO对成人和儿童以及各种临床和生理结局的影响。我们以风险比（RR）及其95%置信区间（CI）的形式呈现干预效果的合并估计值。我们通过评估试验方法学组成部分来评估偏倚风险，并通过试验序贯分析评估随机误差风险。
我们的主要目的是评估INO对死亡率的影响。我们发现INO对最长随访期死亡率无统计学显著影响：INO组250/654例死亡（38.2%），对照组221/589例死亡（37.5%）（RR 1.04，95%CI 0.9至1.19；I²统计量 = 0%；证据质量中等）。我们发现INO对28天死亡率无统计学显著影响：INO组202/587例死亡（34.4%），对照组166/518例死亡（32.0%）（RR 1.08，95%CI 0.92至1.27；I²统计量 = 0%；证据质量中等）。在儿童中，INO对死亡率无统计学显著影响：INO组25/89例死亡（28.1%）,对照组34/96例死亡（35.4%）（RR 0.78，95%CI 0.51至1.18；I²统计量 = 22%；证据质量中等）。我们的次要目的是评估INO的利弊。对于动脉血氧分压（PaO₂）/吸入氧分数（FiO₂），我们发现在24小时时有显著改善（平均差值（MD）15.91，95%CI 8.25至23.56；I²统计量 = 25%；11项试验，614名参与者；证据质量中等）。对于氧合指数，我们注意到在24小时时有显著改善（MD -2.31，95%CI -2.73至 -1.89；I²统计量 = 0%；5项试验，368名参与者；证据质量中等）。对于无呼吸机天数，差异无统计学意义（MD -0.57，95%CI -1.82至0.69；I²统计量 = 0%；5项试验，804名参与者；证据质量高）。INO组肾衰竭有统计学显著增加（RR 1.59，95%CI 1.17至2.16；I²统计量 = 0%；证据质量高）。
证据不足支持在任何类型的AHRF重症患者中使用INO。吸入一氧化氮可导致氧合的短暂改善，但不会降低死亡率，并且可能有害，因为它似乎会增加肾功能损害。
