A Randomized, Placebo-Controlled, Double-Blind, Crossover Trial of Inhaled Nitric Oxide in Patients With Mild-to-Severe COPD.

research_question

What is the effect of inhaled nitric oxide (iNO) on exercise capacity in patients without hypoxemia with mild-to-severe COPD without pulmonary hypertension, and are there structural and/or functional predictors of response?

吸入一氧化氮（iNO）对没有低氧血症的轻度至重度COPD患者在没有肺动脉高压的情况下运动能力的影响是什么，以及是否存在结构和/或功能性的反应预测因素？

study_design_and_methods

Sixty-one patients with mild-to-severe COPD (mean FEV1, 65% ± 18% predicted) were recruited to this randomized, placebo-controlled, double-anonymized, crossover trial. Assessments included pulmonary function, echocardiography, and quantitative CT scan.

招募了61名轻度至重度慢性阻塞性肺疾病（COPD）患者（平均第一秒用力呼气容积（FEV1）为65% ± 18%预测值）参与这项随机、安慰剂对照、双盲、交叉试验。评估内容包括肺功能、超声心动图和定量计算机断层扫描（CT扫描）。

Small vessel volume fraction, defined as the vascular volume of blood vessels with a cross-sectional area < 5 mm2 (BV5) divided by total vascular volume (TVV), was used as an index of small vessel perfusion or pulmonary vascular pruning.

小血管体积分数，定义为横截面积小于5 mm2的血管体积（BV5）除以总血管体积（TVV），被用作小血管灌注或肺血管修剪的指标。

Participants received iNO or placebo (randomized) during 2 separate incremental exercise tests to determine exercise capacity (peak rate of oxygen consumption [Vo2peak]).

参与者在两个独立的递增运动测试期间接受iNO或安慰剂（随机分配），以确定运动能力（峰值氧耗量[Vo2peak]）。

Results

The mean effect of iNO on Vo2peak was 0.36 mL/kg/min (95% CI, -0.18 to 0.89) in an unadjusted linear mixed effects model.

在未调整的线性混合效应模型中，iNO对Vo2peak的平均效应为0.36 mL/kg/min（95% CI, -0.18至0.89）。

In prespecified analyses, there was evidence of iNO effect modification by BV5/TVV, whereby higher BV5/TVV was associated with greater iNO-induced improvement in Vo2peak (adjusted mean change, 0.14 mL/kg/min; 95% CI, 0.02-0.26 per 1% increment in BV5/TVV), independent of severity of airflow obstruction, pulmonary diffusing capacity, emphysema, or total lung capacity. iNO-induced increases in Vo2peak were associated with improved ventilatory efficiency and reduced dyspnea (both P < .05).

在预先设定的分析中，有证据表明吸入性一氧化氮（iNO）的效果受到骨小梁体积分数（BV5/TVV）的调节，较高的BV5/TVV与iNO诱导的Vo2peak（最大摄氧量）改善更大相关（调整后的平均变化为每增加1%的BV5/TVV，Vo2peak增加0.14 mL/kg/min；95%置信区间为0.02-0.26），这与气流阻塞的严重程度、肺扩散能力、肺气肿或总肺容量无关。iNO诱导的Vo2peak增加与通气效率的改善和呼吸困难的减少有关（两者P < .05）。

interpretation

Our results show that despite a null mean effect of iNO on Vo2peak in unadjusted analysis, a significant drug-induced improvement in Vo2peak was observed in patients with higher BV5/TVV.

我们的结果显示，尽管在未调整分析中iNO对Vo2peak的平均效果为零，但在BV5/TVV较高的患者中观察到显著的药物诱导的Vo2peak改善。

Improvements in Vo2peak with iNO were associated with improved ventilatory efficiency and reduced dyspnea.

吸入一氧化氮后最大摄氧量的改善与通气效率的提高和呼吸困难的减轻有关。

Our findings suggest a potential COPD pulmonary vascular endotype responsive to inhaled pulmonary vasodilators, characterized by greater small vessel perfusion or less vascular pruning, that is independent of severity of airflow obstruction, diffusing capacity, emphysema, or lung size.

我们的发现表明，存在一种潜在的COPD肺血管内皮型，对吸入性肺血管扩张剂有反应，其特征是小血管灌注增加或血管修剪减少，这与气流阻塞的严重程度、扩散能力、肺气肿或肺大小无关。

clinical_trial_registration

ClinicalTrials.gov; No.: NCT03679312; URL: www.

ClinicalTrials.gov; 编号: NCT03679312; 网址: www.

clinicaltrials

gov.

5年总生存率为60%（95%置信区间，55%-65%）。