Inhaled nitric oxide in fibrotic and advanced interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials.

Clinical Snapshot

Key Findings

• P Value: p = 0.81 (primary outcome); p = 0.12 (adverse events); p = 0.39 (MVPA)

• Effect Size: Mean Difference (MD) in 6MWD: +1.83 metres favouring iNO

• Primary Outcome: 6-Minute Walk Distance (6MWD): iNO versus placebo showed no statistically significant or clinically meaningful improvement

• Nnt Or Sensitivity: No NNT calculable given non-significant binary safety outcome (RR 1.12; 95% CI 0.97–1.30). MVPA SMD 0.32 (95% CI −0.93 to 1.56) — small, non-significant effect. No sensitivity analyses or NNT for harm reported.

• Confidence Interval: 95% CI: −12.98 m to +16.64 m (well below the established MCID of ~25–30 m)

Clinical Application

iNO requires specialised delivery systems (continuous-flow or demand-valve devices), making ambulatory use logistically complex and costly. Unlike oral or inhaled pulmonary vasodilators (e.g., treprostinil), iNO is not a standard outpatient therapy. The infrastructure requirements limit feasibility in most community and general respiratory settings. In Australia, iNO is not PBS-listed for ILD or PH-ILD indications. The TGA has approved iNO (e.g., INOmax) for neonatal hypoxic respiratory failure but not for adult ILD. Inhaled treprostinil (Tyvaso) is not currently PBS-subsidised for PH-ILD in Australia, though oral treprostinil (Tyvaso DPI equivalent) and other ERA/PDE5i agents have limited PBS access for Group 1 PAH. RACGP and Thoracic Society of Australia and New Zealand (TSANZ) guidelines do not recommend iNO for ILD outside clinical trial settings. This meta-analysis reinforces the current Australian position that iNO should not be routinely used in ILD. Clinicians managing PH-ILD should refer to specialist centres and consider enrolment in clinical trials. Adults with fibrotic ILD (including IPF, connective tissue disease-ILD, and other progressive fibrosing ILDs) with or without associated pulmonary hypertension (Group 3 PH), experiencing reduced exercise capacity. Most applicable to patients being considered for supplemental or adjunctive pulmonary vasodilator therapy.

Abstract

PURPOSE: Interstitial lung disease (ILD) can lead to pulmonary hypertension (PH), contributing to reduced exercise capacity in patients with ILD. Inhaled nitric oxide (iNO) reduces pulmonary artery pressure and pulmonary vascular resistance and may improve exercise capacity in this population; however, the available evidence remains limited. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of iNO versus placebo in patients with ILD. METHODS: We systematically searched PubMed, Embase, Cochrane databases, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing iNO with placebo in patients with ILD. The primary endpoint was 6-minute walk distance (6MWD). Secondary endpoint was moderate-to-vigorous physical activity (MVPA). Safety endpoint was any adverse events. Continuous endpoints were reported using mean differences (MDs) or standardized mean differences (SMDs), and binary endpoints were reported using risk ratios (RRs), all with 95% confidence intervals (CIs). RESULTS: Four RCTs, including one crossover trial, enrolling 274 patients were analyzed. Of these, 172 received iNO. The median follow-up period was 12 weeks. In the pooled analyses, iNO likely results in little to no difference in 6MWD compared with placebo (MD 1.83m; 95% CI -12.98 to 16.64; p = 0.81), and may result in little to no difference in any adverse events (RR 1.12; 95% CI 0.97 to 1.30; p = 0.12) and MVPA (SMD 0.32; 95% CI -0.93 to 1.56; p = 0.39). CONCLUSION: INO did not demonstrate improvements in 6MWD or MVPA. These findings do not support routine use of iNO in this population.

References

1. 1.Nakahara, S., Hirao, Y., Fujiuchi, B., & Matsuda, B. (2026). Inhaled nitric oxide in fibrotic and advanced interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials. PLoS ONE. https://doi.org/10.1371/journal.pone.0351862