Summary of findings 4. Summary of findings: nitric oxide compared with placebo for chronic pulmonary infection in cystic fibrosis.

Nitric oxide compared with placebo for chronic pulmonary infection in cystic fibrosis
Patient or population: children (12 or over) and young adults with cystic fibrosis Settings: unclear if inpatient or outpatient Intervention: inhaled NO (10 ppm inhaled overnight for 5 ‐ 7 days; 20 ppm or 40 ppm inhaled continuously for 44 hours) Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	NO
Pulmonary exacerbations	This outcome was not measured in this trial.
Respiratory function mean change in FEV1 % predicted from baseline Follow‐up: 20 days	The mean change in FEV1 % predicted in the control group is 6.17%.	The mean FEV1 % predicted in the intervention group was 2% lower (10% lower to 6% higher).	MD ‐1.95 (‐9.94 to 6.04)	12 (1)	⊕⊕⊝⊝ lowa,b	There was no significant difference between the NO group and placebo (P = 0.63).
Adverse events Follow‐up: 48 hours to 20 days	In one trial 4 participants reported adverse events including epistaxis, cough and cold, increased cough and haemoptysis but all were considered mild and only possibly related to the trial treatment. In the placebo group only one adverse event was reported, which was epistaxis (Howlin 2017). Sagel reported no serious adverse events in either NO or placebo group at either the low dose or high dose of NO (Sagel 2009).			30 (2)	⊕⊝⊝⊝ very lowa,b
Need for antibiotics	This outcome was not measured.
QoL	This outcome was not measured.
Sputum microbiology Follow‐up: 48 hours to 20 days	One trial showed a significant reduction in S aureus colony counts in the high‐dose NO group relative to placebo (P = 0.03) and a near significant reduction in P aeruginosa colony counts in the high‐dose group relative to placebo (P = 0.06) (Sagel 2009). The second trial found a significant reduction in P aeruginosa biofilm aggregates compared with those receiving placebo with antibiotics over the 7‐day treatment period (P = 0.029) and there was less P aeruginosa biofilm in the NO group compared with placebo (Howlin 2017).			30 (2)	⊕⊝⊝⊝ very lowb,c
Inflammatory markers	This outcome was not measured.
*The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in 1 second; NO: nitric oxide; P aeruginosa: Pseudomonas aeruginosa; RR: risk ratio; S aureus: Staphylococcus aureus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

^a Downgraded once from risk of bias because of uncertainty around selective reporting of outcomes.
^b Downgraded once due to imprecision from very low number of participants and low event rates.
^c Downgraded twice for risk of bias within the included trials. There were concerns around randomisation, allocation concealment, selective reporting and attrition bias.