Table 1.
Details of randomised trials of inhaled nitric oxide (NO) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
| Author (funding*) | Population | Details of NO administration | Control group and crossovers |
|---|---|---|---|
| Day,w1 1997 (not for profit) | 24 children, 1 centre. Acute bilateral CXR infiltrates, PEEP >6 cm H2O, FiO2 >0.5 for >12 hours. Enrolment ≤48 h after meeting study criteria | 10 ppm until oxygenation and PEEP criteria met | Usual care. All patients randomised to control received NO 10 ppm after 24 hour; no crossovers before 24 hour |
| Schwebel,w2 1997 (not for profit; industry supplied gas) | 19 adults, 17 centres. Any CXR infiltrates, P/F <200 mm Hg, 10<PAOP<18 mm Hg, 6<PEEP<10 cm H2O. Duration of ARDS ≤24 hours | 10 ppm for 17 hours, then at clinician's discretion; mean 4.6 days (range 1.25 to 11) | Placebo gas (nitrogen). Crossovers mandated before 17 hours if P/F ≤100 mm Hg and permitted thereafter (at least 5/10 patients randomised to control received NO) |
| Dellinger,w3 1998 (industry) | 177 adults, 30 centres. AECC criteria for ARDS and FiO2 ≥0.5, PEEP ≥8 cm H2O. Duration of ARDS ≤72 hours | 1.25, 5, 20, 40 or 80 ppm until 28 days or oxygenation and PEEP criteria met. Protocol for weaning NO | Placebo gas (nitrogen). No crossovers |
| Michael,w4 1998 (not for profit) | 40 patients, 1 centre; 37/40 ≥18 years. AECC criteria for ARDS except P/F ≤150 mm Hg and FiO2 ≥0.8 for ≥12 hours or ≥0.65 for ≥24 hours | 5, 10, 15, 20 ppm every 6 hours for 24 hours then clinically adjusted; mean dose ∼13 ppm, tapered if oxygenation not improved by 72 hours | Usual care. Patients with oxygenation failure received NO (2 patients before 72 hours and 7 patients after 72 hours, of 20 randomised to control) |
| Troncy,w5 1998 (not for profit) | 30 adults, 1 centre. Lung injury score30 ≥2.5 | Initial titration (2.5, 5, 10, 20, 30, 40 ppm every 10 min) and daily re-titration; mean dose 5.3 ppm. Duration: until oxygenation and PEEP criteria met; mean 8 (SD 5) days | Usual care. No crossovers |
| Dobyns,w6 1999 (not for profit) | 108 children (>1 month old, median age 2.5 years), 7 centres. Any CXR infiltrates, OI ≥15 on 2 arterial blood gases within 6 hours (mean duration of ventilation before randomisation 3.5 days in NO group, 3.7 days in control group) | 10 ppm for 72 hours, then weaned if failure criteria not met | Usual care. Patients meeting failure criteria could receive NO (27/55 patients randomised to control met failure criteria and 2 other patients withdrawn from control group; 29 patients likely received NO) |
| Lundin,w7 1999 (not for profit and industry) | 180 adults, 43 centres. Any CXR infiltrates, P/F ≤165 mm Hg, PEEP ≥5 cm H2O, mean airway pressure >10 cm H2O. Duration of ventilation 0.75-4 days. NO responder† | 1-40 ppm (“lowest effective dose”); mean dose 9 (SD 8) ppm, until end point met (reversal of ALI or severe respiratory failure), up to 30 days; mean 9 (SD 6) days | Usual care. Patients meeting severe respiratory failure criteria could receive NO (6/87 patients randomised to control received NO) |
| Payen,w8 1999 (not for profit; industry supplied gas) | 203 adults, 23 centres. AECC criteria for ARDS, lung injury score30 2-3 after 24 hours of “therapeutic optimisation” (mean duration of ventilation before randomisation: 5.3 days in NO group, 5.9 days in control group) | 10 ppm, until oxygenation and PEEP criteria met; median 5 days | Placebo gas (nitrogen). Patients meeting failure criteria crossed to other group (19/105 patients randomised to control and 12/98 patients randomised to NO crossed over) |
| Mehta,w9 2001 (not for profit and industry) | 14 adults, 1 centre. Bilateral CXR infiltrates, P/F <200 mm Hg, PEEP ≥8 cm H2O, PAOP <18 cmH2O. Duration of ARDS ≤5 days | Daily titration (5, 10, 20 ppm every 30 min) for 4 days. Most received 5-10 ppm on day 2-4; continued until oxygenation criteria met; mean 8 (SD 9) days | Usual care. No crossovers |
| Gerlach,w10 2003 (not for profit) | 40 adults, 1 centre. Bilateral CXR infiltrates, P/F ≤150 mm Hg, PEEP ≥10 cm H2O, PAOP ≤18 mm Hg. Duration of ventilation ≥48 hours with FiO2 ≥0.6 (median duration of ventilation before randomisation: 14 days in NO group, 11.5 days in control group) | 10 ppm (with daily dose response analysis) until weaning initiated | Usual care. No crossovers |
| Park,w11 2003 (not reported) | 17 adults, 1 centre. AECC criteria for ARDS. Duration of ARDS ≤2 days | 5 ppm for mean 3.5 (SD 1.5) days (stopping criteria not reported). Patients also received one lung recruitment manoeuvre (same as control group). Third group (n=6) received NO 5 ppm alone for 8.2 (SD 4.7) days | One lung recruitment manoeuvre (inflation pressure of 30-35 cm H2O for 30 seconds). No crossovers |
| Taylor,w12 2004 (industry) | 385 adults, 46 centres. AECC criteria for ALI except P/F ≤250 mm Hg, 0.5 ≤ FiO2 ≤0.95 on PEEP ≥8 cm H2O. Duration of ALI ≤3 days | 5 ppm for 28 days or until oxygenation and PEEP criteria met | Placebo gas (nitrogen). No crossovers |
AECC=American-European Consensus Conference1; CXR=chest radiograph; LIS=lung injury score,30 OI=oxygenation index (100×mean airway pressure/(PaO2/FiO2)), PAOP=pulmonary artery occlusion pressure; PEEP=positive end expiratory pressure; P/F ratio=partial pressure of inspired oxygen (PaO2)/fraction of inspired oxygen (FiO2).
*Funding refers to data collection and analysis and supply of study gas (where information available).
†Patients given NO 0, 2, 10, 40 ppm every 10 min and response defined as relative increase in PaO2 of 25% (n=140) or 20% (n=40). Responders were randomised.