Table 1.

Randomized controlled trials on nitric oxide administration for the treatment of various clinical conditions.

Trial	Aim/hypothesis	Population (N)	Treatment group	Control group	NO dose	Primary endpoint	Main results
Respiratory failure
Wu, 2016 [19]	Efficacy in PPHN	Newborns (86)	iNO + HFOV	HFOV	20–80 ppm	PAP, FiO2, OI, duration of MV and O2 therapy, mortality	All endpoints better in the iNO than in control group
Bronicki, 2015 [20]	iNO ↓ MV duration in HRF	Pediatric (55)	iNO until death or 28 d or ventilator free	Placebo until death or 28 d or ventilator free	5 ppm	VFD at 28 d	VFD greater in the iNO group (p = 0.05)
González, 2010 [21]	Early iNO prevents severe HRF in moderate HRF and PAH	Newborns (56)	iNO + conventional MV	Conventional MV	20 ppm	Rate of progression to OI > 40	25% iNO vs 61% control group (p < 0.05)
Su, 2008 [22]	iNO ↓ OI in HRF	Preterm infants (65)	iNO + conventional care	Conventional care	5–20 ppm	Mean OI at 24 h	OI ↓ in the iNO group (p < 0.01)
Dani, 2007 [23]	iNO ↓ BPD and/or death in HRF	Preterm infants (40)	iNO at 10 ppm for 4 h, then 6 ppm until extubation or FiO2 <30% w/MAP <8 cm H2O + conventional care	Conventional care	6–10 ppm	BPD incidence and death	50% iNO vs 90% control group (p = 0.016)
Lindwall, 2005 [24]	Effect of iNO on oxygenation in HRF	Preterm infants (15)	iNO for 30 min + nasal CPAP	Nasal CPAP + placebo	10 ppm	Changes in oxygenation measured as aAPO2	aAPO2 ↑ 20% in the iNO group (p = 0.006)
Schreiber, 2003 [25]	iNO ↓ incidence of chronic lung disease/ death	Preterm infants (207)	iNO 10 ppm day 1, then 5 ppm for 6 d	Placebo	5–10 ppm	Incidence of chronic lung disease/death	48,6% iNO vs 63.7% control group (p = 0.03)
Sadiq, 2003 [26]	iNO prevents worsening of PAH in PPHN	near-term and term infants (80)	iNO + conventional care	Conventional care	Up to 80 ppm	Development of severe PPHN	15% iNO vs 58% control group (p < 0.0005)
Srisuparp, 2002 [27]	Safety and effect of iNO on oxygenation in mild to moderate HRF	Preterm infants (34)	iNO 20 ppm, then weaned to 5 ppm over 1–2 d	Conventional care	5–20 ppm	IVH incidence, OI, paO2	No differences in IVH incidence between groups. OI ↓ 15% and paO2 ↑ by 50% in iNO group (p = 0.04 and 0.02, respectively)
Baxter, 2002 [28]	Efficacy of iNO on oxygenation, shunt and PVRI in HRF	Adults (14)	iNO + 100% O2 for 30 min, then 30 min wash-out, then no iNO + 100% O2 for 30 min.	Randomized cross-over	5–25 ppm	Shunt, PVRI, oxygenation	iNO ↓ pulmonary shunt (p = 0.002). Other endpoints: ns
Christou, 2000 [29]	iNO ↓ mortality and ↓ ECMO use in PPHN	near-term and term newborns (40)	iNO + HFOV	HFOV	Up to 40 ppm	Mortality, ECMO use	ECMO use: 14% iNO vs 55% control group (p = 0.007), Mortality: ns.
Clark, 2000 [30]	Low-dose iNO ↓ ECMO use in PPHN	near-term and term newborns (248)	iNO at 20 ppm up to 1 d, then 5 ppm up to 4 d	Placebo	5–20 ppm	ECMO use	ECMO use: 38% iNO vs 64% control group (p = 0.001)
The Franco- Belgium Collaborative NO Trail Group, 1999 [31]	iNO ↑ oxygenation in HRF	preterm and near-term newborns (204)	iNO	Placebo	10 ppm	OI change at 2 h	OI ↓ 6.2 iNO vs 2.9 control group (p = 0.005)
Dobyns, 1999 [32]	iNO effect on oxygenation in HRF	Children (108)	iNO for minimum 3 d + MV	MV	10 ppm	OI	OI ↓ 10.2 iNO vs 2.7 control group (p < 0.05)
Troncy, 1998 [33]	iNO effect on lung function in ARDS	Adults (30)	iNO + conventional care	Conventional care	0.5–40 ppm	P/F, alveolar dead space, lung compliance, venous admixture	P/F ↑ 59% in INO vs 9.3% control group (p = 0.02). Other endpoints: ns
Michael, 1998 [34]	iNO effect on oxygenation in ARDS	Adults (40)	iNO + conventional care up to 3 d	Conventional care	5–20 ppm	P/F	P/F t in the first 24 h in the iNO group.
Dellinger, 1998 [35]	iNO effect on oxygenation in ARDS	Adults (117)	iNO	Placebo	1.25–80 ppm	paO2 ↑ >20%	~60% responders in iNO vs 24% control group in the first 4 h (p ≤ 0.021)
The NINOS Group, 1997 [36]	iNO ↓ ECMO use and/ or death in HRF	near-term and term newborns (235)	iNO	100% O2	20 ppm	ECMO use and/or death	64% iNO vs 46% vs control group (p = 0.006)
Wessel, 1997 [37]	iNO effect on mortality, ECMO use and oxygenation in PPHN	near-term and term Newborns (49)	iNO + conventional care	Conventional care	5–80 ppm	Mortality, ECMO use, OI	OI ↓ 31% iNO vs control group.Other endpoints: ns
Roberts Jr, 1997 [38]	iNO effect on oxygenation in PPHN	Term infants (58)	iNO + conventional care	Placebo + conventional care	80 ppm	Doubling rate of oxygenation	53% iNO vs 7% control group (p = 0.002)
NCT00240487	Determine iNO treatment timing in pediatric ARDS	Children (52)	iNO for the first 4 h, then no iNO for 4 h	No iNO for the first 4 h, then iNO for 4 h	10 ppm	Changes in P/F ratio	ns
Van Meurs, 2007 [39]	iNO ↓ BPD and/or death in HRF	Preterm infants (29)	iNO + conventional care up to 14 d	Conventional care	5–10 ppm	BPD incidence and death	ns
Field, 2007 [40]	Assess clinical and cost-effectiveness of iNO in HRF	Infants (60)	iNO + conventional care	Conventional care	5–20 ppm	Death and severe disability	ns
Kinsella, 2006 [41]	iNO ↓ BPD and/or death in HRF	Preterm infants (793)	iNO for 21 d or until extubation + conventional care	Conventional care	5 ppm	BPD incidence and death	ns
Meurs, 2005 [42]	iNO ↓ BPD and/or death in HRF	Preterm infants (420)	iNO	Conventional care	5–10 ppm	BPD incidence and death	ns
Hascoet, 2005 [43]	Safety and efficacy in infants w/HRF	Preterm infants (860)	iNO	Placebo	5 ppm	Intact survival at 28 d	ns
Taylor, 2004 [44]	Efficacy of iNO in ARDS	Adults (385)	iNO until 28 d or discontinuation of assisted breathing or death	Placebo until 28 d or discontinuation of assisted breathing or death	5 ppm	Days alive and off assisted breathing	ns
Konduri, 2004 [45]	iNO ↓ incidence of ECMO/death in HRF	near-term and term infants (299)	iNO	Placebo	5–20 ppm	Incidence of ECMO/ death	ns
Finer, 2001 [46]	No differences in oxygenation improvement between low and high dose of iNO in pts w/ HRF	near-term and term infants (36)	Low-dose iNO (LD)	High-dose iNO (HD)	LD: 1–2 ppm HD: 10–20 ppm	paO2, OI	ns
Cornfield, 1999 [47]	iNO ↑ oxygenation in PPHN	near-term and term infants (38)	iNO 2 ppm, 20 ppm if worsening oxygenation	Placebo, 20 ppm if worsening oxygenation	2–20 ppm	OI	ns
Kinsella, 1999 [48]	iNO ↑ survival in HRF	Preterm infants (80)	iNO	Placebo	5 ppm	Survival to discharge	ns
Lundin, 1999 [49]	iNO ↑ reversal of ALI in pts previously responder to iNO	Adults (268)	iNO up to 30 days or endpoint reached	Conventional care	1–40 ppm	Rate of ALI reversal	ns
Davidson, 1998 [50]	Efficacy of iNO on PPHN	Term infants (155)	iNO + conventional care	Conventional care	5–80 ppm	Major Sequelae Index (incidence of death, ECMO, neurologic	ns
The NINOS Group, 1997 [51]	iNO ↓ ECMO use and/ or death in HRF and congenital diaphragmatic hernia	near-term and term infants (53)	iNO	100% O2	20 ppm	injury, BPD) ECMO use/death	ns
Barefield, 1996 [52]	iNO ↓ ECMO use in PPHN	near-term and term infants (17)	iNO + conventional MV	Conventional MV	20–80 ppm	ECMO use	ns
Pulmonary Arterial Hypertension
Nathan, 2020 [53]	iNO ↑ physical activity in PAH + pulmonary fibrosis	Adults (41)	Pulsed iNO for 8w	Placebo	30 μg/kg IBW/h	moderate/vigorous physical activity improvement	↑ in the iNO vs control group
Vonbank, 2003 [54]	iNO safety in pts w/ PAH due to COPD	Adults (40)	Pulsed iNO + O2 over 3 months	O2	20 ppm	Pulmonary and systemic hemodynamics. Arterial oxygenation. NO2	↑ in pulmonary hemodynamics. Other endpoints: ns
Hasuda, 2000 [55]	iNO ↑ exercise capacity in precapillary PAH	Adults (14)	iNO + exercise on a cycle ergometer	Exercise on a cycle ergometer (Randomized cross-over)	20 ppm	Peak exercise load, anaerobic threshold, VO2	Only VO2 ↑ in the iNO vs control group
Van Meurs, 1997 [56]	iNO effect on oxygenation HRF	Preterm (11)	iNO	Placebo, (Randomized, cross-over)	1–20 ppm	P/F	P/F ↑ >25% in 10 out of 11 participants
AKI prevention after CPB
Lei, 2018 [18]	NO ↓ AKI after CPB	Adults (244)	NO for 24 h	Placebo	80 ppm	AKI occurrence
							50% NO vs 64% control group (p = 0.014)
NO during CPB for CHD
Elzein, 2020 [57]	NO ↓ ischemia/ reperfusion injury	Newborns (24)	NO	Placebo	40 ppm	Multiple markers of organ injury	Only Tn lower in the iNO vs control group (p = 0.009)
James, 2016 [58]	NO ↓ LCOS	Children (198)	NO	Placebo	20 ppm	LCOS incidence	15% iNO vs 31% control group (p = 0.007)
Checchia, 2013 [59]	NO ↓ ischemia/ reperfusion injury	Children (16)	NO	Placebo	20 ppm	Duration MV, ICU LOS, TnI and BNP levels	All endpoints better in the iNO group (p < 0.05)
Miller, 2000 [60]	NO ↓ PAH crises	Infants (124)	NO	Placebo	10 ppm	Number of PAH crises	4 PAH crises NO vs 7 control group (p < 0.001)
Day, 2000 [61]	NO ↓ PAH crises	Infants (40)	NO	Placebo	20 ppm	Number of PAH crises	ns
Niebler, 2021 [62]	NO ↓ activation and depletion of PLTs	Infants (40)	NO	Placebo	20 ppm	PLTs count	ns
Resuscitation
Sekar, 2020 [63]	Prevention of O2 exposure during resuscitation	Preterm infants needing help with breathing (28)	iNO for 17 min	Placebo for 17 min	20 ppm	Cumulative FiO2, time w/FiO2 >60%, pre/postductal saturation, heart rate, need for intubation	Cumulative FiO2 (p = 0.001) and time w/FiO2 >60% (p < 0.0001) lower in the iNO group
Transfusions
Berra, 2014 [16]	Blood transfusions older than 40 d ↑ PAP	Obese adults (14)	Transfusion with 3-d, 40-d, and 40-d old blood with iNO	Randomized cross-over	80 ppm	PAP	40 d old blood ↑ PAP. iNO prevents it
Sickle cell disease
Head, 2010 [64]	iNO ↓ intensity of painful crisis	Adults (23)	iNO for 4 h	Room air	80 ppm	Mean change of pain score after 4 h of iNO	iNO ↓ pain scores (p = 0.02)
Maitre, 2015 [65]	iNO ↓ treatment failure in pts with acute chest syndrome	Adults (100)	iNO for 3 d	Placebo	80 ppm	Treatment failure rate at 3 d	ns
Gladwin, 2011 [66]	iNO ↓ duration of painful crisis	>10 years old (150)	iNO up to 3 d	Placebo	40–80 ppm	Time to resolution of painful crisis	ns
Severe malaria
Bangirana, 2018 [67]	Neuroprotective role of iNO	Children (130)	iNO up to 72 h	Room air	80 ppm	Neurocognitive outcomes	↓ fine motor impairment in iNO vs control group (RR, 95% CI: 0.36, 0.14–0.96)
Conroy, 2016 [68]	Safety of iNO	Children (180)	iNO for 3 d	Room air	80 ppm	MetHb levels >10% mandate treatment interruption	MetHb >10% in 5.7% patients in iNO group. Authors conclude iNO is safe if MetHb is measured during administration
Hawkes, 2015 [69]	iNO ↑ severe malaria outcome	Children (180)	iNO up to 3 d	Room air	80 ppm	Ang-2 levels in the first 3 d	ns
Mwanga- Amumpaire, 2015 [70]	iNO ↑ Ang-1	Children (92)	iNO for at least 2 d	Room air	80 ppm	Ang-1 levels at 2 d	ns

Legend:

^↓decreases/decreased

^↑increases/increased.

Abbreviations: aAPO2, alveolar-arterial oxygen tension difference; AKI, acute kidney injury; ALI, acute lung injury; Ang-1/Ang-2, angiotensin 1 and 2; ARDS, acute respiratory distress syndrome; BNP, B-type natriuretic peptide; BPD, bronchopulmonary dysplasia; CI, confidence interval; cmH2O, centimeters of water; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; d, day(s); d, day(s); ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; h, hour(s); h, hour; HFOV, high frequency oscillatory ventilation; HRF, hypoxic respiratory failure; IBW, ideal body weight; iNO, inhaled nitric oxide; IVH, intraventricular hemorrhage; LCOS: low cardiac output syndrome; LOS, length of stay; MAP, mean arterial pressure; MetHb, methemoglobin; MV, mechanical ventilation; n.a., not available; NO, nitric oxide; NO2, nitrogen dioxide; ns, not significant; O2, oxygen; OI, oxygenation index; P/F, partial oxygen pressure-to-fraction of inspired oxygen ratio; PAH, pulmonary artery hypertension; paO2, partial pressure of oxygen; PAP, pulmonary artery pressure; PLTs, platelets; PPHN, persistent pulmonary hypertension of the newborn; ppm, part per million; PVRI, pulmonary vascular resistances index; RR, relative risk; Tn, troponin; VFD, ventilator- free days; VO2, oxygen consumption; w, week(s); w/, with.