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Óxido nítrico inhalado para la insuficiencia respiratoria en recién nacidos prematuros

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Referencias

References to studies included in this review

Ballard 2006 {published data only}

Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New England Jounal of Medicine 2006;355:343‐53. CENTRAL
Di Fiore JM, Hibbs AM, Zadell AE, Merrill JD, Eichenwald EC, Puri AR, et al. The effect of inhaled nitric oxide on pulmonary function in preterm infants. Journal of Perinatology 2007;27:766‐71. CENTRAL
Hibbs AM, Walsh MC, Martin RJ, Truog WE, Lorch SA, Alessandrini E, et al. One‐year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial. Journal of Pediatrics 2008;153:525‐9. CENTRAL
Walsh MC, Hibbs AM, Martin CR, Cnaan A, Keller RL, Vittinghoff E, et al. Two‐year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. Journal of Pediatrics 2010;156:556‐61.e1. CENTRAL

Dani 2006 {published data only}

Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatrica 2006;95:1116‐23. CENTRAL

EUNO 2009 {published data only}

Durrmeyer X, Hummler H, Sanchez‐Luna M, Carnielli VP, Field D, Greenough A, et al. Two‐year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics 2013;132(3):e695‐703. [PUBMED: 23940237]CENTRAL
Mercier JC, Hummler H, Durrmeyer X, Sanchez‐Luna M, Carnielli V, Field D, et al. Inhaled nitric oxide for the prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomized controlled trial. Lancet 2010;376:346‐54. CENTRAL

Hascoet 2005 {published and unpublished data}

Hascoet JM, Fresson J, Claris O, Hamon I, Lombet J, Liska A, et al. The safety and efficacy of nitric oxide therapy in premature infants. Journal of Pediatrics 2005;146:318‐23. CENTRAL

INNOVO 2005 {published data only}

Ahluwalia J, Tooley J, Cheema I, Sweet DG, Curley AE, Halliday HL, et al. A dose response study of inhaled nitric oxide in hypoxic respiratory failure in preterm infants. Early Human Development 2006;82:477‐83. CENTRAL
Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, Fenton AC, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomized controlled trial (ISRCTN 17821339). Pediatrics 2005;115:926‐36. CENTRAL
Huddy CL, Bennett CC, Hardy P, Field D, Elbourne D, Grieve R, et al. The INNOVO multicentre randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4‐5 years. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93:F430‐5. CENTRAL

Kinsella 1999 {published data only}

Kinsella JP, Walsh WF, Bose CL, Gerstmann DR, Labella JJ, Sardesai S. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomized controlled trial. Lancet 1999;354:1061‐5. CENTRAL

Kinsella 2006 {published and unpublished data}

Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. New England Journal of Medicine 2006;355:354‐64. CENTRAL
Watson RS, Clermont G, Kinsella JP, Kong L, Arendt RE, Cutter G, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics 2009;124:1333‐43. CENTRAL

Kinsella 2014 {published data only}

Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, et al. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. Journal of Pediatrics 2014;165(6):1101‐8. [PUBMED: 25063725]CENTRAL

Mercier 1999 {published data only}

Franco‐Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomized controlled trial. Lancet 1999;354:1066‐71. CENTRAL
Mercier JC, Dehan M, Breart G, Clement S, O'Nody P. Inhaled nitric oxide in neonatal respiratory failure. A randomized clinical trial. Pediatric Research 1998;43:290A (Abstract). CENTRAL
Truffert P, Llado‐Paris J, Mercier JC, Dehan M, Bréart G, Franco‐Belgian iNO Study Group. Early inhaled nitric oxide in moderately hypoxemic preterm and term newborns with RDS: the RDS subgroup analysis of the Franco‐Belgian iNO Randomized Trial. European Journal of Pediatrics 2003;162:646‐7. CENTRAL

Schreiber 2003 {published data only}

Mestan K, Marks J, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. New England Journal of Medicine 2005;353:23‐32. CENTRAL
Schreiber MD, Gin‐Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. New England Journal of Medicine 2003;349:2099‐107. CENTRAL

Srisuparp 2002 {published data only}

Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. Journal of the Medical Association of Thailand 2002;85:S469‐78. CENTRAL

Su 2007 {published data only}

Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. Journal of Perinatology 2008;28:112‐6. CENTRAL

Subhedar 1997 {published data only}

Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high‐risk preterm infants treated with inhaled nitric oxide. Acta Paediatrica 2001;90:573‐6. CENTRAL
Subhedar NV, Ryan SW, Shaw NJ. Open randomized controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Archives of Disease in Childhood. Fetal Neonatal Edition 1997;77:F185‐90. CENTRAL
Subhedar NV, Shaw NJ. Changes in oxygenation and pulmonary haemodynamics in preterm infants treated with inhaled nitric oxide. Archives of Disease in Childhood. Fetal Neonatal Edition 1997;77:F191‐7. CENTRAL

Van Meurs 2005 {published data only}

Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. American Journal of Perinatology 2009;26:317‐22. CENTRAL
Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A, Stevenson DK, et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. Journal of Pediatrics 2007;151:16‐22, 22.e1‐3. CENTRAL
Van Meurs KP, Wright L, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine 2005;353:13‐22. CENTRAL

Van Meurs 2007 {published data only}

Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure. Journal of Perinatology 2007;27:347‐52. CENTRAL

Wei 2014 {published data only}

Wei QF, Pan XN, Li Y, Feng L, Yao LP, Liu GL, et al. Efficacy of inhaled nitric oxide in premature infants with hypoxic respiratory failure. Zhongguo Dang Dai Er Ke za Zhi [Chinese Journal of Contemporary Pediatrics] 2014;16(8):805‐9. [PUBMED: 25140772]CENTRAL

Yoder 2013 {published data only}

Yoder BA. Inhaled NO for prevention of BPD: update on the NEWNO Trial. Hot Topics in Neonatology; 2013 December 8; Washington, DC. 2013. CENTRAL

References to studies excluded from this review

Day 1996 {published data only}

Day RW, Lynch JM, White KS, Ward RM. Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension. Pediatrics 1996;98:698‐705. CENTRAL

Lindwall 2005 {published data only}

Lindwall R, Blennow M, Svensson M, Jonsson B, Berggren‐Bostrom E, Flanby M, et al. A pilot study of inhaled nitric oxide in preterm infants treated with nasal continuous positive airway pressure for respiratory distress syndrome. Intensive Care Medicine 2005;31:959‐64. CENTRAL

Skimming 1997 {published data only}

Skimming JW, Bender KA, Hutchison AA, Drummond WH. Nitric oxide inhalation in infants with respiratory distress syndrome. Journal of Pediatrics 1997;130:225‐30. CENTRAL

Abman 1990

Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium‐derived relaxing factor during transition of pulmonary circulation at birth. American Journal of Physiology 1990;259:H1921‐7.

Abman 1993

Abman SH, Kinsella JP, Schaffer MS, Wilkening RB. Inhaled nitric oxide in the management of a premature newborn with severe respiratory distress and pulmonary hypertension. Pediatrics 1993;92:606‐9.

Askie 2010

Askie LM, Ballard RA, Cutter G, Dani C, Elbourne D, Field D, et al. Inhaled nitric oxide in preterm infants: a systematic review and individual patient data meta‐analysis. BMC Pediatrics 2010;10:15.

Bland 2005

Bland RD, Albertine KH, Carlton DP, MacRitchie AJ. Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs. American Journal of Respiratory and Critical Care Medicine 2005;172:899‐906.

Cornfield 1992

Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH. Effects of birth‐related stimuli on L‐arginine‐dependent pulmonary vasodilation in ovine fetus. American Journal of Physiology 1992;262:H1474‐81.

Finer 1998

Finer NN, Barrington KJ. Nitric oxide therapy for the newborn infant. Seminars in Neonatology 1998;3:127‐36.

Finer 2000

Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/14651858.CD000399]

Frostell 1991

Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038‐47.

GRADEpro [Computer program]

McMaster University, 2014. GRADEpro [www.gradepro.org]. Ontario: McMaster University, 2014.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane‐handbook.org.

Hoehn 2006

Hoehn T, Krause MF, Buhrer C. Meta‐analysis of inhaled nitric oxide in premature infants: an update. Klinische Padiatrie 2006;218:57‐61.

Hogman 1993

Hogman M, Frostell C, Arnberg H, Hedenstierna G. Bleeding time prolongation and NO inhalation. Lancet 1993;341:1664‐5.

Kinsella 1992

Kinsella JP, McQueston JA, Rosenberg AA, Abman SH. Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. American Journal of Physiology 1992;263:H875‐80.

Kinsella 1994

Kinsella JP, Ivy DD, Abman SH. Inhaled nitric oxide improves gas exchange and lowers pulmonary vascular resistance in severe experimental hyaline membrane disease. Pediatric Research 1994;36:402‐8.

McAndrew 1997

McAndrew J, Patel RP, Jo H, Cornwell T, Lincoln T, Moellering D, et al. The interplay of nitric oxide and peroxynitrite with signal transduction pathways: implications for disease. Seminars in Perinatology 1997;21:351‐66.

McCurnin 2005

McCurnin DC, Pierce RA, Chang LY, Gibson LL, Osborne‐Lawrence S, Yoder BA, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. American Journal of Physiology. Lung Cellular and Molecular Physiology 2005;288:L450‐9.

Peliowski 1995

Peliowski A, Finer N, Etches P, Tierney AJ, Ryan CA. Inhaled nitric oxide for premature infants after prolonged rupture of the membranes. Journal of Pediatrics 1995;126:450‐3.

Roberts 1993

Roberts JD, Chen TY, Kawai N, Wain J, Dupuy P, Shimouchi A, et al. Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circulation Research 1993;72:246‐54.

Rossaint 1993

Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. New England Journal of Medicine 1993;328:399‐405.

Ryan 1996

Ryan SW, Nycyk J, Shaw BNJ. Prediction of chronic neonatal lung disease on day 4 of life. European Journal of Pediatrics 1996;155:668‐71.

Samama 1995

Samama CM, Diaby M, Fellahi JL Mdhafar A, Eyraud D, Arock M. Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1995;83:56‐65.

Schünemann 2013

Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE Working Group. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. www.guidelinedevelopment.org/handbook.Updated October 2013.

Skimming 1995

Skimming JW, DeMarco VG, Cassin S. The effects of nitric oxide inhalation on the pulmonary circulation of preterm lambs. Pediatric Research 1995;37:35‐40.

Soll 2001

Soll R. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4. [DOI: 10.1002/14651858.CD000511]

Van Meurs 1997

Van Meurs KP, Rhine WD, Asselin JM, Durand DJ, Premie INO Collaborative Group. Response of premature infants with severe respiratory failure to inhaled nitric oxide. Pediatric Research 1997;41:271A (Abstract).

Vohr 2005

Vohr BR, Wright LL, Poole K, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks' gestation between 1993 and 1998. Pediatrics 2005;116:635‐43.

Walther 1992

Walther FJ, Benders MJ, Leighton JO. Persistent pulmonary hypertension in premature neonates with severe respiratory distress syndrome. Pediatrics 1992;90:899‐904.

Wirbelauer 2010

Wirbelauer J, Speer CP. Significance of nitric oxide inhalation (NO) in preterm infants < 34 weeks of gestation [Stellenwert der Inhalation von Stickstoffmonoxid (NO) bei Fruhgeborenen<34 Gestationswochen.]. Klinische Padiatrie 2010;222:56‐61.

Wood 2005

Wood NS, Costeloe K, Gibson AT, Hennessy EM, Marlow N, Wilkinson AR. The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Archives of Disease in Childhood. Fetal and Neonatal Edition 2005;90:F134‐40.

References to other published versions of this review

Barrington 1999

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 1. [DOI: 10.1002/14651858.CD000509]

Barrington 2001

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD000509]

Barrington 2006

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD000509]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ballard 2006

Methods

Multi‐centre trial

Participants

582 infants < 1250 grams on assisted ventilation at 7‐21 days (or, if < 800 grams, on CPAP)

Interventions

Inhaled NO at 20 ppm initial dose for 48‐96 hours; the dose was subsequently decreased to 10, 5 and 2 ppm at weekly intervals, with a minimum treatment duration of 24 days

Outcomes

Survival without BPD at 36 weeks' postmenstrual age

Secondary outcomes included duration of oxygen therapy and duration of hospitalisation. In addition, investigators prospectively evaluated the need for hospitalisation and respiratory support, including mechanical ventilation, continuous positive airway pressure and oxygen supplementation at 40, 44, 52 and 60 weeks' postmenstrual age.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised in permuted blocks at study centre

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masking of intervention: yes
Masking of outcome assessment: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Funding Source

Low risk

Funded by a government agency (NICHD); study gas provided by industry (Ikaria)

Dani 2006

Methods

Single‐centre trial

Participants

40 preterm infants ventilated with severe RDS with FiO2 > 0.5 and arterial‐alveolar oxygen ratio < 0.15, despite surfactant treatment

Interventions

iNO at 10 ppm for 4 hours followed by 6 ppm compared with no treatment. Weaning started at 72 hours or when the infant was extubated, or when FiO2 was < 0.3 with mean airway pressure < 8 cmH2O

Outcomes

The primary endpoint was death or BPD. Bronchopulmonary dysplasia was defined as oxygen requirement at 36 weeks' postmenstrual age.

Secondary endpoints were evaluation of ventilation changes during iNO therapy, duration of oxygen treatment, NCPAP and mechanical ventilation, incidence of patent ductus arteriosus (PDA), pulmonary hypertension, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotising enterocolitis (NEC), sepsis and length of stay in the intensive care unit and in hospital.

Notes

Study terminated after 40 infants enrolled. Initially planned to include 26 per group. Unplanned interim analysis was performed because of an impression that the results were significant. No evidence indicated that the analysis was adjusted to account for potential multiple looks at the data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Unclear risk

No evidence of selective reporting, but protocol not available

Other bias

High risk

Early termination of trial due to impression of an effect

Funding Source

Unclear risk

Funding source unclear

EUNO 2009

Methods

Multi‐centre trial

Participants

800 infants between 24 weeks' and 28 weeks' gestation and 6 days enrolled at less than 24 hours of age. If intubated, they had to have received surfactant and could be enrolled if on CPAP requiring > 30% oxygen. Patients were ineligible if they required more than 50% O2 to maintain saturation over 85% on a mean airway pressure ≥ 8 cmH2O.

Interventions

Inhaled NO at 5 ppm for at least 7 and a maximum of 21 days

Outcomes

Primary outcome was survival without BPD at 36 weeks' postmenstrual age. Secondary outcome was survival without severe brain injury on head ultrasonography.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated

Allocation concealment (selection bias)

Low risk

Centralised interactive Web‐based enrolment and randomisation system

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masking of intervention: yes

Masking of outcome assessment: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

Low risk

Funding Source

High risk

Funded by industry (Ikaria), initiated by investigators

Hascoet 2005

Methods

Multi‐centre trial

Participants

860 infants < 32 weeks enrolled but not eligible for study gas unless they developed hypoxic respiratory failure (i.e. need for mechanical ventilation, FiO2 > .40, and arterial alveolar O2 ratio < 0.22 at 6 to 48 hours of age; n = 145

Interventions

Inhaled NO was started at 5 ppm, with adjustments allowed depending on response up to a maximum of 10 ppm. Eventually, 61 were treated with iNO and 84 were given the control intervention. Participants were allowed to receive iNO in either group if they developed refractory hypoxaemia.

Outcomes

Primary outcome was survival to 28 days without death, need for oxygen, IVH > grade 1 or refractory hypoxaemia defined as need for 100% oxygen with PaO2 < 50.

Secondary outcomes included incidence and severity of IVH and periventricular leukomalacia (PVL), BPD or steroid treatment and pulmonary haemorrhage, patent ductus arteriosus (PDA), necrotising enterocolitis and nosocomial infection.

Notes

Open‐label iNO provided to all infants when they met refractory hypoxaemia criteria ‐ 20 infants received treatment before 6 hours and were not included; 28 control infants received open‐label iNO after the randomised intervention.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified, blocked central randomisation

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

High risk

Masking of intervention: no

Masking of outcome assessment: no

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

Registration documents or protocol not found

Funding Source

Low risk

Supported by local sources (University of Nantes) and industry (Air Liquide)

INNOVO 2005

Methods

Multi‐centre trial

Participants

108 preterm infants (< 34 weeks) less than 28 days of age, with "severe respiratory failure"

Interventions

Inhaled NO usually at 5 ppm up to 40 ppm (n = 55) or no supplemental gas (n = 53)

Outcomes

Primary outcomes were (1) death or severe disability at 1 year corrected postnatal age; and (2) death or continued oxygen need at expected date of birth.

Secondary outcomes included length of stay in hospital; length of time on supplemental oxygen; length of time on ventilatory support; pneumothorax; other pulmonary air leak; pulmonary haemorrhage; major cerebral abnormality; necrotising enterocolitis; patent ductus arteriosus needing medical treatment; treatment of retinopathy of prematurity; infection; and age at which full oral feeding was established.
Secondary outcomes at 1 year corrected age included disability and/or impairment of neuromotor development, vision and hearing; respiratory problems; seizures; growth; and hospital admissions.

Notes

Initially planned 200 participants

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation with minimisation

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

High risk

Masking of intervention: no

Masking of outcome assessment: no

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

Unclear risk

Recruited half of planned sample size in the 2‐year time frame

Funding Source

Low risk

Funded by government agency (MRC, UK)

Kinsella 1999

Methods

Multi‐centre trial

Participants

80 preterm infants (≤ 34 weeks) < 7 days of age, with a/AO2 < 0.1 on 2 blood gases after surfactant treatment

Interventions

Inhaled NO at 5 ppm (n = 48) or no supplemental gas (n = 32) for 7 days, after which "trials off" were allowed. Maximum treatment duration was 14 days.

Outcomes

Primary outcome was survival.

Bronchopulmonary dysplasia, intraventricular haemorrhage and duration of ventilation were secondary outcomes.

Notes

Initially planned 210 participants

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central stratified randomisation

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked intervention

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Unclear risk

No protocol or registration document found

Other bias

High risk

Study terminated early after planned first interim analysis, as little difference in outcomes was apparent

Funding Source

Low risk

Funded by government agency (NIH) and in part by industry (iNOtherapeutics)

Kinsella 2006

Methods

Multi‐centre trial

Participants

793 preterm infants < 34 weeks, respiratory failure needing assisted ventilation in first 48 hours

Interventions

iNO at 5 ppm (n = 398) or no iNO (n = 395) for 21 days or until extubation

Outcomes

Primary outcome was death or bronchopulmonary dysplasia.

Secondary outcomes included severe intraventricular haemorrhage, periventricular leukomalacia and ventriculomegaly.

Notes

Baseline and follow‐up cranial ultrasonography was required.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central stratified, blocked randomisation

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinded trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

Low risk

Funding Source

Low risk

Funded by government agency (NHLBI) and in part by industry (iNOtherapeutics)

Kinsella 2014

Methods

Multi‐centre parallel‐group randomised trial

Participants

124 preterm infants with birth weight of 500 to 1250 grams, receiving oxygen by non‐invasive means at < 72 hours of age

Interventions

iNO at 10 ppm (to give effective concentration ≥ 5 ppm) or placebo, for at least 2 weeks and until 30 weeks' postmenstrual age

Outcomes

Death or BPD, IVH, retinopathy of prematurity, necrotising enterocolitis, treatment of infants with PDA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central computer‐generated randomisation

Allocation concealment (selection bias)

Low risk

Placebo‐controlled trial

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

Low risk

Funding Source

Low risk

Funded by government agency (NHLBI), funded in part by industry (Ikaria supplied gases)

Mercier 1999

Methods

Multi‐centre parallel‐group randomised trial

Participants

85 preterm infants (< 33 weeks) with OI of 12.5 to 30 at < 7 days

Interventions

10 ppm inhaled NO (n = 40) or control (n = 45). Open‐label treatment with NO allowed in controls if OI > 30

Outcomes

Primary outcome was decrease in OI after 2 hours of therapy.

Notes

Initially planned 360 infants across both gestational age strata

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised phone randomisation

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

No protocol or registration found

Other bias

Unclear risk

Stopped early because of slowing enrolment

Funding Source

Low risk

Funded by local agency, supported in part by industry (Air Liquide)

Schreiber 2003

Methods

Single‐centre trial

Participants

207 infants < 34 weeks, < 72 hours of age, intubated and ventilated for RDS, birth weight < 2000 grams

Interventions

Randomised to iNO (N = 105) (starting at 10 ppm for 1 day, then 5 ppm for 6 days; thereafter weaned by 1 ppm, stopped if extubated) vs control (N = 102); HFOV (N= 102) vs CMV (N = 105)

Outcomes

Primary outcome was a decrease in death or BPD at 36 weeks.

Notes

Factorial 2 × 2 design comparing high‐frequency ventilation vs conventional treatment and iNO vs placebo gas

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified blocked randomisation

Allocation concealment (selection bias)

Low risk

Masked allocation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo‐controlled trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Unclear risk

No protocol or registration documents found

Funding Source

High risk

Funded by industry (Ikaria), investigator initiated

Srisuparp 2002

Methods

Single‐centre trial

Participants

34 infants weighing < 2000 grams, ventilated after surfactant with an arterial catheter at < 72 hours of age. Also required to satisfy a severity of illness criterion. OI > 4 for birth weight < 1000 grams, > 6 for birth weight 1001‐1250 grams, > 8 for 1251‐1500 grams, > 10 for 1501‐1750 grams and > 12 for 1751‐2000 grams

Interventions

iNO at 20 ppm or standard care, trial of weaning after 72 hours, maximum duration 7 days

Outcomes

Primary outcome was severe intraventricular haemorrhage (grade 3 or 4).

Notes

Performed as a preliminary pilot study, before Schreiber 2003

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details available

Allocation concealment (selection bias)

Unclear risk

Masking of allocation: unclear

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

No registration or protocol found

Funding Source

Unclear risk

Not stated

Su 2007

Methods

Single‐centre randomised trial

Participants

65 preterm infants with birth weight < 1500 grams or gestational age < 32 weeks, intubated with OI ≥ 25

Interventions

iNO initially at a dose of 5ppm, could be increased to 20 ppm in cases of poor response, or decreased if good response obtained; duration of therapy not clear according to protocol, but mean duration of receipt of iNO was 4.9 days

Outcomes

Primary outcome variable was OI 24 hours after randomisation. Secondary outcomes included mortality, BPD, intracranial haemorrhage, patent ductus arteriosus and retinopathy of prematurity.

Notes

Not all of the infants received surfactant: 23 of 32 iNO treated and 24 of 33 controls

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details of randomisation procedures provided

Blinding (performance bias and detection bias)
All outcomes

High risk

Masking of intervention: no

Masking of outcome assessment: no

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Unclear risk

No registration documents or protocol found

Funding Source

Unclear risk

Unclear

Subhedar 1997

Methods

Single‐centre randomised comparison of iNO, dexamethasone, combined therapy and control, using a 2 × 2 factorial design

Participants

42 preterm infants less than 32 weeks' gestation with "high risk" of developing BPD

Interventions

iNO initially administered at 20 ppm and weaned if effective (n = 20) or control (n = 22). Dexamethasone at 1 mg/kg/d for 3 days, followed by 0.5 mg/kg/d for 3 days (n = 21) (3 infants received a lower dose), or no steroids (n = 21)

Outcomes

Primary outcome was survival without bronchopulmonary dysplasia. Secondary outcomes included duration of ventilation, intraventricular haemorrhage and other neonatal complications.

Notes

Initially planned 88 participants

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

High risk

Masking of intervention: no

Masking of outcome measurement: no

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

No registration or protocol found

Other bias

High risk

Terminated early because frequency of adverse primary outcome was close to 100% in all groups

Funding Source

Low risk

Government agency and local funds, some support from industry

Van Meurs 2005

Methods

Multi‐centre trial

Participants

420 preterm infants, < 34 weeks, OI ≥ 10 on 2 blood gases 30 minutes to 12 hours apart. ≥ 4 hours after surfactant

Interventions

iNO initially at 5 ppm to 10 ppm (210) or placebo (210) (if no response at 10 ppm, study gas was stopped). Weaning ≥ 10 hours after initiation. Maximum duration was 336 hours.

Outcomes

Primary outcome was reduced death or BPD at 36 weeks. Secondary outcomes were grade 3 or 4 intraventricular haemorrhage or periventricular leukomalacia, number of days of assisted ventilation and oxygen use, length of hospitalisation and threshold retinopathy of prematurity.

Notes

Initially planned 220 infants per arm; stopped by the data monitoring committee because of apparent increase in severe IVH with no evidence of benefit

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified blocked central randomisation

Allocation concealment (selection bias)

Low risk

Masking of allocation: yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masking of intervention: yes
Masking of outcome assessment: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completeness of follow‐up: yes

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

High risk

Study terminated a little early because of an increase in severe IVH in the intervention group

Funding Source

Low risk

Support from government agency (NICHHD), partial support from industry (Ikaria)

Van Meurs 2007

Methods

Multi‐centre trial

Participants

29 infants at less than 34 weeks' gestation with birth weight > 1500 grams; ventilated with OI > 15 on 2 consecutive blood gases between 30 minutes and 12 hours apart

Interventions

iNO initially at 5 ppm to 10 ppm (210) or placebo (210) (if no response at 10 ppm, study gas was stopped). Weaning ≥ 10 hours after initiation. Maximum duration was 14 days.

Outcomes

Primary outcome was reduced death or BPD at 36 weeks. Secondary outcomes were grade 3 or 4 intraventricular haemorrhage or periventricular leukomalacia, number of days of assisted ventilation and oxygen use, length of hospitalisation and threshold retinopathy of prematurity.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central telephone randomisation, stratified and blocked

Allocation concealment (selection bias)

Low risk

Masked allocation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo‐controlled trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Selective reporting (reporting bias)

Low risk

No evidence

Funding Source

Low risk

Government agency (NICHHD), partial support from industry (Ikaria)

Wei 2014

Methods

Single‐centre randomised trial of iNO vs no treatment gas

Participants

60 preterm infants at less than 34 weeks, receiving mechanical ventilation or CPAP, with OI ≥ 11 2 hours after surfactant therapy

Interventions

iNO initially at 5 ppm or placebo. Duration of therapy 7 days or until ventilation withdrawal

Outcomes

Primary outcome was change in OI status over different times during first 3 days of therapy. Secondary outcomes included mortality, BPD, intraventricular haemorrhage and other neonatal complications.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details available

Allocation concealment (selection bias)

High risk

No details of randomisation procedures provided

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Unclear risk

No registration or protocol found

Funding Source

Unclear risk

Not stated

Yoder 2013

Methods

Multi‐centre parallel‐group randomised trial

Participants

451 preterm infants, < 1250 grams and < 30 weeks, at 5 to 14 days of age, on invasive ventilation, or on non‐invasive support if they weighed < 800 grams

Interventions

iNO at 20 ppm for 3 to 4 days, then 10 ppm for 10 days, then 5 ppm until 24 days

Outcomes

Survival without BPD, duration of respiratory support and hospitalisation

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised computer‐generated

Allocation concealment (selection bias)

Low risk

Placebo‐controlled trial

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No significant attrition

Selective reporting (reporting bias)

Low risk

Registered trial, primary outcomes reported

Other bias

Low risk

Funding Source

High risk

Industry initiated and funded (Ikaria)

a/AO2: arterial‐alveolar oxygen ratio.
BPD: bronchopulmonary dysplasia.
CMV: cytomegalovirus.
CPAP: continuous positive airway pressure.
FiO2: fraction of inspired oxygen.
HVOF: high‐velocity oxygen fuel.
iNO: inhaled nitric oxide.
IVH: intraventricular haemorrhage.
MRC: Medical Research Council.
NEC: necrotising enterocolitis.
NICHD: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
NO: nitric oxide.
PDA: patent ductus arteriosus.
PVL: periventricular leukomalacia.
RDS: respiratory distress syndrome.
ROP: retinopathy of prematurity.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Day 1996

This was a randomised controlled trial of 50 infants with pulmonary hypertension, 16 of whom were at less than 36 weeks' gestation. The definition of prematurity is not the same as that used in this review, and in any case, it is not possible to extract data that refer solely to preterm infants.

Lindwall 2005

No untreated control group was included. Short‐term randomised cross‐over trial of response to inhaled nitric oxide among infants on continuous positive airway pressure

Skimming 1997

No untreated control group was included. This was a randomised comparison of 5 ppm and 20 ppm for 15 minutes in preterm infants.

Data and analyses

Open in table viewer
Comparison 1. Inhaled NO compared with control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death before discharge Show forest plot

17

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 Inhaled NO compared with control, Outcome 1 Death before discharge.

Comparison 1 Inhaled NO compared with control, Outcome 1 Death before discharge.

1.1 Studies with entry before 3 days based on oxygenation

10

1066

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.89, 1.18]

1.2 Studies with entry after 3 days based on BPD risk

3

1075

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.81, 1.71]

1.3 Studies of routine use in preterm infants on respiratory support

4

1924

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.74, 1.10]

2 Death before 36 weeks' postmenstrual age Show forest plot

9

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Inhaled NO compared with control, Outcome 2 Death before 36 weeks' postmenstrual age.

Comparison 1 Inhaled NO compared with control, Outcome 2 Death before 36 weeks' postmenstrual age.

2.1 Studies with entry before 3 days based on oxygenation

5

458

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.72, 1.11]

2.2 Studies with entry after 3 days based on BPD risk

2

493

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.81, 2.20]

2.3 Studies of routine use in preterm infants on respiratory support

2

924

Risk Ratio (M‐H, Fixed, 95% CI)

1.31 [0.90, 1.89]

3 Bronchopulmonary dysplasia among survivors at 36 weeks Show forest plot

15

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 Inhaled NO compared with control, Outcome 3 Bronchopulmonary dysplasia among survivors at 36 weeks.

Comparison 1 Inhaled NO compared with control, Outcome 3 Bronchopulmonary dysplasia among survivors at 36 weeks.

3.1 Studies with entry before 3 days based on oxygenation

8

681

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.76, 1.04]

3.2 Studies with entry after 3 days based on BPD risk

3

990

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.83, 1.01]

3.3 Studies of routine use in preterm infants on respiratory support

4

1782

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.85, 1.05]

4 Death or bronchopulmonary dysplasia at 36 weeks Show forest plot

15

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.4

Comparison 1 Inhaled NO compared with control, Outcome 4 Death or bronchopulmonary dysplasia at 36 weeks.

Comparison 1 Inhaled NO compared with control, Outcome 4 Death or bronchopulmonary dysplasia at 36 weeks.

4.1 Studies with entry before 3 days based on oxygenation

8

958

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.87, 1.01]

4.2 Studies with entry after 3 days based on BPD risk

3

1075

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.85, 1.01]

4.3 Studies of routine use in preterm infants on respiratory support

4

1924

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.87, 1.02]

5 Intraventricular haemorrhage (all grades) Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.5

Comparison 1 Inhaled NO compared with control, Outcome 5 Intraventricular haemorrhage (all grades).

Comparison 1 Inhaled NO compared with control, Outcome 5 Intraventricular haemorrhage (all grades).

5.1 Studies with entry before 3 days based on oxygenation

4

314

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.69, 1.28]

5.2 Studies with entry after 3 days based on BPD risk

1

458

Risk Ratio (M‐H, Fixed, 95% CI)

1.1 [0.48, 2.54]

5.3 Studies of routine use in preterm infants on respiratory support

2

1573

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.88, 1.23]

6 Intraventricular haemorrhage (grade 3 or 4) Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.6

Comparison 1 Inhaled NO compared with control, Outcome 6 Intraventricular haemorrhage (grade 3 or 4).

Comparison 1 Inhaled NO compared with control, Outcome 6 Intraventricular haemorrhage (grade 3 or 4).

6.1 Studies with entry before 3 days based on oxygenation

6

773

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.98, 1.47]

6.2 Studies of routine use in preterm infants on respiratory support

4

1913

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.73, 1.09]

7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia Show forest plot

11

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.7

Comparison 1 Inhaled NO compared with control, Outcome 7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia.

Comparison 1 Inhaled NO compared with control, Outcome 7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia.

7.1 Studies with entry before 3 days based on oxygenation

8

901

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.88, 1.33]

7.2 Studies of routine use in preterm infants on respiratory support

3

1747

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.73, 1.12]

8 Neurodevelopmental disability Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.8

Comparison 1 Inhaled NO compared with control, Outcome 8 Neurodevelopmental disability.

Comparison 1 Inhaled NO compared with control, Outcome 8 Neurodevelopmental disability.

8.1 Studies with entry before 3 days based on oxygenation

2

208

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.78, 1.40]

8.2 Studies with entry after 3 days based on BPD risk

2

498

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.74, 1.09]

8.3 Studies of routine use in preterm infants on respiratory support

3

1223

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.74, 1.13]

9 Bayley MDI or PDI < ‐2 SD Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.9

Comparison 1 Inhaled NO compared with control, Outcome 9 Bayley MDI or PDI < ‐2 SD.

Comparison 1 Inhaled NO compared with control, Outcome 9 Bayley MDI or PDI < ‐2 SD.

9.1 Studies of routine use in preterm infants on respiratory support

2

768

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.36, 0.90]

10 Cerebral palsy Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.10

Comparison 1 Inhaled NO compared with control, Outcome 10 Cerebral palsy.

Comparison 1 Inhaled NO compared with control, Outcome 10 Cerebral palsy.

10.1 Studies with entry before 3 days based on oxygenation

2

209

Risk Ratio (M‐H, Fixed, 95% CI)

1.85 [0.93, 3.71]

10.2 Studies with entry after 3 days based on BPD risk

2

498

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.54, 2.23]

10.3 Studies of routine use in preterm infants on respiratory support

3

1223

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.47]

11 Severe retinopathy of prematurity (≥stage 3) Show forest plot

5

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.11

Comparison 1 Inhaled NO compared with control, Outcome 11 Severe retinopathy of prematurity (≥stage 3).

Comparison 1 Inhaled NO compared with control, Outcome 11 Severe retinopathy of prematurity (≥stage 3).

11.1 Studies with entry before 3 days based on oxygenation

3

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.64, 1.47]

11.2 Studies of routine use in preterm infants on respiratory support

2

331

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.29, 1.46]

12 Retinopathy of prematurity requiring surgery Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.12

Comparison 1 Inhaled NO compared with control, Outcome 12 Retinopathy of prematurity requiring surgery.

Comparison 1 Inhaled NO compared with control, Outcome 12 Retinopathy of prematurity requiring surgery.

12.1 Studies with entry before 3 days based on oxygenation

4

673

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.59, 1.29]

12.2 Studies with entry after 3 days based on BPD risk

1

582

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.78, 1.38]

12.3 Studies of routine use in preterm infants on respiratory support

2

917

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.79, 1.47]

Study flow diagram: review update.
Figuras y tablas -
Figure 1

Study flow diagram: review update.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Inhaled NO compared with control, Outcome 1 Death before discharge.
Figuras y tablas -
Analysis 1.1

Comparison 1 Inhaled NO compared with control, Outcome 1 Death before discharge.

Comparison 1 Inhaled NO compared with control, Outcome 2 Death before 36 weeks' postmenstrual age.
Figuras y tablas -
Analysis 1.2

Comparison 1 Inhaled NO compared with control, Outcome 2 Death before 36 weeks' postmenstrual age.

Comparison 1 Inhaled NO compared with control, Outcome 3 Bronchopulmonary dysplasia among survivors at 36 weeks.
Figuras y tablas -
Analysis 1.3

Comparison 1 Inhaled NO compared with control, Outcome 3 Bronchopulmonary dysplasia among survivors at 36 weeks.

Comparison 1 Inhaled NO compared with control, Outcome 4 Death or bronchopulmonary dysplasia at 36 weeks.
Figuras y tablas -
Analysis 1.4

Comparison 1 Inhaled NO compared with control, Outcome 4 Death or bronchopulmonary dysplasia at 36 weeks.

Comparison 1 Inhaled NO compared with control, Outcome 5 Intraventricular haemorrhage (all grades).
Figuras y tablas -
Analysis 1.5

Comparison 1 Inhaled NO compared with control, Outcome 5 Intraventricular haemorrhage (all grades).

Comparison 1 Inhaled NO compared with control, Outcome 6 Intraventricular haemorrhage (grade 3 or 4).
Figuras y tablas -
Analysis 1.6

Comparison 1 Inhaled NO compared with control, Outcome 6 Intraventricular haemorrhage (grade 3 or 4).

Comparison 1 Inhaled NO compared with control, Outcome 7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia.
Figuras y tablas -
Analysis 1.7

Comparison 1 Inhaled NO compared with control, Outcome 7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia.

Comparison 1 Inhaled NO compared with control, Outcome 8 Neurodevelopmental disability.
Figuras y tablas -
Analysis 1.8

Comparison 1 Inhaled NO compared with control, Outcome 8 Neurodevelopmental disability.

Comparison 1 Inhaled NO compared with control, Outcome 9 Bayley MDI or PDI < ‐2 SD.
Figuras y tablas -
Analysis 1.9

Comparison 1 Inhaled NO compared with control, Outcome 9 Bayley MDI or PDI < ‐2 SD.

Comparison 1 Inhaled NO compared with control, Outcome 10 Cerebral palsy.
Figuras y tablas -
Analysis 1.10

Comparison 1 Inhaled NO compared with control, Outcome 10 Cerebral palsy.

Comparison 1 Inhaled NO compared with control, Outcome 11 Severe retinopathy of prematurity (≥stage 3).
Figuras y tablas -
Analysis 1.11

Comparison 1 Inhaled NO compared with control, Outcome 11 Severe retinopathy of prematurity (≥stage 3).

Comparison 1 Inhaled NO compared with control, Outcome 12 Retinopathy of prematurity requiring surgery.
Figuras y tablas -
Analysis 1.12

Comparison 1 Inhaled NO compared with control, Outcome 12 Retinopathy of prematurity requiring surgery.

Summary of findings for the main comparison. Inhaled NO compared with control for respiratory failure in preterm infants

Inhaled NO compared with control for respiratory failure in preterm infants

Patient or population: respiratory failure in preterm infants
Setting: neonatal intensive care units
Intervention: inhaled NO
Comparison: placebo or no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo or no treatment

Risk with Inhaled NO

Death before discharge ‐ Studies with entry before 3 days based on oxygenation

Study population

RR 1.02
(0.89 to 1.18)

1066
(10 RCTs)

⊕⊕⊕⊕
High

394 per 1000

402 per 1000
(351 to 465)

Death before discharge ‐ Studies with entry after 3 days based on BPD risk

Study population

RR 1.18
(0.81 to 1.71)

1075
(3 RCTs)

⊕⊕⊕⊕
High

83 per 1000

98 per 1000
(67 to 141)

Death before discharge ‐ Studies of routine use in preterm infants on respiratory support

Study population

RR 0.90
(0.74 to 1.10)

1924
(4 RCTs)

⊕⊕⊕⊝
Moderatea

170 per 1000

153 per 1000
(126 to 187)

Death or bronchopulmonary dysplasia at 36 weeks ‐ Studies with entry before 3 days based on oxygenation

Study population

RR 0.94
(0.87 to 1.01)

958
(8 RCTs)

⊕⊕⊕⊕
High

743 per 1000

698 per 1000
(646 to 750)

Death or bronchopulmonary dysplasia at 36 weeks ‐ Studies with entry after 3 days based on BPD risk

Study population

RR 0.92
(0.85 to 1.01)

1075
(3 RCTs)

⊕⊕⊕⊕
High

667 per 1000

614 per 1000
(567 to 674)

Death or bronchopulmonary dysplasia at 36 weeks ‐ Studies of routine use in preterm infants on respiratory support

Study population

RR 0.94
(0.87 to 1.02)

1924
(4 RCTs)

⊕⊕⊕⊕
High

548 per 1000

515 per 1000
(477 to 559)

Intraventricular haemorrhage (grade 3 or 4) ‐ Studies with entry before 3 days based on oxygenation

Study population

RR 1.20
(0.98 to 1.47)

773
(6 RCTs)

⊕⊕⊕⊕
High

231 per 1000

278 per 1000
(227 to 340)

Intraventricular haemorrhage (grade 3 or 4) ‐ Studies of routine use in preterm infants on respiratory support

Study population

RR 0.89
(0.73 to 1.09)

1913
(4 RCTs)

⊕⊕⊕⊝
Moderateb

127 per 1000

113 per 1000
(93 to 139)

Neurodevelopmental disability ‐ Studies with entry before 3 days based on oxygenation

Study population

RR 1.05
(0.78 to 1.40)

208
(2 RCTs)

⊕⊕⊕⊝
Moderatec

455 per 1000

477 per 1000
(355 to 636)

Neurodevelopmental disability ‐ Studies with entry after 3 days based on BPD risk

Study population

RR 0.90
(0.74 to 1.09)

498
(2 RCTs)

⊕⊕⊕⊝
Moderatec

480 per 1000

432 per 1000
(355 to 523)

Neurodevelopmental disability ‐ Studies of routine use in preterm infants on respiratory support

Study population

RR 0.91
(0.74 to 1.13)

1223
(3 RCTs)

⊕⊕⊕⊕
High

195 per 1000

178 per 1000
(144 to 220)

*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and relative effect of the intervention (and its 95% CI).

CI: confidence interval; OR: odds ratio; RR: risk ratio.

GRADE Working Group grades of evidence.
High quality: We are very confident that the true effect lies close to that of the estimate of effect.
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different.
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect.
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

aHighly variable risk ratio in individual trials (I2 = 50%).

bHighly variable risk ratio in individual trials (I2 = 33%).

cBased on 2 studies, wide confidence intervals.

Figuras y tablas -
Summary of findings for the main comparison. Inhaled NO compared with control for respiratory failure in preterm infants
Comparison 1. Inhaled NO compared with control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death before discharge Show forest plot

17

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Studies with entry before 3 days based on oxygenation

10

1066

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.89, 1.18]

1.2 Studies with entry after 3 days based on BPD risk

3

1075

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.81, 1.71]

1.3 Studies of routine use in preterm infants on respiratory support

4

1924

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.74, 1.10]

2 Death before 36 weeks' postmenstrual age Show forest plot

9

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Studies with entry before 3 days based on oxygenation

5

458

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.72, 1.11]

2.2 Studies with entry after 3 days based on BPD risk

2

493

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.81, 2.20]

2.3 Studies of routine use in preterm infants on respiratory support

2

924

Risk Ratio (M‐H, Fixed, 95% CI)

1.31 [0.90, 1.89]

3 Bronchopulmonary dysplasia among survivors at 36 weeks Show forest plot

15

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Studies with entry before 3 days based on oxygenation

8

681

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.76, 1.04]

3.2 Studies with entry after 3 days based on BPD risk

3

990

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.83, 1.01]

3.3 Studies of routine use in preterm infants on respiratory support

4

1782

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.85, 1.05]

4 Death or bronchopulmonary dysplasia at 36 weeks Show forest plot

15

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Studies with entry before 3 days based on oxygenation

8

958

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.87, 1.01]

4.2 Studies with entry after 3 days based on BPD risk

3

1075

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.85, 1.01]

4.3 Studies of routine use in preterm infants on respiratory support

4

1924

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.87, 1.02]

5 Intraventricular haemorrhage (all grades) Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 Studies with entry before 3 days based on oxygenation

4

314

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.69, 1.28]

5.2 Studies with entry after 3 days based on BPD risk

1

458

Risk Ratio (M‐H, Fixed, 95% CI)

1.1 [0.48, 2.54]

5.3 Studies of routine use in preterm infants on respiratory support

2

1573

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.88, 1.23]

6 Intraventricular haemorrhage (grade 3 or 4) Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Studies with entry before 3 days based on oxygenation

6

773

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.98, 1.47]

6.2 Studies of routine use in preterm infants on respiratory support

4

1913

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.73, 1.09]

7 Intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia Show forest plot

11

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 Studies with entry before 3 days based on oxygenation

8

901

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.88, 1.33]

7.2 Studies of routine use in preterm infants on respiratory support

3

1747

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.73, 1.12]

8 Neurodevelopmental disability Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Studies with entry before 3 days based on oxygenation

2

208

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.78, 1.40]

8.2 Studies with entry after 3 days based on BPD risk

2

498

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.74, 1.09]

8.3 Studies of routine use in preterm infants on respiratory support

3

1223

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.74, 1.13]

9 Bayley MDI or PDI < ‐2 SD Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

9.1 Studies of routine use in preterm infants on respiratory support

2

768

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.36, 0.90]

10 Cerebral palsy Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 Studies with entry before 3 days based on oxygenation

2

209

Risk Ratio (M‐H, Fixed, 95% CI)

1.85 [0.93, 3.71]

10.2 Studies with entry after 3 days based on BPD risk

2

498

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.54, 2.23]

10.3 Studies of routine use in preterm infants on respiratory support

3

1223

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.47]

11 Severe retinopathy of prematurity (≥stage 3) Show forest plot

5

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

11.1 Studies with entry before 3 days based on oxygenation

3

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.64, 1.47]

11.2 Studies of routine use in preterm infants on respiratory support

2

331

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.29, 1.46]

12 Retinopathy of prematurity requiring surgery Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

12.1 Studies with entry before 3 days based on oxygenation

4

673

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.59, 1.29]

12.2 Studies with entry after 3 days based on BPD risk

1

582

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.78, 1.38]

12.3 Studies of routine use in preterm infants on respiratory support

2

917

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.79, 1.47]

Figuras y tablas -
Comparison 1. Inhaled NO compared with control