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Referencias

References to studies included in this review

Barefield 1996 {published data only}

Barefield ES, Karke VA, Phillips JB, Carlo WA. Inhaled nitric oxide in term infants with hypoxemic respiratory failure. Journal of Pediatrics 1996;129:279‐86. CENTRAL
Barefield ES, Karke VA, Phillips JB, Carlo WA. Randomized, controlled trial of inhaled NO in ECMO candidates. Pediatric Research 1995;37:195A. CENTRAL

Christou 2000 {published data only}

Christou H, Van Marter LJ, Wessel DL, Allred EN, Kane JW, Thompson JE, et al. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Critical Care Medicine 2000;28:3722‐7. CENTRAL

Clark 2000 {published data only}

Clark RH, Keuser TJ, Walker MW, Southgate MS, Huckaby JL, Perez JA, et al. for the Clinical Inhaled Nitric Oxide Research Group. Low‐dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. New England Journal of Medicine 2000;342:469‐74. CENTRAL

Cornfield 1999 {published data only}

Cornfield DN, Maynard RC, deRegnier RA, Guiang SF, Barbato JE, Milla CE. Randomized, controlled trial of low‐dose inhaled nitric oxide in the treatment of term and near‐term infants with respiratory failure and pulmonary hypertension. Pediatrics 1999;104:1089‐94. CENTRAL

Davidson 1997 {published data only}

Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double‐masked, placebo‐controlled, dose‐response, multicenter study. Pediatrics 1998;101:325‐34. CENTRAL
Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, et al. I‐NO/PPHN Study Group. A double masked, randomized, placebo controlled, dose response study of inhaled nitric oxide for the treatment of persistent pulmonary hypertension of the newborn. Pediatric Research 1997;41:144A (abstract). CENTRAL

Day 1996 {published data only}

Day RW, Lynch JM. Acute hemodynamic and blood gas effects of inhaled nitric oxide in newborns with lung disease and pulmonary hypertension. Pediatric Research 1996;39:330A. CENTRAL
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

Gonzalez 2010 {published data only}

Gonzalez A, Fabres J, D'Apremont I, Urcelay G, Avaca M, Gandolfi C, et al. Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension. Journal of Perinatology 2010;30(6):420‐4. CENTRAL

INNOVO 2007 {published data only}

Field D, Elbourne D, Hardy P, Fenton AC, Ahluwalia J, Halliday HL, et al. INNOVO Trial Collaborating Group. Neonatal ventilation with inhaled nitric oxide vs. ventilatory support without inhaled nitric oxide for infants with severe respiratory failure born at or near term: the INNOVO multicentre randomised controlled trial. Neonatology 2007;91(2):73‐82. CENTRAL

Kinsella 1997 {published data only}

Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Clark RH, et al. Randomized, multicenter trial of inhaled nitric oxide and high frequency ventilation in severe persistent pulmonary hypertension of the newborn. Pediatric Research 1996;39:222A. CENTRAL
Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari EE, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high‐frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. Journal of Pediatrics 1997;131:55‐62. CENTRAL

Konduri 2004 {published data only}

Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, et al. Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near‐term newborn infants with hypoxic respiratory failure. Pediatrics 2004;113(3 Pt 1):559‐64. CENTRAL
Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. Early inhaled nitric oxide therapy for term and near‐term newborn infants with hypoxic respiratory failure: neurodevelopmental follow‐up. Journal of Pediatrics 2007;150(3):235‐40.e1. CENTRAL

Liu 2008 {published data only}

Liu CQ, Ma L, Tang LM, He XJ, Wei SF, Wang SX, et al. A randomized controlled study on the efficacy of inhaled nitric oxide in treatment of neonates with meconium aspiration syndrome. Zhonghua Er Ke za Zhi [Chinese Journal of Pediatrics] 2008;46(3):224‐8. CENTRAL

Mercier 1998 {published data only}

Franco‐Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised 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. Pediatric Research 1998;43:290A. CENTRAL

Ninos 1996 {published and unpublished data}

The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full‐term and nearly full term infants with hypoxic respiratory failure. New England Journal of Medicine 1997;336:597‐604. CENTRAL
The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near‐term infants: neurodevelopmental follow‐up of the The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Journal of Pediatrics 2000;136:611‐7. CENTRAL

Ninos 1997 {unpublished data only}

The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997;99:838‐45. CENTRAL
The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near‐term infants: neurodevelopmental follow‐up of the The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Journal of Pediatrics 2000;136:611‐7. CENTRAL

Roberts 1996 {published data only}

Roberts JD, Fineman J, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. New England Journal of Medicine 1997;336:605‐10. CENTRAL
Roberts JD, Fineman J, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide gas improves oxygenation in PPHN. Pediatric Research 1996;39:241A. CENTRAL

Sadiq 1998 {published and unpublished data}

Sadiq FH, Illinois Multicenter Trial. Treatment of persistent pulmonary hypertension of the newborn with nitric oxide: a randomized trial. Pediatric Research 1998;43:192A. CENTRAL
Sadiq HF, Mantych G, Benawra RS, Devaskar UP, Hocker JR. Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. Journal of Perinatology 2003;23:98‐103. CENTRAL

Wessel 1996 {published data only}

Ellington M, O'Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S. Child health status, neurodevelopmental outcome, and parental satisfaction in a randomized controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 2001;107:1351‐6. CENTRAL
Wessel D, Adatia I, Thompson J, Kane J, Van Marter L, Stark A, et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for PPHN. Pediatric Research 1996;39:252A. CENTRAL
Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1997;100(5):e7. CENTRAL

References to studies excluded from this review

Hoffman 1997 {published data only}

Hoffman GM, Ross GA, Day SE, Rice TB, Nelin LD. Inhaled nitric oxide reduces the utilization of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Critical Care Medicine 1997;25:352‐9. CENTRAL

Pinheiro 1998 {published data only}

Pinheiro JMB, Carey T. Inhaled NO vs. intravenous nitroprusside in neonatal pulmonary hypertension: randomized trial at a center without ECMO. Pediatric Research 1998;43:294A. 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.

Beckman 1990

Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxides. Proceedings of the National Academy of Sciences of the United States of America 1990;87:1620‐4.

Bouchet 1993

Bouchet M, Renaudin MH, Raveau C, Mercier JC Dehan M, Zupan V. Safety requirement for use of inhaled nitric oxide in neonates. Lancet 1993;341:968‐9.

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.

Davidson 1999

Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999;104:231‐6.

Dobyns 1999

Dobyns EL, Griebel J, Kinsella JP, Abman SH, Accurso FJ. Infant lung function after inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatric Pulmonology 1999;28:24‐30.

Etches 1994

Etches PC, Finer NN, Barrington KJ, Graham AJ, Chan WKY. Nitric oxide reverses pulmonary hypertension in the newborn piglet. Pediatric Research 1994;35:15‐9.

Finer 1994

Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski A, Ryan CA. Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. Journal of Pediatrics 1994;124:302‐8.

Fratacci 1991

Fratacci MD, Frostell CG, Chen TY, Wain JC, Robinson DR, Zapol WM. Inhaled nitric oxide ‐ A selective pulmonary vasodilator of heparin‐protamine vasoconstriction in sheep. Anesthesiology 1991;75:990‐9.

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

Greenbaum 1967

Greenbaum R, Bay J, Hargreaves MD, Kain ML, Kelman GR, Nunn JF, et al. Effects of higher oxides of nitrogen on the anaesthetized dog. British Journal of Anaesthesia 1967;39:393‐404.

Haddad 1993

Haddad IY, Ischiropoulos H, Holm BA, Beckman JS, Baker JR, Matalon S. Mechanisms of peroxynitrite‐induced injury to pulmonary surfactants. American Journal of Physiology 1993;265:L555‐64.

Heal 1995

Heal CA, Spencer SA. Methaemoglobinaemia with high‐dose nitric oxide administration. Acta Paediatrica 1995;84:1318‐9.

Higenbottam 1988

Higenbottam T, Pepke‐Zaba J, Scott J, Wollman P, Coutts C, Wallwork J. Inhaled "endothelium‐derived relaxing factor" (EDRF) in primary hypertension (PPH). American Review of Respiratory Disease 1988;137:A107.

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.

Hogman 1993

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

Hogman 1994

Hogman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G. Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiologica Scandinavica 1994;151:125.

Kinsella 1992a

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 1992b

Kinsella JP, Neish SR, Shaffer E, Abman SH. Low‐dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819‐20.

Kinsella 1993

Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. Journal of Pediatrics 1993;123:103‐8.

Lipkin 2002

Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. Journal of Pediatrics 2002;140:306‐10.

MMWR 1988

National Institute for Occupational Safety and Health. NIOSH recommendations for occupational safety and health standards. MMWR 1988;37:21.

Ninos 2000

Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near‐term infants: neurodevelopmental follow‐up of the neonatal inhaled nitric oxide study group (NINOS). Journal of Pediatrics 2000;136:611‐7.

Pepke‐Zaba 1991

Pepke‐Zaba J, Higenbottam TW, Dinh‐Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991;338:1173‐4.

Radomski 1993

Radomski MW, Moncada S. Regulation of vascular homeostasis by nitric oxide. Thrombosis and Haemostasis 1993;70:36‐41.

Rasmussen 1992

Rasmussen TR, Kjaergaard SK, Tarp U, Pedersen OF. Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans. American Review of Respiratory Disease 1992;146:654‐9.

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Roberts 1992

Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818‐9.

Roberts 1993

Roberts JD, Chen T‐Y. Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circulation Research 1993;72:246.

Rosenberg 1997

Rosenberg AA, Kennaugh JM, Moreland SG, Fashaw LM, Hale KA, Torielli FM, et al. Longitudinal follow‐up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. Journal of Pediatrics 1997;131:70‐5.

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.

Schünemann 2013

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

References to other published versions of this review

Finer 1997

Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full‐term and nearly full‐term newborn infants. Cochrane Database of Systematic Reviews 1997, Issue 4. [DOI: 10.1002/14651858.CD000399]

Finer 1999

Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full‐term and nearly full‐term newborn infants. Cochrane Database of Systematic Reviews 1999, Issue 1. [DOI: 10.1002/14651858.CD000399]

Finer 2001

Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full‐term and nearly full‐term newborn infants (Cochrane Review). Cochrane Database of Systematic Reviews 2001, Issue 2. [DOI: 10.1002/14651858.CD000399.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barefield 1996

Methods

Single‐centre randomised study. Masking of allocation: yes. Masking of intervention: no. Completeness of follow‐up: yes. Masking of outcome measurement: no

Participants

17 near‐term infants ≥ 35 weeks with PaO2 < 100 mmHg on 100% oxygen on ventilator
Patients with congenital diaphragmatic hernia were excluded.

Interventions

iNO at 20 to 40 ppm increased to 80 if PaO2 stayed < 100 mmHg. Use of iNO allowed in case of failure of control treatment, if PaO2 was (1) < 80 mmHg (10.7 kPa) for longer than 1 hour, (2) < 40 mmHg (5.3 kPa) beyond 1 hour or (3) < 30 mmHg (4 kPa) beyond 30 minutes
High‐frequency ventilation not allowed during study

Outcomes

Primary outcome: 'treatment failure' or meeting ECMO criteria (defined as PaO2 < 80 mmHg for > 1 hour, < 40 mmHg after 1 hour or < 30 mmHg after 30 minutes)
Secondary outcomes: oxygenation index, PaO2, alveolar arterial oxygen gradient, after 30 and 60 minutes; death and ultimate use of high‐frequency ventilation or ECMO

Notes

Admission OI in control group averaged 26, in treatment group 38

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not described

Allocation concealment (selection bias)

Low risk

Sequentially numbered, opaque, sealed envelopes

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 registered or published protocol found

Funding Source(s)

Low risk

Charitable foundation (March of Dimes)

Christou 2000

Methods

Single‐centre randomised study. Masking of allocation: yes. Masking of intervention: no. Completeness of follow‐up: yes. Masking of outcome: no

Participants

42 near‐term infants ≥ 34 weeks with PaO2 < 100 mmHg on 100%oxygen on ventilator. 41 infants after exclusion of 1 case of congenital heart disease. Patients with diaphragmatic hernia were excluded. Some evidence showing increased pulmonary artery pressure on echocardiography required

Interventions

40 ppm iNO reduced to 20 ppm after 1 hour. Combined therapy with high‐frequency ventilation and iNO allowed

Outcomes

Death before discharge or requirement for ECMO. Secondary outcomes included changes in oxygenation and duration of ventilation and oxygen therapy.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Low risk

Adequate

Blinding (performance bias and detection bias)
All outcomes

High risk

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Other bias

High risk

Study terminated early after ad hoc committee reviewed the data

Funding Source(s)

Low risk

Supported by local and government agencies

Clark 2000

Methods

Multi‐centre randomised trial. Masking of allocation: yes. Masking of intervention: yes. Completeness of follow‐up: yes. Masking of outcome: yes

Participants

248 near‐term infants, ≥ 34 weeks, ≤ 4 days of age, with OI ≥ 25

Interventions

20 ppm iNO or nitrogen placebo. Inhaled NO gas weaned to 5 ppm after 24 hours for a maximum of 96 hours

Outcomes

Death before discharge, need for ECMO, chronic lung disease, neurological injury

Notes

No calculation of sample size for the trial is described.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Cards on which treatment assignments were written were randomly ordered (shuffled by hand 3 times) and placed in sequentially numbered opaque envelopes in blocks of 8.

Allocation concealment (selection bias)

Low risk

Adequate

Blinding (performance bias and detection bias)
All outcomes

Low risk

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Other bias

Unclear risk

Uncertain how sample size was determined

Funding Source(s)

High risk

Funded "in part" by INOtherapeutics; no other sources listed

Cornfield 1999

Methods

Three‐centre randomised trial. Masking of allocation: cannot tell. Masking of intervention: no. Completeness of follow‐up: yes. Masking of outcome: no

Participants

38 near‐term infants with OI ≥ 25, < 1 week old, with echocardiographically proven pulmonary hypertension

Interventions

Inhaled NO at 2 ppm or no therapy

Outcomes

Primary outcome: failure, defined as OI > 35 after 1 hour of treatment

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number table

Allocation concealment (selection bias)

Unclear risk

Unclear

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 registered or published protocol found

Other bias

Low risk

Funding Source(s)

Low risk

Local funds and charitable sources

Davidson 1997

Methods

Multi‐centre randomised trial, with nitrogen used as placebo gas

Participants

155 term infants with echocardiographic evidence of pulmonary hypertension. PaO2 between 40 and 100 mmHg in 100% oxygen. Randomised equally to each of the 4 groups
Excluded infants with congenital diaphragmatic hernia or other causes of pulmonary hypoplasia
Did not allow surfactant therapy or concurrent high‐frequency ventilation

Interventions

Inhaled nitric oxide at 5, 20 or 80 ppm or control, gas stopped upon 'failure', defined as PaO2 < 40 mmHg for longer than 30 minutes

Outcomes

Major sequelae index: composite index of death, ECMO, neurological sequelae or bronchopulmonary dysplasia
Oxygenation

Notes

Terminated early because of poor enrolment

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised by a "scratch‐off card"

Allocation concealment (selection bias)

Low risk

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo‐controlled masked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Other bias

Unclear risk

Terminated early for poor enrolment

Funding Source(s)

High risk

Industry funded (Ohmeda)

Day 1996

Methods

Single‐centre randomised parallel‐group study

Participants

22 term or premature infants with OI > 25 and < 40, plus right‐to‐left ductal shunting or estimated peak right ventricular pressure > 75% of systemic systolic pressure

Interventions

20 ppm iNO. High‐frequency jet ventilation allowed concurrently. Back‐up use of iNO allowed in case of failure of control treatment. Few details of other therapy given

Outcomes

Primary outcomes: oxygenation index, PaO2, echocardiographic Doppler changes

Notes

If the condition of infants in the controlled trial deteriorated to an OI > 40, iNO was given.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised by "blind draw"

Allocation concealment (selection bias)

Unclear risk

Not clearly described

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 registered or published protocol found

Other bias

Unclear risk

No sample size calculation presented

Funding Source(s)

Low risk

Local sources

Gonzalez 2010

Methods

Two‐centre randomised trial

Participants

56 infants > 34 weeks, < 48 hours old, with OI between 10 and 30

Interventions

Immediate iNO at 20 ppm, or no iNO unless OI increases to > 40

Outcomes

Primary outcome was the proportion with OI increasing to > 40. Secondary outcomes were death, days of ventilation and chronic lung disease.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Low risk

Opaque sealed sequential envelopes

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Funding Source(s)

Unclear risk

Local (university) sources and industry (AGA, SA)

INNOVO 2007

Methods

Multi‐centre parallel‐group randomised controlled trial

Participants

60 full‐term infants ≥ 34 weeks with severe hypoxic respiratory failure for whom attending physician was unsure whether iNO was indicated

Interventions

iNO at 20 ppm or no iNO

Outcomes

Survival without severe disability to 1 year of age

Notes

Sample size determined by limit to trial duration

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation by random number generator with minimisation

Allocation concealment (selection bias)

Low risk

Enrolled before allocation

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes reported

Selective reporting (reporting bias)

Low risk

Protocol registered (ISRCTN 17821339). Primary outcome variables consistent with publication

Funding Source(s)

Low risk

Government agency

Kinsella 1997

Methods

Randomised multi‐centre controlled parallel‐group trial of iNO compared with high‐frequency ventilation

Participants

205 near‐term infants, OI > 40. Stratified by disease process; infants with diaphragmatic hernia (n = 34) were included as a separate stratum

Interventions

iNO at 40 ppm was compared with high‐frequency ventilation with the SensorMedics oscillator. Initial randomisation was followed by back‐up treatment with alternate therapy in cases of failure. This was followed by further cross‐over to combination treatment with high‐frequency ventilation and iNO if alternate therapy failed.
iNO therapy was administered via a standard time‐cycled pressure‐limited ventilator. High‐frequency ventilation was aimed at a lung recruitment strategy. Surfactant treatment after enrolment was prohibited. iNO dose was increased to 40 ppm in case of failure to maintain PaO2 > 60 mmHg.

Outcomes

Sustained PaO2 ≥ 60 mmHg. Failure defined as PaO2 < 60 mmHg after 2 hours of therapy or lack of improvement in PaO2 before 2 hours. Some data on infants with diaphragmatic hernia were presented separately.

Notes

Complex study design; we abstracted only results from the initial randomisation. All infants who failed were exposed to iNO at some stage in the protocol. Study was stopped after interim analysis, suggesting no difference between initial treatment limbs.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Allocation concealment (selection bias)

Low risk

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 registered or published protocol found

Funding Source(s)

Low risk

Local and government sources

Konduri 2004

Methods

Multi‐centre randomised controlled trial

Participants

All 302 enrolled (3 excluded, as they turned out to have congential heart disease) infants were ≥ 34 weeks' gestation, with hypoxic respiratory failure and OI between 15 and 25, while receiving ≥ 80% oxygen, on 2 blood gases between 15 minutes and 12 hours apart

Interventions

iNO at 5 ppm; iNO could be increased to 20 ppm in the case of partial response; treated up to 14 days. Controls received nitrogen, or iNO if OI increased to > 25.

Outcomes

Primary outcome: occurrence or death or requirement for ECMO
Secondary hypotheses were that early iNO therapy would (1) reduce the probability of using standard iNO therapy; (2) decrease progression to severe respiratory failure, defined as OI > 40; and (3) would not increase neurodevelopmental impairment among surviving infants at 18 to 24 months of age.

Notes

Study terminated early because of slowing enrolment; 75% of anticipated sample enrolled; study terminated without knowledge of results at that point

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central computerised randomisation

Allocation concealment (selection bias)

Low risk

Randomised by telephone after enrolment

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked gas administration

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Low risk

Study registered in 2000 (after start of trial but before completion); NCT00005773. Primary and secondary outcomes match registration documents.

Other bias

Unclear risk

Early termination without examination of data

Funding Source(s)

Unclear risk

Government agency, partial industry support

Liu 2008

Methods

Single‐centre randomised trial

Participants

46 infants with meconium aspiration syndrome, over 36 weeks, > 2.5 kg, OI > 15

Interventions

iNO at 15 ppm or no additional gas

Outcomes

Primary outcome variable unclear; outcomes reported include changes in OI and in echocardiography, survival, certain medical complications and duration of assisted ventilation

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not clearly reported but may be acceptable; 'random number method'

Allocation concealment (selection bias)

Unclear risk

No relevant information

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes of all participants reported

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Funding Source(s)

Unclear risk

Uncertain

Mercier 1998

Methods

Randomised multi‐centre trial of iNO

Participants

204 infants; 107 near term, ≥ 33 weeks' gestation. OI 15 to 40, on 2 blood gases 1 hour apart. Congenital diaphragmatic hernia excluded, congenital heart disease excluded, < 7 days of age only

Interventions

iNO at 10 ppm for 2 hours, continued if response. Controls could be treated after 2 hours.

Outcomes

Primary outcome: change in OI at 2 hours after initiation of treatment. Secondary outcomes: death, brain injury, long‐term oxygen therapy, duration of hospitalisation

Notes

ECMO not available as back‐up therapy

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Allocation concealment (selection bias)

Low risk

Adequate

Blinding (performance bias and detection bias)
All outcomes

High risk

Unmasked study gas administration

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Other bias

Unclear risk

Terminated early for poor enrolment

Funding Source(s)

Unclear risk

Government agency and industry support

Ninos 1996

Methods

Randomised multi‐centre study, with oxygen used as placebo gas

Participants

235 near‐term infants, ≥ 34 weeks' gestation, OI > 25 on 2 blood gases, 15 minutes apart. Congenital diaphragmatic hernia excluded, congenital heart disease excluded, < 14 days of age only

Interventions

iNO at 20 ppm, trial at 80 ppm if no response to 20 ppm (in treatment group). Comparison with control. Both groups received 'maximal therapy' before study entry, including surfactant in the majority, high‐frequency ventilation at experienced centres, muscle relaxation and inotropes. Induction of alkalosis with target pH of 7.45‐7.60 was also used as a guideline. All of these treatment strategies were continued in controls. Investigators were not allowed to start high‐frequency ventilation or to administer surfactant after study entry.

Outcomes

Survival to 120 days or discharge home, without requiring ECMO. Secondary outcomes were oxygenation (OI and PaO2) after 30 minutes, length of hospital stay, days of assisted ventilation and incidence of air leak or bronchopulmonary dysplasia. Neurodevelopment at 18‐24 months

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Prepared by study centre

Allocation concealment (selection bias)

Low risk

Telephone randomisation system

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked gas administration

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Selective reporting (reporting bias)

Low risk

Study registered, NCT00005776, in 2000 (after completion). Outcomes in registration documents are reported in the main publication.

Funding Source(s)

Unclear risk

Started with government agency support, industry support after study commenced

Ninos 1997

Methods

Randomised multi‐centre trial of iNO in infants with diaphragmatic hernia, with oxygen used as placebo gas

Participants

53 near‐term infants with diaphragmatic hernia, ≥ 34 weeks' gestation, < 14 days of age

Interventions

iNO at 20 ppm, trial at 80 ppm if no response to 20 ppm (in treatment group). Comparison with control. Both groups received 'maximal therapy' before study entry, including surfactant in the majority, high‐frequency ventilation at experienced centres, muscle relaxation and inotropes. Induction of alkalosis with target pH of 7.45‐7.60 was also used as a guideline. All of these treatment strategies were continued in controls. Investigators were not allowed to start high‐frequency ventilation or to administer surfactant after study entry.

Outcomes

Survival to 120 days or discharge home, without requiring ECMO. Secondary outcomes were oxygenation (OI and PaO2) after 30 minutes, length of hospital stay, days of assisted ventilation and incidence of air leak or bronchopulmonary dysplasia. Neurodevelopment at 18‐24 months

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised blocked randomisation

Allocation concealment (selection bias)

Low risk

Telephone randomisation system

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked gas administration

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for

Selective reporting (reporting bias)

Unclear risk

Study registered, NCT00005776, in 2000 (after completion). Outcomes as registered are reported.

Funding Source(s)

Low risk

Planned and commenced with government agency support; industry support provided after study commenced

Roberts 1996

Methods

Multi‐centre randomised study, with nitrogen used for placebo gas

Participants

58 'full‐term infants' on FiO2 1.0 with PaO2 < 55 mmHg. All had echocardiographic signs of pulmonary hypertension.
Patients excluded if they had received high‐frequency ventilation
Patients with diaphragmatic hernia excluded, or other causes of pulmonary hypoplasia

Interventions

iNO at 80 ppm or control. Control patients received conventional ventilation. Surfactant was not allowed during the study.

Outcomes

Primary outcome was 'success', defined as improved OI to < 40, without a fall in PaO2 or hypotension.
Secondary outcomes were oxygenation, both OI and PaO2, after 30 minutes of therapy.

Notes

Study was terminated after an interim analysis showed an effect at P < 0.05. Original sample size was not described.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described in the publication

Allocation concealment (selection bias)

Low risk

Adequate

Blinding (performance bias and detection bias)
All outcomes

Low risk

Masked gas administration

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete outcome assessment

Selective reporting (reporting bias)

Unclear risk

No registered or published protocol found

Other bias

High risk

Early termination after examination of data

Funding Source(s)

Low risk

Government agency

Sadiq 1998

Methods

Multi‐centre randomised trial

Participants

87 infants > 2 kg birth weight, with A‐aDO2 500‐599 after surfactant on 2 gases 1 hour apart, on 100% oxygen with echocardiographic evidence of PPHN

Interventions

iNO at 10 ppm or control; iNO increased up to 80 ppm until no further increases in arterial PaO2 occurred

Outcomes

Primary outcome variable was progression to severe PPHN, defined as an A‐aDO2 persistently > 600. Secondary outcome variables included death, ECMO rate, length of hospitalisation, amount and duration of mechanical ventilation, number of days of oxygen use and need for supplemental oxygen at 28 days of life.

Notes

Study was terminated early after approval of iNO by the Federal Drug Administration, as this impaired recruitment.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Randomisation order was determined a priori, in blocks of 10, by coin toss with folded group assignment cards.

Allocation concealment (selection bias)

Low risk

Cards were placed in sequentially numbered opaque envelopes for each centre.

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 registered or published protocol found

Other bias

Unclear risk

Early termination, but not because of examination of data

Funding Source(s)

Unclear risk

Not described

Wessel 1996

Methods

Single‐centre randomised trial. Masking of allocation: not clear. Masking of intervention: no. Completeness of follow‐up: yes. Masking of outcome: no

Participants

49 near‐term infants ≥ 34 weeks, PaO2 < 100 mmHg on 100% oxygen; all had evidence of PPHN on echocardiography

Interventions

iNO at 80 ppm, reduced to 40 ppm after 1 hour. All received muscle relaxants and sedation and conventional ventilation.

Outcomes

Primary outcomes were oxygenation as well as death and need for ECMO.
Secondary outcomes were duration of mechanical ventilation, duration of hospitalisation and need for oxygen after hospital discharge.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Unclear

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 registered or published protocol found

Funding Source(s)

Low risk

Supported by local and charitable sources

A‐aDO2: alveolar‐arterial oxygen difference.
ECMO: extracorporeal membrane oxygenation.
FiO2: fraction of inspired oxygen.
iNO: inhaled nitric oxide.
NO: nitric oxide.
OI: oxygenation index.
PaO2: partial pressure of arterial oxygen.
PPHN: persistent pulmonary hypertension of the newborn

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Hoffman 1997

Non‐randomised retrospective study; infants were treated or were not treated according to availability of inhaled nitric oxide. The time period over which infants were studied was different between control and inhaled nitric oxide groups.

Pinheiro 1998

Randomised comparison of inhaled nitric oxide with intravenous nitroprusside. Study was stopped after enrolment of 25 participants owing to decreasing enrolment. Inhaled nitric oxide produced much greater improvements in oxygenation than were produced by nitroprusside.

Data and analyses

Open in table viewer
Comparison 1. Inhaled NO versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death or use of ECMO Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 Inhaled NO versus control, Outcome 1 Death or use of ECMO.

Comparison 1 Inhaled NO versus control, Outcome 1 Death or use of ECMO.

1.1 Death or use of ECMO; studies that did not allow back‐up use of iNO in controls

8

859

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.57, 0.77]

1.2 Death or use of ECMO; studies that allowed back‐up use of iNO in controls

1

107

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.34, 4.16]

1.3 Death or use of ECMO; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.95, 1.26]

2 Death before hospital discharge Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Inhaled NO versus control, Outcome 2 Death before hospital discharge.

Comparison 1 Inhaled NO versus control, Outcome 2 Death before hospital discharge.

2.1 Death; studies that did not allow back‐up use of iNO in controls

8

860

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.60, 1.31]

2.2 Death; studies that allowed back‐up use of iNO in controls

1

107

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.34, 4.16]

2.3 Death; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.74, 1.96]

3 Use of ECMO before hospital discharge Show forest plot

8

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 Inhaled NO versus control, Outcome 3 Use of ECMO before hospital discharge.

Comparison 1 Inhaled NO versus control, Outcome 3 Use of ECMO before hospital discharge.

3.1 Use of ECMO before hospital discharge; studies that did not allow back‐up use of iNO in controls

7

815

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.50, 0.71]

3.2 Use of ECMO before hospital discharge; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [1.00, 1.62]

4 Failure to improve oxygenation (PaO2) Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.4

Comparison 1 Inhaled NO versus control, Outcome 4 Failure to improve oxygenation (PaO2).

Comparison 1 Inhaled NO versus control, Outcome 4 Failure to improve oxygenation (PaO2).

4.1 Failure to improve PaO2; studies that did not allow back‐up use of iNO in controls

2

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Failure to improve PaO2; infants with diaphragmatic hernia

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Oxygenation index 30 to 60 minutes after treatment Show forest plot

6

753

Mean Difference (IV, Fixed, 95% CI)

‐8.59 [‐11.53, ‐5.65]

Analysis 1.5

Comparison 1 Inhaled NO versus control, Outcome 5 Oxygenation index 30 to 60 minutes after treatment.

Comparison 1 Inhaled NO versus control, Outcome 5 Oxygenation index 30 to 60 minutes after treatment.

5.1 OI 30 to 60 minutes after treatment; studies that did not allow back‐up use of iNO in controls

5

709

Mean Difference (IV, Fixed, 95% CI)

‐8.45 [‐11.42, ‐5.48]

5.2 OI 30 to 60 minutes after treatment; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

‐16.1 [‐38.04, 5.84]

6 PaO2 30 to 60 minutes after treatment Show forest plot

5

707

Mean Difference (IV, Fixed, 95% CI)

32.62 [23.56, 41.67]

Analysis 1.6

Comparison 1 Inhaled NO versus control, Outcome 6 PaO2 30 to 60 minutes after treatment.

Comparison 1 Inhaled NO versus control, Outcome 6 PaO2 30 to 60 minutes after treatment.

6.1 PaO2 after 30 to 60 minutes; studies that did not allow back‐up use of iNO in controls

4

663

Mean Difference (IV, Fixed, 95% CI)

43.91 [32.30, 55.51]

6.2 PaO2 after 30 to 60 minutes; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

15.10 [0.64, 29.56]

7 Change in oxygenation index after treatment Show forest plot

2

277

Mean Difference (IV, Fixed, 95% CI)

‐13.61 [‐18.53, ‐8.70]

Analysis 1.7

Comparison 1 Inhaled NO versus control, Outcome 7 Change in oxygenation index after treatment.

Comparison 1 Inhaled NO versus control, Outcome 7 Change in oxygenation index after treatment.

7.1 Change in OI; studies that did not allow back‐up use of iNO in controls

1

233

Mean Difference (IV, Fixed, 95% CI)

‐15.1 [‐20.52, ‐9.68]

7.2 Change in OI; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

‐6.7 [‐18.39, 4.99]

8 Change in PaO2 after treatment Show forest plot

2

277

Mean Difference (IV, Fixed, 95% CI)

15.27 [7.18, 23.36]

Analysis 1.8

Comparison 1 Inhaled NO versus control, Outcome 8 Change in PaO2 after treatment.

Comparison 1 Inhaled NO versus control, Outcome 8 Change in PaO2 after treatment.

8.1 Change in PaO2; studies that did not allow back‐up use of iNO in controls

1

233

Mean Difference (IV, Fixed, 95% CI)

50.4 [32.14, 68.66]

8.2 Change in PaO2; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

6.70 [‐2.32, 15.72]

9 Neurodevelopmental disability at 18 to 24 months among survivors Show forest plot

2

301

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.66, 1.44]

Analysis 1.9

Comparison 1 Inhaled NO versus control, Outcome 9 Neurodevelopmental disability at 18 to 24 months among survivors.

Comparison 1 Inhaled NO versus control, Outcome 9 Neurodevelopmental disability at 18 to 24 months among survivors.

10 Hearing impairment in at least 1 ear among survivors Show forest plot

2

178

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.72, 1.68]

Analysis 1.10

Comparison 1 Inhaled NO versus control, Outcome 10 Hearing impairment in at least 1 ear among survivors.

Comparison 1 Inhaled NO versus control, Outcome 10 Hearing impairment in at least 1 ear among survivors.

10.1 Hearing impairment among survivors; studies that did not allow back‐up use of iNO in controls

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.71, 1.84]

10.2 Hearing impairment among survivors; infants with diaphragmatic hernia

1

21

Risk Ratio (M‐H, Fixed, 95% CI)

0.93 [0.39, 2.19]

11 Cerebral palsy among survivors Show forest plot

3

321

Risk Ratio (M‐H, Fixed, 95% CI)

1.23 [0.62, 2.45]

Analysis 1.11

Comparison 1 Inhaled NO versus control, Outcome 11 Cerebral palsy among survivors.

Comparison 1 Inhaled NO versus control, Outcome 11 Cerebral palsy among survivors.

11.1 Cerebral palsy among survivors; studies that did not allow back‐up use of iNO in controls

2

299

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.49, 2.14]

11.2 Cerebral palsy among survivors; infants with diaphragmatic hernia

1

22

Risk Ratio (M‐H, Fixed, 95% CI)

8.33 [0.45, 154.78]

12 BSID MDI > 2 SD below the mean Show forest plot

2

283

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.38, 1.12]

Analysis 1.12

Comparison 1 Inhaled NO versus control, Outcome 12 BSID MDI > 2 SD below the mean.

Comparison 1 Inhaled NO versus control, Outcome 12 BSID MDI > 2 SD below the mean.

13 BSID PDI > 2 SD below the mean Show forest plot

2

283

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.25, 0.94]

Analysis 1.13

Comparison 1 Inhaled NO versus control, Outcome 13 BSID PDI > 2 SD below the mean.

Comparison 1 Inhaled NO versus control, Outcome 13 BSID PDI > 2 SD below the mean.

Open in table viewer
Comparison 2. Inhaled NO at moderate compared with severe criteria for illness severity

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death or use of ECMO Show forest plot

5

495

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.62, 1.27]

Analysis 2.1

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 1 Death or use of ECMO.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 1 Death or use of ECMO.

2 Death before hospital discharge Show forest plot

5

495

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.38, 1.26]

Analysis 2.2

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 2 Death before hospital discharge.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 2 Death before hospital discharge.

3 Use of ECMO before hospital discharge Show forest plot

4

439

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.66, 1.54]

Analysis 2.3

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 3 Use of ECMO before hospital discharge.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 3 Use of ECMO before hospital discharge.

4 Progression to severe disease criteria Show forest plot

6

512

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.55, 0.79]

Analysis 2.4

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 4 Progression to severe disease criteria.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 4 Progression to severe disease criteria.

5 Chronic lung disease Show forest plot

3

437

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.54, 1.53]

Analysis 2.5

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 5 Chronic lung disease.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 5 Chronic lung disease.

6 Neurodevelopmental disability at 18 to 24 months among survivors Show forest plot

1

234

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.74, 1.74]

Analysis 2.6

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 6 Neurodevelopmental disability at 18 to 24 months among survivors.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 6 Neurodevelopmental disability at 18 to 24 months among survivors.

7 Hearing impairment among survivors Show forest plot

1

234

Risk Ratio (M‐H, Fixed, 95% CI)

0.31 [0.03, 2.95]

Analysis 2.7

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 7 Hearing impairment among survivors.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 7 Hearing impairment among survivors.

8 Cerebral palsy among survivors Show forest plot

1

234

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.53, 3.39]

Analysis 2.8

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 8 Cerebral palsy among survivors.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 8 Cerebral palsy among survivors.

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

Study flow diagram: review update.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

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

Comparison 1 Inhaled NO versus control, Outcome 1 Death or use of ECMO.
Figuras y tablas -
Analysis 1.1

Comparison 1 Inhaled NO versus control, Outcome 1 Death or use of ECMO.

Comparison 1 Inhaled NO versus control, Outcome 2 Death before hospital discharge.
Figuras y tablas -
Analysis 1.2

Comparison 1 Inhaled NO versus control, Outcome 2 Death before hospital discharge.

Comparison 1 Inhaled NO versus control, Outcome 3 Use of ECMO before hospital discharge.
Figuras y tablas -
Analysis 1.3

Comparison 1 Inhaled NO versus control, Outcome 3 Use of ECMO before hospital discharge.

Comparison 1 Inhaled NO versus control, Outcome 4 Failure to improve oxygenation (PaO2).
Figuras y tablas -
Analysis 1.4

Comparison 1 Inhaled NO versus control, Outcome 4 Failure to improve oxygenation (PaO2).

Comparison 1 Inhaled NO versus control, Outcome 5 Oxygenation index 30 to 60 minutes after treatment.
Figuras y tablas -
Analysis 1.5

Comparison 1 Inhaled NO versus control, Outcome 5 Oxygenation index 30 to 60 minutes after treatment.

Comparison 1 Inhaled NO versus control, Outcome 6 PaO2 30 to 60 minutes after treatment.
Figuras y tablas -
Analysis 1.6

Comparison 1 Inhaled NO versus control, Outcome 6 PaO2 30 to 60 minutes after treatment.

Comparison 1 Inhaled NO versus control, Outcome 7 Change in oxygenation index after treatment.
Figuras y tablas -
Analysis 1.7

Comparison 1 Inhaled NO versus control, Outcome 7 Change in oxygenation index after treatment.

Comparison 1 Inhaled NO versus control, Outcome 8 Change in PaO2 after treatment.
Figuras y tablas -
Analysis 1.8

Comparison 1 Inhaled NO versus control, Outcome 8 Change in PaO2 after treatment.

Comparison 1 Inhaled NO versus control, Outcome 9 Neurodevelopmental disability at 18 to 24 months among survivors.
Figuras y tablas -
Analysis 1.9

Comparison 1 Inhaled NO versus control, Outcome 9 Neurodevelopmental disability at 18 to 24 months among survivors.

Comparison 1 Inhaled NO versus control, Outcome 10 Hearing impairment in at least 1 ear among survivors.
Figuras y tablas -
Analysis 1.10

Comparison 1 Inhaled NO versus control, Outcome 10 Hearing impairment in at least 1 ear among survivors.

Comparison 1 Inhaled NO versus control, Outcome 11 Cerebral palsy among survivors.
Figuras y tablas -
Analysis 1.11

Comparison 1 Inhaled NO versus control, Outcome 11 Cerebral palsy among survivors.

Comparison 1 Inhaled NO versus control, Outcome 12 BSID MDI > 2 SD below the mean.
Figuras y tablas -
Analysis 1.12

Comparison 1 Inhaled NO versus control, Outcome 12 BSID MDI > 2 SD below the mean.

Comparison 1 Inhaled NO versus control, Outcome 13 BSID PDI > 2 SD below the mean.
Figuras y tablas -
Analysis 1.13

Comparison 1 Inhaled NO versus control, Outcome 13 BSID PDI > 2 SD below the mean.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 1 Death or use of ECMO.
Figuras y tablas -
Analysis 2.1

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 1 Death or use of ECMO.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 2 Death before hospital discharge.
Figuras y tablas -
Analysis 2.2

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 2 Death before hospital discharge.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 3 Use of ECMO before hospital discharge.
Figuras y tablas -
Analysis 2.3

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 3 Use of ECMO before hospital discharge.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 4 Progression to severe disease criteria.
Figuras y tablas -
Analysis 2.4

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 4 Progression to severe disease criteria.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 5 Chronic lung disease.
Figuras y tablas -
Analysis 2.5

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 5 Chronic lung disease.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 6 Neurodevelopmental disability at 18 to 24 months among survivors.
Figuras y tablas -
Analysis 2.6

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 6 Neurodevelopmental disability at 18 to 24 months among survivors.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 7 Hearing impairment among survivors.
Figuras y tablas -
Analysis 2.7

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 7 Hearing impairment among survivors.

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 8 Cerebral palsy among survivors.
Figuras y tablas -
Analysis 2.8

Comparison 2 Inhaled NO at moderate compared with severe criteria for illness severity, Outcome 8 Cerebral palsy among survivors.

Summary of findings for the main comparison. Inhaled NO compared with control for respiratory failure in infants born at or near term

Inhaled NO compared with control for respiratory failure in infants born at or near term

Patient or population: respiratory failure in infants born at or near term
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 control

Risk with inhaled NO

Death or use of ECMO; studies that did not allow back‐up use of iNO in controls

Study population

RR 0.66
(0.57 to 0.77)

859
(8 RCTs)

⊕⊕⊕⊕
High

540 per 1000

356 per 1000
(308 to 416)

Death or use of ECMO; infants with diaphragmatic hernia

Study population

RR 1.09
(0.95 to 1.26)

84
(2 RCTs)

⊕⊕⊕⊝
Moderatea

870 per 1000

948 per 1000
(826 to 1000)

Death before hospital discharge; studies that did not allow back‐up use of iNO in controls

Study population

RR 0.89
(0.60 to 1.31)

860
(8 RCTs)

⊕⊕⊕⊕
High

120 per 1000

106 per 1000
(72 to 157)

Death before hospital discharge; infants with diaphragmatic hernia

Study population

RR 1.20
(0.74 to 1.96)

84
(2 RCTs)

⊕⊕⊕⊝
Moderatea

391 per 1000

470 per 1000
(290 to 767)

Use of ECMO before hospital discharge; studies that did not allow back‐up use of iNO in controls

Study population

RR 0.60
(0.50 to 0.71)

815
(7 RCTs)

⊕⊕⊕⊕
High

514 per 1000

308 per 1000
(257 to 365)

Use of ECMO before hospital discharge; infants with diaphragmatic hernia

Study population

RR 1.27
(1.00 to 1.62)

84
(2 RCTs)

⊕⊕⊕⊝
Moderatea,b

674 per 1000

856 per 1000
(674 to 1000)

Neurodevelopmental disability at 18 to 24 months among survivors

Study population

RR 0.97
(0.66 to 1.44)

301
(2 RCTs)

⊕⊕⊝⊝
Lowa,b

265 per 1000

257 per 1000
(175 to 382)

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

aSmall numbers of participants studied.

bSubgroup of participants from only 2 trials evaluated.

Figuras y tablas -
Summary of findings for the main comparison. Inhaled NO compared with control for respiratory failure in infants born at or near term
Summary of findings 2. Inhaled NO at moderate compared with severe criteria for illness severity in respiratory failure among infants born at or near term

Inhaled NO at moderate compared with severe criteria for illness severity in respiratory failure among infants born at or near term

Patient or population: infants born at or near term in respiratory failure
Setting: neonatal intensive care units
Intervention: inhaled NO at moderate criteria for illness severity (earlier iNO)
Comparison: inhaled NO at severe criteria for illness severity (later iNO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with inhaled NO at severe criteria for illness severity

Risk with Inhaled NO at moderate criteria for illness severity

Death or requirement for ECMO

Study population

RR 0.88
(0.62 to 1.27)

495
(5 RCTs)

⊕⊕⊝⊝
Lowa,b

192 per 1000

169 per 1000
(119 to 244)

Death before hospital discharge

Study population

RR 0.69
(0.38 to 1.26)

495
(5 RCTs)

⊕⊕⊕⊝
Moderateb

100 per 1000

69 per 1000
(38 to 126)

Use of ECMO before hospital discharge

Study population

RR 1.01
(0.66 to 1.54)

439
(4 RCTs)

⊕⊕⊕⊝
Moderateb

144 per 1000

146 per 1000
(95 to 222)

Progression to severe criteria

Study population

RR 0.66
(0.55 to 0.79)

512
(6 RCTs)

⊕⊕⊕⊝
Moderateb

595 per 1000

392 per 1000
(327 to 470)

Neurodevelopmental disability at 18 to 24 months among survivors

Study population

RR 1.13
(0.74 to 1.74)

234
(1 RCT)

⊕⊕⊕⊝
Moderateb

248 per 1000

280 per 1000
(183 to 431)

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

bVery wide confidence intervals.

Figuras y tablas -
Summary of findings 2. Inhaled NO at moderate compared with severe criteria for illness severity in respiratory failure among infants born at or near term
Table 1. Additional important outcomes

Study

Ventilator days

Oxygen days

Hospitalisation days

Gonzalez

Early iNO

Median 6, range 3‐28

Median 11.5, range 5‐90

Late iNO

Median 8, range 4‐37

Median 18, range 6‐142

Konduri

Early iNO

Median 8, IQR 6‐12

Median 13, IQR 9‐19

Median 17, IQR 12‐22

Late iNO

Median 8, IQR 6‐12

Median 13, IQR 9‐19

Median 18, IQR 12‐30

Sadiq

Early iNO

Mean 8,7, SD 4

Mean 14, SD 8

Mean 21, SD 14

Late iNO

Mean 10, SD 6

Mean 18, SD 17

Mean 21, SD 11

IQR: interquartile range; SD: standard deviation.

Figuras y tablas -
Table 1. Additional important outcomes
Comparison 1. Inhaled NO versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death or use of ECMO Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Death or use of ECMO; studies that did not allow back‐up use of iNO in controls

8

859

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.57, 0.77]

1.2 Death or use of ECMO; studies that allowed back‐up use of iNO in controls

1

107

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.34, 4.16]

1.3 Death or use of ECMO; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.95, 1.26]

2 Death before hospital discharge Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Death; studies that did not allow back‐up use of iNO in controls

8

860

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.60, 1.31]

2.2 Death; studies that allowed back‐up use of iNO in controls

1

107

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.34, 4.16]

2.3 Death; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.74, 1.96]

3 Use of ECMO before hospital discharge Show forest plot

8

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Use of ECMO before hospital discharge; studies that did not allow back‐up use of iNO in controls

7

815

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.50, 0.71]

3.2 Use of ECMO before hospital discharge; infants with diaphragmatic hernia

2

84

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [1.00, 1.62]

4 Failure to improve oxygenation (PaO2) Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Failure to improve PaO2; studies that did not allow back‐up use of iNO in controls

2

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Failure to improve PaO2; infants with diaphragmatic hernia

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Oxygenation index 30 to 60 minutes after treatment Show forest plot

6

753

Mean Difference (IV, Fixed, 95% CI)

‐8.59 [‐11.53, ‐5.65]

5.1 OI 30 to 60 minutes after treatment; studies that did not allow back‐up use of iNO in controls

5

709

Mean Difference (IV, Fixed, 95% CI)

‐8.45 [‐11.42, ‐5.48]

5.2 OI 30 to 60 minutes after treatment; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

‐16.1 [‐38.04, 5.84]

6 PaO2 30 to 60 minutes after treatment Show forest plot

5

707

Mean Difference (IV, Fixed, 95% CI)

32.62 [23.56, 41.67]

6.1 PaO2 after 30 to 60 minutes; studies that did not allow back‐up use of iNO in controls

4

663

Mean Difference (IV, Fixed, 95% CI)

43.91 [32.30, 55.51]

6.2 PaO2 after 30 to 60 minutes; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

15.10 [0.64, 29.56]

7 Change in oxygenation index after treatment Show forest plot

2

277

Mean Difference (IV, Fixed, 95% CI)

‐13.61 [‐18.53, ‐8.70]

7.1 Change in OI; studies that did not allow back‐up use of iNO in controls

1

233

Mean Difference (IV, Fixed, 95% CI)

‐15.1 [‐20.52, ‐9.68]

7.2 Change in OI; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

‐6.7 [‐18.39, 4.99]

8 Change in PaO2 after treatment Show forest plot

2

277

Mean Difference (IV, Fixed, 95% CI)

15.27 [7.18, 23.36]

8.1 Change in PaO2; studies that did not allow back‐up use of iNO in controls

1

233

Mean Difference (IV, Fixed, 95% CI)

50.4 [32.14, 68.66]

8.2 Change in PaO2; infants with diaphragmatic hernia

1

44

Mean Difference (IV, Fixed, 95% CI)

6.70 [‐2.32, 15.72]

9 Neurodevelopmental disability at 18 to 24 months among survivors Show forest plot

2

301

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.66, 1.44]

10 Hearing impairment in at least 1 ear among survivors Show forest plot

2

178

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.72, 1.68]

10.1 Hearing impairment among survivors; studies that did not allow back‐up use of iNO in controls

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.71, 1.84]

10.2 Hearing impairment among survivors; infants with diaphragmatic hernia

1

21

Risk Ratio (M‐H, Fixed, 95% CI)

0.93 [0.39, 2.19]

11 Cerebral palsy among survivors Show forest plot

3

321

Risk Ratio (M‐H, Fixed, 95% CI)

1.23 [0.62, 2.45]

11.1 Cerebral palsy among survivors; studies that did not allow back‐up use of iNO in controls

2

299

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.49, 2.14]

11.2 Cerebral palsy among survivors; infants with diaphragmatic hernia

1

22

Risk Ratio (M‐H, Fixed, 95% CI)

8.33 [0.45, 154.78]

12 BSID MDI > 2 SD below the mean Show forest plot

2

283

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.38, 1.12]

13 BSID PDI > 2 SD below the mean Show forest plot

2

283

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.25, 0.94]

Figuras y tablas -
Comparison 1. Inhaled NO versus control
Comparison 2. Inhaled NO at moderate compared with severe criteria for illness severity

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death or use of ECMO Show forest plot

5

495

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.62, 1.27]

2 Death before hospital discharge Show forest plot

5

495

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.38, 1.26]

3 Use of ECMO before hospital discharge Show forest plot

4

439

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.66, 1.54]

4 Progression to severe disease criteria Show forest plot

6

512

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.55, 0.79]

5 Chronic lung disease Show forest plot

3

437

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.54, 1.53]

6 Neurodevelopmental disability at 18 to 24 months among survivors Show forest plot

1

234

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.74, 1.74]

7 Hearing impairment among survivors Show forest plot

1

234

Risk Ratio (M‐H, Fixed, 95% CI)

0.31 [0.03, 2.95]

8 Cerebral palsy among survivors Show forest plot

1

234

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.53, 3.39]

Figuras y tablas -
Comparison 2. Inhaled NO at moderate compared with severe criteria for illness severity