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Cochrane Database of Systematic Reviews

Inhaled nitric oxide for respiratory failure in preterm infants

Information

DOI:
https://doi.org/10.1002/14651858.CD000509.pub5Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 03 January 2017see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Neonatal Group

Copyright:
  1. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Keith J Barrington

    Correspondence to: Department of Pediatrics, CHU Ste‐Justine, Montreal, Canada

    [email protected]

  • Neil Finer

    Department of Pediatrics, University of California San Diego, San Diego, USA

  • Thomas Pennaforte

    Université de Montréal, Montreal, Canada

Contributions of authors

KJB and NF were involved in development and writing of the review protocol, the literature search and appraisal, data extraction and completion of the final review. TP assisted in revision of the article, analysis of publications and completion of the latest update.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201600005C

Declarations of interest

Dr Barrington was Chair of the Canadian Medical Advisory Committee for iNO therapeutics for one meeting in 2004.
Dr Barrington and Dr Finer were participants in a research project funded by Ikaria, an individual patient data meta‐analysis of iNO in the preterm, from which neither received any income.

Dr Barrington received an honorarium for speaking at a symposium funded by Mallinckrodt on the topic of probiotics.

Acknowledgements

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Version history

Published

Title

Stage

Authors

Version

2017 Jan 03

Inhaled nitric oxide for respiratory failure in preterm infants

Review

Keith J Barrington, Neil Finer, Thomas Pennaforte

https://doi.org/10.1002/14651858.CD000509.pub5

2010 Dec 08

Inhaled nitric oxide for respiratory failure in preterm infants

Review

Keith J Barrington, Neil Finer

https://doi.org/10.1002/14651858.CD000509.pub4

2007 Jul 18

Inhaled nitric oxide for respiratory failure in preterm infants

Review

Keith J Barrington, Neil Finer

https://doi.org/10.1002/14651858.CD000509.pub3

2006 Jan 25

Inhaled nitric oxide for respiratory failure in preterm infants

Review

Keith J Barrington, N N Finer

https://doi.org/10.1002/14651858.CD000509.pub2

2001 Oct 23

Inhaled nitric oxide for respiratory failure in preterm infants

Review

Keith J Barrington, Neil N Finer

https://doi.org/10.1002/14651858.CD000509

Differences between protocol and review

The initial protocol did not foresee dividing included trials into three groups according to indications for enrolment. We added methods, the plan for Summary of findings tables and GRADE recommendations, which were not included in the original protocol.

We added the following outcomes post hoc (as reported in trials but not prespecified): oxygenation within two hours of therapy, pulmonary artery pressure, duration of assisted ventilation.

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Study flow diagram: review update.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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).
Figures and Tables -
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).
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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).
Figures and Tables -
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.
Figures and Tables -
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.

Figures and Tables -
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]

Figures and Tables -
Comparison 1. Inhaled NO compared with control