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نقش نیتریک اکسید در درمان نارسایی تنفسی در نوزادان متولد شده در دوران ترم یا نزدیک ترم

Appendices

Appendix 1. Search strategy 2016

(Nitric OR Nitrix Oxide) with database specific terms:

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)

Clinicaltrials.gov: (infant)

Controlled‐trials.com: (infant)

WHO Trials database: (infant OR neonate)

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