Sildenafil for pulmonary hypertension in neonates

Lauren E Kelly; Arne Ohlsson<sup>a</sup>; Prakeshkumar S Shah

doi:10.1002/14651858.CD005494.pub4

Cochrane Database of Systematic Reviews

Sildenafil para la hipertensión pulmonar en recién nacidos

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DOI:

https://doi.org/10.1002/14651858.CD005494.pub4 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

04 agosto 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Neonatología

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Lauren E Kelly

Department of Paediatrics, University of Toronto Mount Sinai Hospital, Toronto, Canada
Arne Ohlsson^a

Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

Deceased
Prakeshkumar S Shah

Correspondencia a: Department of Paediatrics and Institute of Health Policy, Management and Evaluation, University of Toronto Mount Sinai Hospital, Toronto, Canada

[email protected]

Contributions of authors

LE Kelly reviewed the literature to identify trials, collected and entered data into RevMan, updated the review text, and revised the final version of this revision. A Ohlsson reviewed and edited the protocol, checked the search strategy and data entry, verified the data entered, and revised the final version of all versions of this review. PS Shah developed and edited the protocol, identified trials, wrote and edited the review, verified data entered into RevMan, and revised the final version of all versions of this review.

Sources of support

Internal sources

Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada.

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

The review authors have no conflicts of interest to declare.

Acknowledgements

We would like to sincerely thank Drs. Augusta Sola, Jayendra Gohil, and Husam Salama for providing data on their studies. We would like to acknowledge the help of Dr. Cecilia Herbozo for translation of the Herrera 2006 study from Spanish. We acknowledge the valuable contributions made by Jennifer Spano and Collen Ovelman from the CNRG, who performed the literature searches.

Version history

Published

Title

Stage

Authors

Version

2017 Aug 04

Sildenafil for pulmonary hypertension in neonates

Review

Lauren E Kelly, Arne Ohlsson, Prakeshkumar S Shah

https://doi.org/10.1002/14651858.CD005494.pub4

2011 Aug 10

Sildenafil for pulmonary hypertension in neonates

Review

Prakeshkumar S Shah, Arne Ohlsson

https://doi.org/10.1002/14651858.CD005494.pub3

2007 Jul 18

Sildenafil for pulmonary hypertension in neonates

Review

Prakeshkumar S Shah, Arne Ohlsson

https://doi.org/10.1002/14651858.CD005494.pub2

2005 Oct 19

Sildenafil for pulmonary hypertension in neonates

Protocol

Prakeshkumar S Shah, Arne Ohlsson

https://doi.org/10.1002/14651858.CD005494

Differences between protocol and review

An additional author (LEK) was added to this review team. We added to this update a post hoc comparison of sildenafil versus placebo as adjuvant therapy to inhaled nitric oxide.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans; Infant, Newborn;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram: review update.

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Figure 2

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

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Figure 3

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

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Analysis 1.1

Comparison 1 Sildenafil versus placebo, Outcome 1 Pulmonary arterial pressure.

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Comparison 1 Sildenafil versus placebo, Outcome 2 PaO2 in mmHg (absolute values).

Analysis 1.2

Comparison 1 Sildenafil versus placebo, Outcome 2 PaO₂ in mmHg (absolute values).

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Analysis 1.3

Comparison 1 Sildenafil versus placebo, Outcome 3 Mean arterial blood pressure in mmHg.

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Analysis 1.4

Comparison 1 Sildenafil versus placebo, Outcome 4 All‐cause mortality.

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Analysis 1.5

Comparison 1 Sildenafil versus placebo, Outcome 5 Oxygenation index (absolute values).

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Analysis 1.6

Comparison 1 Sildenafil versus placebo, Outcome 6 Change in oxygenation index.

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Comparison 1 Sildenafil versus placebo, Outcome 7 A‐a DO2 difference.

Analysis 1.7

Comparison 1 Sildenafil versus placebo, Outcome 7 A‐a DO₂ difference.

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Analysis 1.8

Comparison 1 Sildenafil versus placebo, Outcome 8 Mean airway pressure.

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Analysis 2.1

Comparison 2 Sildenafil versus active control, Outcome 1 All‐cause mortality.

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Analysis 2.2

Comparison 2 Sildenafil versus active control, Outcome 2 Time to adequate response (days).

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Analysis 2.3

Comparison 2 Sildenafil versus active control, Outcome 3 Duration of ventilation (days).

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Analysis 2.4

Comparison 2 Sildenafil versus active control, Outcome 4 Inotropic agent.

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Analysis 3.1

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 1 All‐cause mortality.

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Analysis 3.2

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 2 Length of stay in hospital (days).

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Analysis 3.3

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 3 Inotropic agent.

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Analysis 3.4

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 4 Duration of ventilation (days).

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Analysis 3.5

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 5 Retinopathy of prematurity.

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Summary of findings for the main comparison. Sildenafil compared with placebo for pulmonary hypertension in neonates

Sildenafil compared with placebo for pulmonary hypertension in neonates
Patient or population: pulmonary hypertension in neonates Setting: neonatal intensive care unit Intervention: sildenafil Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with sildenafil
PaO₂ in mmHg (absolute values) After 24‐25 hours	Mean PaO₂ in mmHg (absolute values) After 24 to 25 hours = 0	MD 15.31 higher (6.49 higher to 24.13 higher)	‐	57 (2 RCTs)	⊕⊕⊝⊝ LOW^a,b	Evidence was downgraded due to unreported methodological features and imprecision (small sample size)
Change in oxygenation index After 24 hours of treatment	Mean change in oxygenation index After 24 hours = 0	MD 38.79 lower (56.97 lower to 20.61 lower)	‐	12 (1 RCT)	⊕⊕⊝⊝ LOW^a,b	Evidence was downgraded due to unreported methodological features and imprecision (small sample size)
All‐cause mortality	Study population		RR 0.20 (0.07 to 0.56)	77 (3 RCTs)	⊕⊕⊝⊝ LOW^a,b	Evidence was downgraded due to unreported methodological features and imprecision (small sample size)
	432 per 1000	77 per 1000 (22 to 238)
*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; MD: mean difference; 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 the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the 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
^aImprecise due to small sample size ^bRisk of bias due to unclear randomisation allocation and lack of clinical trial registration

Summary of findings for the main comparison. Sildenafil compared with placebo for pulmonary hypertension in neonates

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Summary of findings 2. Sildenafil compared with active control for pulmonary hypertension in neonates

Sildenafil compared with active control for pulmonary hypertension in neonates
Patient or population: pulmonary hypertension in neonates Setting: neonatal intensive care unit Intervention: sildenafil Comparison: magnesium sulphate
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with magnesium sulphate	Risk with sildenafil
All‐cause mortality	Study population		RR 0.55 (0.05 to 5.75)	65 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b	Evidence was downgraded due to very serious imprecision, as results from this single study have not been replicated and risk of bias is evident in study design (missing data)
	59 per 1000	32 per 1000 (3 to 338)
*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; MD: mean difference; 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 the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the 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
^aImprecise due to small sample size; only one included study ^bRisk of bias due to missing data (not analysed as intent to treat)

Summary of findings 2. Sildenafil compared with active control for pulmonary hypertension in neonates

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Summary of findings 3. Sildenafil plus iNO compared with placebo plus iNO for pulmonary hypertension in neonates

Sildenafil plus iNO compared with placebo plus iNO for pulmonary hypertension in neonates
Patient or population: pulmonary hypertension in neonates Setting: neonatal intensive care unit Intervention: sildenafil plus iNO Comparison: placebo plus iNO
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo plus iNO	Risk with sildenafil plus iNO
All‐cause mortality	Study population		RR 1.27 (0.26 to 6.28)	24 (1 RCT)	⊕⊕⊝⊝ LOW^a	Evidence was downgraded due to imprecision .
	182 per 1000	231 per 1000 (38 to 690)
Length of stay in hospital (days)	Mean length of stay in hospital was 17.81 days.	MD 5.39 higher (5.31 lower to 16.09 higher)	‐	24 (1 RCT)	⊕⊕⊝⊝ LOW^a	Evidence was downgraded due to imprecision .
*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; MD: mean difference; 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 the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the 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
^aImprecise due to very small sample size; only one included study

Summary of findings 3. Sildenafil plus iNO compared with placebo plus iNO for pulmonary hypertension in neonates

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Comparison 1. Sildenafil versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pulmonary arterial pressure Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Baseline	1	40	Mean Difference (IV, Fixed, 95% CI)	1.10 [‐7.68, 9.88]
2 PaO₂ in mmHg (absolute values) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 At baseline	2	64	Mean Difference (IV, Fixed, 95% CI)	8.06 [1.58, 14.54]
2.2 After first dose	2	64	Mean Difference (IV, Fixed, 95% CI)	11.09 [1.65, 20.52]
2.3 After 6 to 7 hours of treatment	2	64	Mean Difference (IV, Fixed, 95% CI)	14.30 [5.25, 23.34]
2.4 After 24 to 25 hours of treatment	2	58	Mean Difference (IV, Fixed, 95% CI)	15.31 [6.49, 24.13]
2.5 After 72 hours or at the end of treatment	1	24	Mean Difference (IV, Fixed, 95% CI)	20.98 [14.81, 27.15]
3 Mean arterial blood pressure in mmHg Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 Before initiation of therapy	2	53	Mean Difference (IV, Fixed, 95% CI)	5.65 [2.69, 8.61]
3.2 At the end of therapy	2	40	Mean Difference (IV, Fixed, 95% CI)	22.70 [1.23, 44.17]
4 All‐cause mortality Show forest plot	3	77	Risk Difference (M‐H, Fixed, 95% CI)	‐0.36 [‐0.53, ‐0.18]

5 Oxygenation index (absolute values) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 At baseline	3	77	Mean Difference (IV, Fixed, 95% CI)	‐0.74 [‐8.11, 6.64]
5.2 After first dose	3	77	Mean Difference (IV, Fixed, 95% CI)	‐12.53 [‐18.60, ‐6.47]
5.3 After 6 to 7 hours of treatment	2	75	Mean Difference (IV, Fixed, 95% CI)	‐20.07 [‐26.12, ‐14.02]
5.4 After 24 to 25 hours of treatment	3	69	Mean Difference (IV, Fixed, 95% CI)	‐19.15 [‐24.52, ‐13.77]
5.5 After 30 hours of treatment	1	11	Mean Difference (IV, Fixed, 95% CI)	‐45.46 [‐61.87, ‐29.05]
5.6 After 36 hours of treatment	1	8	Mean Difference (IV, Fixed, 95% CI)	‐31.75 [‐45.74, ‐17.76]
5.7 After 72 hours or at the end of treatment	1	24	Mean Difference (IV, Fixed, 95% CI)	‐19.47 [‐23.42, ‐15.52]
6 Change in oxygenation index Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 After first dose	1	13	Mean Difference (IV, Fixed, 95% CI)	‐17.14 [‐27.75, ‐6.53]
6.2 After 24 hours of treatment	1	12	Mean Difference (IV, Fixed, 95% CI)	‐38.79 [‐56.97, ‐20.61]
6.3 After 30 hours of treatment	1	11	Mean Difference (IV, Fixed, 95% CI)	‐33.08 [‐50.85, ‐15.31]
6.4 After 36 hours of treatment	1	8	Mean Difference (IV, Fixed, 95% CI)	‐44.75 [‐65.55, ‐23.95]
7 A‐a DO₂ difference Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.1 Baseline	2	64	Mean Difference (IV, Fixed, 95% CI)	0.99 [‐11.54, 13.51]
7.2 At 6 to 7 hours of treatment	1	24	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐27.72, 27.74]
7.3 At 24 to 25 hours of treament	2	57	Mean Difference (IV, Fixed, 95% CI)	1.59 [‐18.98, 22.16]
7.4 At 72 hours or at the end of treatment	1	24	Mean Difference (IV, Fixed, 95% CI)	‐18.34 [‐26.59, ‐10.09]
8 Mean airway pressure Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 Baseline	2	64	Mean Difference (IV, Fixed, 95% CI)	‐2.09 [‐3.30, ‐0.88]
8.2 At 6 to 7 hours of treatment	2	63	Mean Difference (IV, Fixed, 95% CI)	‐5.94 [‐7.36, ‐4.52]
8.3 At 24 to 25 hours of treatment	2	57	Mean Difference (IV, Fixed, 95% CI)	‐6.64 [‐8.49, ‐4.80]
8.4 At 72 hours or at the end of treatment	1	24	Mean Difference (IV, Fixed, 95% CI)	‐8.58 [‐10.37, ‐6.79]

Comparison 1. Sildenafil versus placebo

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Comparison 2. Sildenafil versus active control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	1	65	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.13, 0.07]

2 Time to adequate response (days) Show forest plot	1	65	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐4.20, 3.00]

3 Duration of ventilation (days) Show forest plot	1	65	Mean Difference (IV, Fixed, 95% CI)	‐1.30 [‐4.54, 1.94]

4 Inotropic agent Show forest plot	1	65	Risk Difference (M‐H, Fixed, 95% CI)	‐0.37 [‐0.59, ‐0.15]

Comparison 2. Sildenafil versus active control

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Comparison 3. Sildenafil plus iNO versus placebo plus iNO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	1	24	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.27, 0.37]

2 Length of stay in hospital (days) Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	5.39 [‐5.31, 16.09]

3 Inotropic agent Show forest plot	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.37, 3.00]

4 Duration of ventilation (days) Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	1.26 [‐1.32, 3.84]

5 Retinopathy of prematurity Show forest plot	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Sildenafil plus iNO versus placebo plus iNO

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Sildenafil para la hipertensión pulmonar en recién nacidos

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