Scolaris Content Display Scolaris Content Display

Sildenafil bei Neugeborenen mit Lungenhochdruck

Contraer todo Desplegar todo

Referencias

Al Omar 2016 {published data only}

Al Omar S, Salama H, Al Hail M, Al Rifai H, Bunahia M, El Kasem W, et al. Effect of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. A feasibility study. Journal of Neonatal‐Perinatal Medicine 2016;9(3):251‐9. [DOI: 10.3233/NPM‐16161; PUBMED: 27589542]CENTRAL

Baquero 2006 {published data only}

Baquero H, Neira F, Venegas ME, Sola A, Soliz A. Outcome at 18 months of age after sildenafil therapy for refractory neonatal hypoxemia. Pediatric Academic Societies' Annual Meeting; 2005 May 14‐17; Washington DC, United States 2005;57:2119. [PAS 2005: 57: 2119]CENTRAL
Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117(4):1077‐83. [DOI: 10.1542/peds.2005‐0523; PUBMED: 16585301]CENTRAL

Herrera 2006 {published data only}

Herrea TR, Concha GP, Holberto CJ, Loera GRG, Rodríguez BI. Oral sildenafil as an alternative treatment in the persistent pulmonary hypertension in newborns [Sildenafil oral como alternativa en el tratamiento de recien nacidos con hipertension pulmonar persistente]. Revista Mexicana de Pediatria 2006;73(4):159‐63. CENTRAL

Uslu 2011 {published data only}

Uslu S, Kumtepe S, Bulbul A, Comert S, Bolat F, Muhoglu A. A comparison of magnesium sulphate and sildenafil in the treatment of the newborns with persistent pulmonary hypertension; a randomized controlled trial. Journal of Tropical Pediatrics 2011;57(4):245‐50. [DOI: 10.1093/tropej/fmq091; PUBMED: 20923790]CENTRAL

Vargas‐Origel 2010 {published and unpublished data}

Vargas‐Origel A, Gomez‐Rodriguez G, Aldana‐Valenzuela C, Vela‐Huerta MM, Alarcon‐Santos SB, Amador‐Licona N. The use of sildenafil in persistent pulmonary hypertension of the newborn. American Journal of Perinatology 2010;27(3):225‐30. [DOI: 10.1055/s‐0029‐1239496; PUBMED: 19866403]CENTRAL

Kahveci 2014 {published data only}

Khaveci H, Yilmaz O, Avsar UZ, Ciftel M, Kilic M, Laloglu F, et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatric Pulmonology 2014;49(12):1205‐13. [DOI: 10.1002/ppul.22985; PUBMED: 24420987]CENTRAL

König 2014 {published data only}

König K, Barfield CP, Guy KJ, Drew SM, Anderson CC. The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. Journal of Maternal‐Fetal & Neonatal Medicine 2014;27(5):439‐44. [DOI: 10.3109/14767058.2013.818650; PUBMED: 23796045]CENTRAL

Namachivayam 2006 {published data only}

Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS. Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children. American Journal of Respiratory and Critical Care Medicine 2006;174(9):1042‐7. [DOI: 10.1164/rccm.200605‐694OC; PUBMED: 16917115]CENTRAL

Sayed 2015 {published data only}

Sayed A, Bisheer N. Outcome of oral sildenafil in neonatal persistent pulmonary hypertension of non‐cardiac causes. Journal of Neonatal‐Perinatal Medicine 2015;8(3):215‐20. [DOI: 10.3233/NPM‐15814137; PUBMED: 26485555]CENTRAL

Steinhorn 2009 {published data only}

Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. Journal of Pediatrics 2009;155(6):841‐7. [DOI: 10.1016/j.jpeds.2009.06.012; PUBMED: 19836028]CENTRAL

Stocker 2003 {published data only}

Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Medicine 2003;29(11):1996‐2003. [DOI: 10.1007/s00134‐003‐2016‐4; PUBMED: 14530859]CENTRAL

Alipour 2017 {published data only}

Alipour MR, Lookzadeh MH, Namayandeh SM, Pezeshkpour Z, Sarebanhassanabadi M. Comparison of tadalfil and sildenafil in controlling neonatal persistent pulmonary hypertension. Iran Journal of Pediatrics 2017;27(1):6385‐9. [DOI: 10.5812/ijp.6385]CENTRAL

NCT01373749 {unpublished data only}

NCT01373749. Nitro oxide inhalation continued with sildenafil on neonatal persistent pulmonary hypertension [Compare of continued nitro oxide inhalation and nitro oxide inhalation continued with oral sildenafil on treatment of neonatal persistent pulmonary hypertension]. clinicaltrials.gov/show/NCT01373749 (first received 31 May 2011). CENTRAL

NCT01757782 {unpublished data only}

NCT01757782. Oral sildenafil in persistent pulmonary hypertension secondary to meconium aspiration syndrome in newborns [Oral sildenafil in persistent pulmonary hypertension secondary to meconium aspiration syndrome in newborns: a randomized placebo controlled trial]. clinicaltrials.gov/show/NCT01757782 (first received 18 December 2012). [ClinicalTrials.gov: NCT01757782]CENTRAL

Soliz 2009 {published data only}

Soliz A, Concha E, Romero F. Oral sildenafil treatment as therapy for persistent pulmonary hypertension of the newborn: a multicenter randomized trial. Pediatric Academic Societies' Annual Meeting; 2009 May 2‐5; Baltimore MD, United States. 2009. [E‐PAS2009:5420.12]CENTRAL

NCT01720524 {unpublished data only}

NCT01720524. A study to evaluate safety and efficacy of IV sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn. clinicaltrials.gov/show/NCT01720524 (first received 17 September 2012). CENTRAL

Abrams 2000

Abrams D, Schulze‐Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84(2):E4. [PUBMED: 10908271]

Adatia 2002

Adatia I. Recent advances in pulmonary vascular disease. Current Opinion in Pediatrics 2002;14(3):292‐7. [PUBMED: 12011667]

Barrington 2010

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 4. [DOI: 10.1002/14651858.CD000509.pub4]

Behn 2001

Behn D, Potter MJ. Sildenafil‐mediated reduction in retinal function in heterozygous mice lacking the gamma‐subunit of phosphodiesterase. Investigative Ophthalmology and Visual Science 2001;42(2):523‐7. [PUBMED: 11157892]

Burton 2000

Burton AJ, Reynolds A, O'Neill D. Sildenafil (Viagra) a cause of proliferative diabetic retinopathy?. Eye 2000;14(Pt 5):785‐6. [DOI: 10.1038/eye.2000.205; PUBMED: 11116706]

Carroll 2003

Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Archives of Disease in Childhood 2003;88(9):827‐8. [PUBMED: 12937112]

Dukarm 1998

Dukarm RC, Morin FC, Russell JA, Steinhorn RH. Pulmonary and systemic effects of the phosphodiesterase inhibitor dipyridamole in newborn lambs with persistent pulmonary hypertension. Pediatric Research 1998;44(6):831‐7. [DOI: 10.1203/00006450‐199812000‐00002; PUBMED: 9853914]

Erickson 2002

Erickson S, Reyes J, Bohn D, Adatia I. Sildenafil (Viagra) in childhood and neonatal pulmonary hypertension. Journal of the American College of Cardiology 2002;39:402.

Finer 2017

Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Systematic Reviews 2017, Issue 1. [DOI: 10.1002/14651858.CD000399.pub3]

Gersony 1984

Gersony WM. Neonatal pulmonary hypertension: pathophysiology, classification, and etiology. Clinics in Perinatology 1984;11(3):517‐24. [PUBMED: 6488670]

Goldman 1996

Goldman AP, Tasker RC, Haworth SG, Sigston PE, Macrae DJ. Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1996;98(4 Pt 1):706‐13. [PUBMED: 8885950]

GRADEpro GDT [Computer program]

GRADE Working Group, McMaster University. GRADEpro GDT. Version accessed 19 April 2017. Hamilton (ON): GRADE Working Group, McMaster University, 2014.

Higgins 2011

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

Humbert 2004

Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. New England Journal of Medicine 2004;351(14):1425‐36. [DOI: 10.1056/NEJMra040291; PUBMED: 15459304]

Iacovidou 2012

Iacovidou N, Syggelou A, Fanos V, Xanthos T. The use of sildenafil in the treatment of persistent pulmonary hypertension of the newborn: a review of the literature. Current Pharmaceutical Design 2012;12(21):3034‐45. [PUBMED: 22564297]

Ichinose 2001

Ichinose F, Erana‐Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Critical Care Medicine 2001;29(5):1000‐5. [PUBMED: 11378612]

Ikeda 2005

Ikeda D, Tsujino I, Ohira H, Itoh N, Kamigaki M, Ishimaru S, et al. Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension. Journal of Cardiovascular Pharmacology 2005;45(4):286‐9. [PUBMED: 15772514]

Juliana 2005

Juliana AE, Abbad FC. Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. European Journal of Pediatrics 2005;164(10):626‐9. [DOI: 10.1007/s00431‐005‐1724‐x; PUBMED: 16012855]

Kanthapillai 2004

Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary hypertension. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD003562.pub2]

Kehat 2010

Kehat R,  Bonsall DJ,  North R,  Connors B. Ocular findings of oral sildenafil use in term and near‐term neonates. Journal of AAPOS 2010;14(2):159‐62. [DOI: 10.1016/j.jaapos.2009.12.161; PUBMED: 20199882]

Kinsella 2000

Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Seminars in Perinatology 2000;24(6):387‐95. [PUBMED: 11153900]

Kumar 2002

Kumar S. Indian doctor in protest after using Viagra to save "blue babies". British Medical Journal 2002;325(7357):181. [PUBMED: 12142299 ]

Lewin 2002

Lewin S. Viagra neonatal experimentation ‐ the Pandora's box!. Indian Pediatrics 2002;39(9):894‐5. [PUBMED: 12368555]

Marsh 2004

Marsh CS, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. British Journal of Ophthalmology 2004;88(2):306‐7. [PUBMED: 14736800]

Mesubi 2009

Mesubi OO, Ashwath R, Mhanna MJ. Oral sildenafil in premature infants with pulmonary arterial hypertension secondary to bronchopulmonary dysplasia. Pediatric Academic Societies Annual meeting; 2009 May 2‐5; Baltimore MD, United States. 2009. [E‐PAS2009:615]

Mourani 2009

Mourani PM,  Sontag MK,  Ivy DD,  Abman SH. Effects of long‐term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. Journal of Pediatrics 2009;154(3):379‐84. [DOI: 10.1016/j.jpeds.2008.09.021; PUBMED: 18950791]

Oliver 2002

Oliver J, Webb DJ. Sildenafil for "blue babies". Such unlicensed drug use might be justified as last resort. British Medical Journal 2002;325(373):1174. [PUBMED: 12433774]

Patole 2002

Patole S, Travadi J. Sildenafil for "blue babies". Ethics, conscience, and science have to be balanced against limited resources. British Medical Journal 2002;325(7373):1174. [PUBMED: 12434819]

Pierce 2005

Pierce CM, Petros AJ, Fielder AR. No evidence for severe retinopathy of prematurity following sildenafil. British Journal of Ophthalmology 2005;89(2):250. [PUBMED: 15665374]

Rabe 1994

Rabe KF, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. American Journal of Physiology 1994;266(5 Pt 1):L536‐43. [PUBMED: 7515580]

RevMan 2014 [Computer program]

Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Roberts 1997

Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. New England Journal of Medicine 1997;336(9):605‐10. [DOI: 10.1056/NEJM199702273360902; PUBMED: 9032045]

Sastry 2004

Sastry BKS, Narasimhan C, Reddy K, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension. Journal of the American College of Cardiology 2004;43(7):1149‐53. [DOI: 10.1016/j.jacc.2003.10.056; PUBMED: 15063421]

Schünemann 2013

Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE Working Group. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. https://gdt.gradepro.org/app/handbook/handbook.htmlUpdated October 2013.

Shah 2004

Shah PS, Hellmann J, Adatia I. Clinical characteristics and follow up of Down syndrome infants without congenital heart disease who presented with persistent pulmonary hypertension of newborn. Journal of Perinatal Medicine 2004;32(2):168‐70. [DOI: 10.1515/JPM.2004.030; PUBMED: 15085894]

Shekerdemian 2002

Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 2002;165(8):1098‐102. [DOI: 10.1164/ajrccm.165.8.2107097; PUBMED: 11956051]

Shekerdemian 2004

Shekerdemian LS, Ravn HB, Penny DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatric Research 2004;55(3):413‐8. [DOI: 10.1203/01.PDR.0000112033.81970.C2; PUBMED: 14711900]

Shivanna 2009

Shivanna B, Eichenwald EC, Stark AR. Sildenafil use in the newborn intensive care units is associated with improvement in pulmonary hypertension. Pediatric Academic Societies' Annual Meeting; 2009 May 2‐5; Baltimore MD, United States2009. [E‐PAS2009:621]

Simiyu 2006

Simiyu DE, Okello C, Nyakundi EG, Tawakal AH. Sildenafil in management of persistent pulmonary hypertension of the newborn: report of two cases. East African Medical Journal 2006;83(6):337‐40. [PUBMED: 16989380]

Spillers 2010

Spillers J. PPHN: is sildenafil the new nitric? A review of the literature. Advances in Neonatal Care 2010;10(2):69‐74. [DOI: 10.1097/ANC.0b013e3181d5c501; PUBMED: 20386371]

Subhedar 2002

Subhedar NV, Jauhari P, Natarajan R. Cost of inhaled nitric oxide therapy in neonates. Lancet 2002;359(9319):1781‐2. [DOI: 10.1016/S0140‐6736(02)08632‐4; PUBMED: 12049900]

Travadi 2003

Travadi JN, Patole SK. Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Pediatric Pulmonology 2003;36(6):529‐35. [DOI: 10.1002/ppul.10389; PUBMED: 14618646]

Walsh‐Sukys 2000

Walsh‐Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;105:14‐20.

Wessel 1997

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:e7.

Shah 2007

Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD005494.pub2; PUBMED: PMID: 17636802]

Shah 2011

Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database of Systematic Reviews 2011, Issue 8. [DOI: 10.1002/14651858.CD005494.pub3; PUBMED: PMID 21833954 ]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al Omar 2016

Methods

Randomised controlled trial
Study location: neonatal intensive care unit at the Hamad Medical Corporation, in Doha, Qatar
Study period: over 3 years from September 2011 to September 2014

Participants

24 neonates born at 34 weeks or later with PPHN and OI > 20

Group 1: n = 13

Male: 7/13 (%)
Mean GA: 38.1 (SD 2.3) weeks
Mean birth weight: 3107 (SD 700) g

Group 2: n = 11

Male: 8/11 (%)
Mean GA: 39 (SD 1.61) weeks
Mean birth weight: 3179 (SD 627) g

Interventions

iNO starting dose 20 ppm, weaning 2% to 4% every hour

Group 1: iNO with 2 mg/kg sildenafil q6hours via orogastric tube (50 mg tablet crushed and diluted with 10 mL Orabase to prepare 5 mg/mL)

Group 2: iNO with placebo (saline via orogastric tube)

Outcomes

Oxygen index (absolute values and change from baseline, after first dose and every 6 hours for 7 days; improvement in OI, defined as a decrease of 10% from previously calculated value)

A‐a gradient

Haemodynamic parameters

Days of hospitalisation

Mortality (all‐cause within 28 days of life)

Inotropic agent

ROP

Length of stay

Notes

Registered with clinicaltrials.gov NCT01558466

Trial was funded by an investigator grant

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random sequence generation (information obtained from author Salama)

Allocation concealment (selection bias)

Low risk

Randomisation by sealed envelope competed by pharmacy

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treating physicians and nurses were unaware of treatment allocation

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Respiratory therapists were unaware of treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data are reported on all 24 randomised neonates

Selective reporting (reporting bias)

Low risk

All registered outcomes were reported

Other bias

Low risk

Appears free of other bias

Baquero 2006

Methods

Randomised controlled trial
Study location: neonatal intensive care unit at the Hospital Niño Jesús in Barranquilla, Colombia
Study period: 2003 to 2004

Participants

13 neonates > 35.5 weeks' PMA with persistent hypoxaemia despite mechanical ventilation (OI ≥ 40) and echocardiographic diagnosis of PPHN were enrolled, at < 3 days old
Group 1: n = 7
Male: 4/7 (57%)

Mean GA: 38.4 (SD 2.6) weeks
Mean birth weight: 2803 (SD 617) grams
Mean OI: 56 (SD 16.8)

Group 2: n = 6
Male: 3/6 (50%)
Mean GA: 37.2 (SD 1.9) weeks
Mean birth weight: 2710 (SD 554) grams
Mean OI: 46 (SD 9.5)

Interventions

Group 1: sildenafil (via orogastric tube) first dose of 1 mg/kg (0.5 mL/kg), subsequent doses every 6 hours; could be doubled to 2 mg/kg (1 mL/kg) if OI did not improve and BP remained stable until participant received a maximum of 8 doses, or until OI improved to < 20
Group 2: same volume of placebo (Orabase) first dose of 0.5 mL/kg, subsequent doses every 6 hours; could be doubled to 1 mL/kg if OI did not improve

Outcomes

Mortality
Changes in OI
Changes in mean arterial blood pressure

Notes

OI was determined for all 7 participants in sildenafil group for baseline and for first 6 doses. Oxygenation index was reported for only 4 participants for the seventh dose (2 met the pre‐set exit criteria for the study, and 1 died)
OI was determined for all 6 participants in the placebo group at baseline, after dose 1, and after dose 2. One participant died before the third dose (measurement reported for 5 participants after third dose and after fourth dose); one participant died before fifth dose (measurements reported for 4 participants at doses 5, 6, and 7)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information on sequence generation was reported

Allocation concealment (selection bias)

Low risk

Randomisation was by simple allocation of pre‐sealed numbers. No information is provided on whether envelopes were opaque or were sequentially numbered

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Bedside clinicians were masked to treatment

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Primary outcome measures are not subjective

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data on all enrolled participants were reported

Selective reporting (reporting bias)

Unclear risk

A protocol or trial registration was not available to assess selective reporting

Other bias

Unclear risk

Small sample size; study was terminated prematurely

Herrera 2006

Methods

Randomised controlled trial
Study location: newborns treated in the intensive care unit of the Hospital Universitario de la Facultad de Medicina de la Universidad Autónoma de Nueco León, in San Andreas, Mexico Study period: May 2004 to October 2005

Participants

24 term neonates with PPHN and OI > 25

Group 1: n = 13

Male: 5/13 (38%)
Mean GA: 37 (SD 3.1) weeks
Mean birth weight: 2741 (SD 66) grams

Group 2: n = 11

Male: 6/11 (55%)
Mean GA: 36.2 (SD 3.1) weeks
Mean birth weight: 2651(SD 71) grams

Interventions

Group 1: sildenafil 2 mg/kg via orogastric tube (duration of administration ‐ 72 hours)
Group 2: distilled water (2 mL/kg)

Outcomes

Changes in OI, PaCO2, A‐a DO2, PaO2
Changes in mean arterial blood pressure
Duration of intubation

Death

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Sequence generation methods were not reported

Allocation concealment (selection bias)

Unclear risk

Reported as blinded study, but no information provided on how treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study was described as blinded, but no information was provided on how blinding was achieved

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study was described as blinded, but no information was provided on how blinding was achieved

Incomplete outcome data (attrition bias)
All outcomes

High risk

Newborns whose data were incomplete or who were transferred to other hospitals were excluded

Selective reporting (reporting bias)

Unclear risk

A protocol or trial registration was not available for assessment of selective reporting

Other bias

Low risk

Appears free of other bias

Uslu 2011

Methods

Randomised clinical trial
Study location: neonatal intensive care unit of Diyarbakir Children's Hospital, Turkey
Study period: 1 February 2007 to 30 April 2008

Participants

65 term and near‐term neonates (35 to 42 weeks' GA) with persistent hypoxaemic respiratory failure (PAP ≥ 40 mmHg, OI ≥ 30, and need for mechanical ventilation) associated with PPHN were enrolled

Group 1: sildenafil (n = 31)
Male: 16/31 (52%)
Mean PMA: 38.5 (SD 1.6) weeks
Mean birth weight: 3229 (SD 364) grams
Mean OI: 43.3 (SD 6.3)

Group 2: MgSo4 (n = 34)

Male: 20/34 (59%)
Mean PMA: 38.3 (SD 1.7) weeks
Mean birth weight: 3296 (SD 339) grams
Mean OI: 44.0 (SD 8.8)

Interventions

Group 1: 25 mg tablet of sildenafil diluted with 25 mL sterile water for final concentration of 1 mg/mL. Dose of solution (0.5 mg/kg) was given via orogastric tube every 6 hours. Dose could be doubled (until maximum of 2 mg/kg) if OI did not improve. Sildenafil dose was tapered 50% after reaching OI level < 15 and PAP < 20 mmHg and was terminated in 1 day

Group 2: MgSO4 loading dose of 200 mg/kg infused IV over 30 minutes followed by maintenance dose of 20 mg/kg/h. If OI did not improve sufficiently, MgSO4 infusion rate was increased slowly (10 mg/kg/h to maximum 100 mg/kg/h). When OI level was < 15 and PAP was < 20 mmHg, MgSO4 infusion was decreased gradually (10 mg/kg/h) and was terminated in 1 day

Outcomes

Primary outcome: time of adequate clinical response (defined as a decrease in PAP to < 20 mmHg (improvement in PAP) and in OI to < 15 (improvement in OI))

Secondary outcomes:

Duration of mechanical ventilation

Support of inotropic agent

Mortality rate

Adverse events

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent researcher used a computer‐generated randomisation table

Allocation concealment (selection bias)

Low risk

Allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

As MgSO4 was given IV and sildenafil was given by orogastric tube, care providers could not be blinded to treatment groups

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Data collector nurse, paediatric cardiologist, and ultrasonographer were blinded. Only the neonatologist who gave medical care to participants was not blinded to the type of treatment received

Incomplete outcome data (attrition bias)
All outcomes

High risk

Data were not analysed as intent to treat. Data were incomplete (missing) for 7 neonates (2 MgSO4, 5 sildenafil), 3 of whom had gastrointestinal bleeding

Selective reporting (reporting bias)

Unclear risk

A protocol or trial registration was not available for assessment of selective reporting

Other bias

Low risk

Appears free of other bias

Vargas‐Origel 2010

Methods

Randomised controlled trial
Study location: neonatal intensive care unit at the Unidad Medica de Alta Espexialidad No. 48, in Guanajuato, Mexico
Study period: not reported

Participants

40 term neonates with PPHN and OI > 20

Group 1: n = 31

Male: 16/31(%)
Mean GA: 37.8 (SD 1.6) weeks
Mean birth weight: 2993 (SD 532) grams

Group 2: n = 20

Male: 13/20 (%)
Mean GA: 38.8 (SD 1.9) weeks
Mean birth weight: 3043 (SD 563) grams

Interventions

Group 1: sildenafil 2 mg/kg via orogastric tube 3 mg/kg/dose until OI < 10
Group 2: normal saline

Outcomes

Changes in OI, PaO2, A‐aDO2, PaCO2, mean airway pressure
Changes in mean arterial blood pressure

Mortality

Time on mechanical ventilation

Notes

Published manuscript described 31 participants in the sildenafil group (20 randomised to receive placebo, and another 11 randomised to receive nitric oxide). We contacted study authors and retrieved data for the first 40 infants (20 in each group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence was generated by a random numbers table (information provided by study author).

Allocation concealment (selection bias)

Low risk

Allocation was generated by 2 nurses who were not involved with the study.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as blinded. "Pharmacy prepared the solution and bedside clinicians were unaware of group assignment" (information provided by study author).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Described as blinded. "Outcome assessment was masked as nurses were unaware of treatment allocation" (information provided by study author)

Incomplete outcome data (attrition bias)
All outcomes

High risk

Published report had combined data on 51 participants and did not include information on when the change in randomisation occurred

Selective reporting (reporting bias)

Unclear risk

Protocol or trial registration was not available for assessment of selective reporting

Other bias

Unclear risk

Published data included subsequent participants; therefore, it is difficult to assess other bias

A‐a DO2 = alveolar‐arterial oxygen difference
BP = blood pressure
GA = gestational age
iNO = inhaled nitric oxide

MgSO4 = magnesium sulphate
OI = oxygenation index
PaCO2 = partial pressure of carbon dioxide in arterial blood
PaO2 = partial pressure of oxygen in arterial blood

PAP = pulmonary artery pressure

PMA = postmenstrual age
PPHN = persistent pulmonary hypertension of the newborn
ROP = retinopathy of prematurity

SD = standard deviation

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Kahveci 2014

Retrospective study design

König 2014

Unclear whether patients had persistent pulmonary hypertension in neonates (PPHN); newborns on nitric oxide (NO) were excluded

Namachivayam 2006

Included patients whose age ranged from 0.1 years onwards
Most participants had associated congenital heart disease

Sayed 2015

Single‐arm study; no control arm

Steinhorn 2009

Open‐label single‐arm study; no randomisation

Stocker 2003

Only infants after cardiac surgery were included

Characteristics of studies awaiting assessment [ordered by study ID]

Alipour 2017

Methods

Randomised controlled trial

Participants

32 neonates born at 34 weeks or later with PPHN (cyanosis that continued 30 minutes after ventilation with 100% supplemental oxygen via hood)

Group 1: n = 16

No participant demographics were reported

Group 2: n = 16

No participant demographics were reported

Interventions

Tadalafil orally; 1 mg/kg/d

Sildenafil orally; 1 mg/kg/dose 3 times daily

Outcomes

Tricuspid regurgitation (TR) severity assessed by echocardiography at baseline and after 6 months

Mean pulmonary arterial pressure (MPAP) recorded via echocardiography based on gradient of pulmonary insufficiency or gradient TR on Doppler echocardiography

Right ventricular end‐diastolic diameter (RVEDD) assessed by echocardiography at baseline and after 6 months

Main pulmonary artery (MPA) diameter assessed by echocardiography at baseline and 6 months after treatment

Notes

Funding support, potential conflicts, and trial registration were not reported. This study was classified as awaiting classification, as the review authors required clarification of the time period of measurement. It is reported that echocardiography took place 6 months after treatment, which we believe could have taken hours. We have contacted the corresponding author multiple times

NCT01373749

Methods

Randomised clinical trial

Participants

Inclusion criteria:

Diagnosis of PPHN in the NICU, primary disease:neonate respiratory distress syndrome, meconium aspiration syndrome of newborn, severe neonatal infectious pneumonia.

Pulmonary artery pressure > 50 mmHg, mechanical ventilation over 48 hours, primary OI (PO2/FiO2) < 300, difference of SpO2 between upper and lower limbs > 10%, high FiO2, oxygen inhalation test: positive

Exclusion criteria:
Congenital heart disease, diaphragmatic hernia

Interventions

Nitric oxide inhalation continued with sildenafil vs inhaled nitric oxide alone

Outcomes

Primary outcome measures:

Persistent normal pulmonary artery pressure

Pulmonary artery pressure returned to a normal level (< 30 mmHg) and lasting over 48 hours

Secondary outcome measures:

Recovery without complication (time frame: 1 month after therapy)

Incidence of pulmonary disease (chronic lung disease)

Incidence of brain injury (hypoxic‐ischaemic encephalopathy)

Heart structure change (right ventricle enlarged)

Notes

Status verified as "recruiting" in January 2011 by Third Military Medical University

NCT01757782

Methods

Randomised controlled trial

Participants

40 neonates (GA > 34 weeks) admitted within 12 hours of delivery with diagnosis of MAS and development of PPHN

Group 1: n = 20

Male: 9/20 (%)
Mean birth weight: 2767 (SD 100) grams

Group 2: n = 20

Male: 12/20 (%)
Mean birth weight: 2691 (SD 90) grams

Interventions

Group 1: oral sildenafil (1 mg/kg/dose q6hours) administered through feeding tube for a total of 8 doses (treatment for 2 days)

Group 2: placebo

Outcomes

Oxygen saturation

Oxygenation index

Length of hospitalisation

Duration of mechanical ventilation

Mortality

Notes

We identified study through ClinicalTrials.gov and contacted study authors, who stated that trial results are unavailable yet, but recruitment has been completed

Soliz 2009

Methods

Randomised clinical trial

Participants

49 term neonates with PPHN and OI > 25 were included

Interventions

Randomised to placebo (n = 20) vs sildenafil (n = 29)

Outcomes

OI, mean blood pressure and mean airway pressure

Notes

Difficult to differentiate from included studies, as some study authors overlap

FiO2 = fraction of inspired oxygen
GA = gestational age
MAS = meconium aspiration syndrome
MPA = mean pulmonary artery
MPAP = mean pulmonary arterial pressure
NICU = neonatal intensive care unit
OI = oxygenation index
PO2 = partial pressure of oxygen
PPHN = persistent pulmonary hypertension in the neonate
RVEDD = right ventricular end‐diastolic diameter
SD = standard deviation
SpO2 = peripheral capillary oxygen saturation
TR = tricuspid regurgitation

Characteristics of ongoing studies [ordered by study ID]

NCT01720524

Trial name or title

A study to evaluate the safety and efficacy of IV sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn

Methods

Multi‐centre randomised placebo‐controlled double‐blind 2‐armed parallel‐group study

Participants

Inclusion criteria:

Neonates with persistent pulmonary hypertension of the newborn

Age ≤ 96 hours and ≥ 34 weeks' gestational age

Oxygenation index > 15 and < 60

Concurrent treatment with inhaled nitric oxide and ≥ 50% oxygen

Exclusion criteria:

Prior or immediate need for extracorporeal membrane oxygenation or cardiopulmonary resuscitation

Expected duration of mechanical ventilation < 48 hours

Profound hypoxaemia

Life‐threatening or lethal congenital anomaly

Interventions

Treatment: intravenous (IV) sildenafil

· Loading dose of 0.1 mg/kg over 30 minutes followed by maintenance dose of 0.03 mg/kg/h. To infuse minimum of 48 hours and maximum of 14 days

Control: placebo

IV placebo or 0.9% sodium chloride or 10% dextrose. Infusion rate based on weight

Outcomes

Primary outcome measures (at day 14 or until discharge):

· Time on inhaled nitric oxide treatment after initiation of IV study drug

· Treatment failure rate, defined as need for additional treatment targeting persistent pulmonary hypertension of the newborn

Secondary outcome measures:

· Time to final weaning off mechanical ventilation for persistent pulmonary hypertension of the newborn

· Time from initiation of study drug to treatment failure

· Change in oxygenation parameters at 6, 12, and 24 hours from baseline

· Sildenafil plasma concentrations and corresponding pharmacokinetic (PK) parameters

· Safety parameters: incidence and severity of adverse events and abnormal laboratory parameters

Long‐term outcomes (12 and 24 months):

· Developmental progress of participants as assessed by Bayley Scales of Infant Development and Behavior Questionnaire

· Safety as assessed by adverse events and survival

· Neurological progress of participants as assessed by the Neurology Optimality Score, also known as the Hammersmith Infant Neurological Examination

· Visual status of participants as assessed by eye examination of anterior and posterior segments

· Audiological status of participants as assessed by physiological and behavioural tests

Starting date

17 September 2012

Contact information

Pfizer CT.gov call centre: 1‐800‐718‐1021

Notes

Includes a long‐term follow‐up investigation of developmental progress at 12 and 24 months

Data and analyses

Open in table viewer
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

Analysis 1.1

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

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

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

Analysis 1.2

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

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

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

Analysis 1.3

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

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

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]

Analysis 1.4

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

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

5 Oxygenation index (absolute values) Show forest plot

3

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 1.5

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

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

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

Analysis 1.6

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

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

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

Analysis 1.7

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

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

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

Analysis 1.8

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

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

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]

Open in table viewer
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]

Analysis 2.1

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

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

2 Time to adequate response (days) Show forest plot

1

65

Mean Difference (IV, Fixed, 95% CI)

‐0.60 [‐4.20, 3.00]

Analysis 2.2

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

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

3 Duration of ventilation (days) Show forest plot

1

65

Mean Difference (IV, Fixed, 95% CI)

‐1.30 [‐4.54, 1.94]

Analysis 2.3

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

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

4 Inotropic agent Show forest plot

1

65

Risk Difference (M‐H, Fixed, 95% CI)

‐0.37 [‐0.59, ‐0.15]

Analysis 2.4

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

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

Open in table viewer
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]

Analysis 3.1

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

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

2 Length of stay in hospital (days) Show forest plot

1

24

Mean Difference (IV, Fixed, 95% CI)

5.39 [‐5.31, 16.09]

Analysis 3.2

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

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

3 Inotropic agent Show forest plot

1

24

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.37, 3.00]

Analysis 3.3

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

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

4 Duration of ventilation (days) Show forest plot

1

24

Mean Difference (IV, Fixed, 95% CI)

1.26 [‐1.32, 3.84]

Analysis 3.4

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

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

5 Retinopathy of prematurity Show forest plot

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 3.5

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

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

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

Study flow diagram: review update.

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

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

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

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

Comparison 1 Sildenafil versus placebo, Outcome 1 Pulmonary arterial pressure.
Figuras y tablas -
Analysis 1.1

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

Comparison 1 Sildenafil versus placebo, Outcome 2 PaO2 in mmHg (absolute values).
Figuras y tablas -
Analysis 1.2

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

Comparison 1 Sildenafil versus placebo, Outcome 3 Mean arterial blood pressure in mmHg.
Figuras y tablas -
Analysis 1.3

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

Comparison 1 Sildenafil versus placebo, Outcome 4 All‐cause mortality.
Figuras y tablas -
Analysis 1.4

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

Comparison 1 Sildenafil versus placebo, Outcome 5 Oxygenation index (absolute values).
Figuras y tablas -
Analysis 1.5

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

Comparison 1 Sildenafil versus placebo, Outcome 6 Change in oxygenation index.
Figuras y tablas -
Analysis 1.6

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

Comparison 1 Sildenafil versus placebo, Outcome 7 A‐a DO2 difference.
Figuras y tablas -
Analysis 1.7

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

Comparison 1 Sildenafil versus placebo, Outcome 8 Mean airway pressure.
Figuras y tablas -
Analysis 1.8

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

Comparison 2 Sildenafil versus active control, Outcome 1 All‐cause mortality.
Figuras y tablas -
Analysis 2.1

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

Comparison 2 Sildenafil versus active control, Outcome 2 Time to adequate response (days).
Figuras y tablas -
Analysis 2.2

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

Comparison 2 Sildenafil versus active control, Outcome 3 Duration of ventilation (days).
Figuras y tablas -
Analysis 2.3

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

Comparison 2 Sildenafil versus active control, Outcome 4 Inotropic agent.
Figuras y tablas -
Analysis 2.4

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

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 1 All‐cause mortality.
Figuras y tablas -
Analysis 3.1

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

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 2 Length of stay in hospital (days).
Figuras y tablas -
Analysis 3.2

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

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 3 Inotropic agent.
Figuras y tablas -
Analysis 3.3

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

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 4 Duration of ventilation (days).
Figuras y tablas -
Analysis 3.4

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

Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 5 Retinopathy of prematurity.
Figuras y tablas -
Analysis 3.5

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

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)

⊕⊕⊝⊝
LOWa,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)

⊕⊕⊝⊝
LOWa,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)

⊕⊕⊝⊝
LOWa,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

Figuras y tablas -
Summary of findings for the main comparison. Sildenafil compared with placebo for pulmonary hypertension in neonates
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 LOWa,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)

Figuras y tablas -
Summary of findings 2. Sildenafil compared with active control for pulmonary hypertension in neonates
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)

⊕⊕⊝⊝
LOWa

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)

⊕⊕⊝⊝
LOWa

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

Figuras y tablas -
Summary of findings 3. Sildenafil plus iNO compared with placebo plus iNO for pulmonary hypertension in neonates
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]

Figuras y tablas -
Comparison 1. Sildenafil versus placebo
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]

Figuras y tablas -
Comparison 2. Sildenafil versus active control
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]

Figuras y tablas -
Comparison 3. Sildenafil plus iNO versus placebo plus iNO