Comparison 1 Sildenafil versus placebo, Outcome 1 Pulmonary arterial pressure. Comparison 2 Sildenafil versus active control, Outcome 2 Time to adequate response (days). et al. We graded the evidence as low to very low owing to imprecision related to the small number of included studies. We rated the quality of evidence as low to very low owing to imprecision related to small sample size and unclear methodological features. Al Omar 2016 reported the duration of ventilation (days). Krim L, Outcomes evaluated in the post hoc subgroup analysis did not influence our overall recommendations. WalshSukys MC, Bulbul A, Pierce C, Blinding of participants and personnel (performance bias). After performing a revised literature search, we made a post hoc modification. We categorised the methods as: a. Oral sildenafil as an alternative treatment in the persistent pulmonary hypertension in newborns. For each included study, we categorised the method used to conceal the allocation sequence as: a. A large multicentre multinational trial in highincome countries undertaken to evaluate the effectiveness of intravenous sildenafil versus placebo in terms of duration of nitric oxide treatment and treatment failure (additional treatment required for PPHN) is currently ongoing and may shed further light on this topic ({"type":"clinical-trial","attrs":{"text":"NCT01720524","term_id":"NCT01720524"}}NCT01720524). These trials were conducted in resourcelimited settings such as Columbia, Mexico, Qatar, and Turkey. After administration of intervention for 30 hours: Results show a statistically significant reduction in OI after administration of six doses of sildenafil alone (at 30 hours after administration) compared with placebo (MD 33.08, 95% CI 50.85 to 15.31; one study, 11 participants; heterogeneity estimates not applicable). Values for mean arterial blood pressure after completion of therapy were available for only one of the survivors (Baquero 2006) in the placebo group (45.3 mmHg), whereas values were provided for six survivors in the sildenafil group: (mean + SD) 43.7 + 3.3 mmHg. Nyakundi EG, Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. Comparison 2 Sildenafil versus active control, Outcome 1 Allcause mortality. The site is secure. None of the three included studies that performed this comparison reported these data. The time to reach the adequate clinical response [defined as . Morin FC 3rd, If needed, we planned to explore the impact of the level of bias by undertaking sensitivity analyses. the contents by NLM or the National Institutes of Health. Outcome of oral sildenafil in neonatal persistent pulmonary hypertension of non-cardiac causes. iNO = inhaled nitric oxide, MgSO4 = magnesium sulphate After 72 hours: Data show a statistically significant reduction in OI in the sildenafil alone group compared with the placebo group after 72 hours of treatment (MD 19, 95% CI 23.42 to 15.52; one study, 24 participants; heterogeneity estimates not applicable) (Analysis 1.5). After administration of intervention for 24 hours: Data show a statistically significant reduction in OI after administration of five doses of sildenafil alone (at 24 hours after administration) compared with placebo (MD 38.79, 95% CI 56.97 to 20.61; one study, 12 participants; heterogeneity estimates not applicable). We identified two new studies that met our inclusion criteria (Al Omar 2016; Uslu 2011). Kane JW, PaCO2 = partial pressure of carbon dioxide in arterial blood We applied the I2 test of heterogeneity and used GRADE to assess the quality of evidence. Sildenafil and another pulmonary vasodilator versus another pulmonary vasodilator or placebo. Such unlicensed drug use might be justified as last resort, Sildenafil for "blue babies". In some babies, this transition does not occur and pressure remains high; this does not allow blood to go to the lungs to get adequate oxygen. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3), MEDLINE via PubMed (1966 to 18 April 2017), Embase (1980 to 18 April 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 18 April 2017). Described as blinded. 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. Steinhorn 2009 was an openlabel doseescalating study. Researchers reported these data in graphical format and did not provide mean and variance measures. Steinhorn RH, Baquero 2006 and VargasOrigel 2010 provided data on mean arterial blood pressure before the start of therapy in all participants and at the end of therapy among survivors. Okello C, One review author entered data into RevMan 5.3 (RevMan 2014); the other review authors crosschecked the printout against data entered into abstraction forms, and corrected errors by consensus. Sildenafil has been studied in neonatal animal models. After administration of intervention for 30 hours: Data show a statistically significant reduction in OI in the sildenafil alone group compared with the placebo group after 30 hours of treatment (MD 45.46, 95% CI 61.87 to 29.05; one study, 11 participants; heterogeneity estimate not applicable). We assessed each criterion as having low, high, or unclear risk. For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We used standard review methods of the CNRG to select studies for inclusion, to extract study data, and to assess the methodological quality of identified studies. See Appendix 2 for a detailed description of risk of bias for each domain. PaO2 = partial pressure of oxygen in arterial blood, PMA = postmenstrual age Haworth SG, We contacted study authors and retrieved data for the first 40 infants (20 in each group). In one study of only 65 participants, sildenafil was effective in reducing the need for inotropes. Was knowledge of the allocated intervention adequately prevented during the study? Sastry BKS, Neira F, Lookzadeh MH, Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Baquero 2006 reported these data for individual participants in a table format. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). official website and that any information you provide is encrypted MAS = meconium aspiration syndrome Newly added studies include Al Omar 2016 and Uslu 2011. Clinicians make the echocardiographic diagnosis of PPHN by demonstrating the presence of extrapulmonary righttoleft shunting at the ductal or atrial level in the absence of severe pulmonary parenchymal disease with Doppler evidence of tricuspid regurgitation (Shah 2004; Wessel 1997). Results show no significant differences in the need for an inotropic agent between groups given sildenafil or placebo adjuvant to iNO therapy (RR 1.06, 95% CI 0.37 to 3.00; RD 0.02, 95% CI 0.37 to 0.41; one study, 24 participants; heterogeneity estimate not applicable) (Analysis 3.3). Baquero 2006 reported no grade 3 or 4 intraventricular haemorrhage in any of the infants in either group. We searched clinical trials registries for ongoing or recently completed trials ((clinicaltrials.gov); the World Health Organization International Trials Registry and Platform (www.whoint/ictrp/search/en/); the ISRCTN Registry)). OI = oxygenation index Investigators compared data using descriptive statistics and Student's ttest. We excluded 74 fulltext articles that did not meet our inclusion criteria; 65 were not randomised clinical trials, and 9 did not recruit neonates. University of Toronto Mount Sinai Hospital, Department of Paediatrics, TorontoCanada, University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, TorontoCanada, University of Toronto Mount Sinai Hospital, Department of Paediatrics and Institute of Health Policy, Management and Evaluation, 600 University Avenue, TorontoONCanada, M5G 1XB. Augusta Sola, Jayendra Gohil, and Husam Salama for providing data on their studies. Approximately 30% of patients fail to respond to iNO. Comert S, Allocation was generated by 2 nurses who were not involved with the study. {"type":"clinical-trial","attrs":{"text":"NCT01757782","term_id":"NCT01757782"}}, {"type":"clinical-trial","attrs":{"text":"NCT01373749","term_id":"NCT01373749"}}, {"type":"clinical-trial","attrs":{"text":"NCT01720524","term_id":"NCT01720524"}}, {"type":"clinical-trial","attrs":{"text":"NCT01670136","term_id":"NCT01670136"}}, {"type":"clinical-trial","attrs":{"text":"NCT01558466","term_id":"NCT01558466"}}. Aa DO2 = alveolararterial oxygen difference Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension, Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Connors B. Ocular findings of oral sildenafil use in term and nearterm neonates, Inhaled nitric oxide: current and future uses in neonates, Indian doctor in protest after using Viagra to save "blue babies". During cardiac catheterisation, pulmonary hypertension is defined as pulmonary arterial pressure (PAP) greater than 25 to 30 mmHg (Adatia 2002). Advances in our understanding of the physiology of vasoactive mediators have revealed a high concentration of phosphodiesterases in the pulmonary vasculature (Rabe 1994). Loera GRG, Infants with BPD who develop PH often require supplemental respiratory . Al Omar S, Protocol first published: Issue 4, 2005 Investigators reported all registered outcomes. Version 5.1.0 [updated March 2011]. Three studies that compared sildenafil and placebo (no sildenafil) reported that sildenafil reduced the number of deaths. Sequence was generated by a random numbers table (information provided by study author). Abstract. It would be crucial for such studies to include longterm neurodevelopmental followup, as studies to this point have not provided sufficient information on longterm treatment effects. In neonates who did not respond to . 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 randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) 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 preterm or very low birth weight or low birth weight or VLBW or LBW). At 24 to 25 hours after administration: Mean airway pressure was significantly lower in the sildenafil alone group than in the placebo group (MD 6.64, 95% CI 8.49 to 4.80 cm of H2O; two studies, 57 participants; I2 = 0% none). Clinical efficacy of sildenafil in primary pulmonary hypertension. Pulmonary hypertension (PH) is a frequently occurring complication in neonates with high risk factors such as intrauterine hypoxia, congenital diaphragmatic hernia (CDH), bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS), and meconium aspiration syndrome ( 1 - 3 ). Soliz A, Butrous G, We have contacted the corresponding author multiple times, Nitric oxide inhalation continued with sildenafil vs inhaled nitric oxide alone, Status verified as "recruiting" in January 2011 by Third Military Medical University, 40 neonates (GA > 34 weeks) admitted within 12 hours of delivery with diagnosis of MAS and development of PPHN, Group 1: oral sildenafil (1 mg/kg/dose q6hours) administered through feeding tube for a total of 8 doses (treatment for 2 days), We identified study through ClinicalTrials.gov and contacted study authors, who stated that trial results are unavailable yet, but recruitment has been completed, 49 term neonates with PPHN and OI > 25 were included, Randomised to placebo (n = 20) vs sildenafil (n = 29), OI, mean blood pressure and mean airway pressure, Difficult to differentiate from included studies, as some study authors overlap, A study to evaluate the safety and efficacy of IV sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn, Multicentre randomised placebocontrolled doubleblind 2armed parallelgroup study. Data show no significant differences in the number of days in hospital between groups given sildenafil versus placebo as adjuvant to iNO therapy (MD 5.39, 95% CI 5.31 to 16.09; one study, 24 participants; heterogeneity estimate not applicable) (Analysis 3.2). Schnemann H, Dilleen M, Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 5 Retinopathy of prematurity. Outcome assessment was masked, as nurses were unaware of treatment allocation. HHSN275201600005C. Despite similar numbers of neonates requiring inotropic support at baseline (sildenafil 9.1% (3/31) vs MgSO4 11.8% (4/34)), results show that significantly fewer neonates were receiving inotropic agents in the sildenafil group than in the MgSO4 group (RR 0.55, 95% CI 0.36 to 0.83; RD 0.37, 95% CI 0.59 to 0.15; NNTB 3, 95% CI 2 to 8; one study, 65 participants; heterogeneity estimate not applicable; P < 0.0008) (Analysis 2.4). Yilmaz O, Two review authors separately assessed each study. Trials reported no significant differences in mortality upon comparison of the sildenafil group versus the active control group (one study, 65 participants; typical RR 0.55, 95% CI 0.05 to 5.75), or when iNO was administered to both groups (one study, 24 participants; typical RR 1.27, 95% CI 0.26 to 6.28). Overall, when compared with placebo alone, sildenafil significantly reduced mortality (Table 1). Pezeshkpour Z, Selective reporting bias. Most studies reported steady improvement in oxygenation starting from the first dose of sildenafil. Alipour MR, Uslu 2011 compared sildenafil versus active control (magnesium sulphate; MgSO4). ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT01720524","term_id":"NCT01720524"}}NCT01720524; updated 27 June 2016) reports an estimated enrolment of 64 and includes a plan for 12month and 24month safety and neurodevelopmental followup. For each included study, we described any important concerns we had about other possible sources of bias (e.g. Mortality was significantly reduced in our analyses when sildenafil alone was compared with placebo. We manually searched the reference lists of fulltext versions (RCTs and reviews) identified during the primary literature search. Schreiber MD, Khaveci H, Two participants in the control group had significantly reduced OI before the last dose and were not given the last dose (according to prespecified criteria). Investigators presented data in graphical format, and we could not abstract absolute values. This review evaluated three comparisons against sildenafil: placebo alone, active control, and placebo with iNO. Lasserson T, We followed CNRG recommendations by using the following criteria to describe percentage of heterogeneity: < 25% no heterogeneity, 25% to 49% low heterogeneity, 50% to 74% moderate heterogeneity, and 75% high heterogeneity. Review of 77 articles in full text yielded two additional studies that were eligible for inclusion (Al Omar 2016; Uslu 2011) and three studies (Baquero 2006; Herrera 2006; VargasOrigel 2010) that were included in a previous version of this review (Shah 2011). Published manuscript described 31 participants in the sildenafil group (20 randomised to receive placebo, and another 11 randomised to receive nitric oxide). High: We are very confident that the true effect lies close to that of the estimate of the effect. INTRODUCTION. Morin FC, The review authors have no conflicts of interest to declare. 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. AldanaValenzuela C, Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. Longterm effects of sildenafil use remain unknown. The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study, Journal of MaternalFetal & Neonatal Medicine. Al Rifai H, Route of administration of sildenafil (oral vs intravenous vs inhaled). PPHN = persistent pulmonary hypertension in the neonate We assessed the methods as: a. Nordic Cochrane Centre, The Cochrane Collaboration. At baseline: Mean airway pressure was lower in the sildenafil alone group than in the placebo group (MD 2.09, 95% CI 3.30 to 0.88 cm of H2O; two studies, 64 participants; I2 = 0% none). This study was classified as awaiting classification, as the review authors required clarification of the time period of measurement. Sayed 2015 performed a singlearm uncontrolled evaluation of sildenafil. Data show no differences in mortality rate between sildenafil and MgSO4 (RR 0.55, 95% CI 0.05 to 5.75; RD 0.03; 95% CI 0.13 to 0.07; one study, 65 participants; heterogeneity estimate not applicable) (Analysis 2.1). One study (Al Omar 2016) evaluated sildenafil used as adjuvant therapy with nitric oxide against placebo with nitric oxide. Shaul PW, Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator. We categorised the methods as: 5. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants. Careers, Unable to load your collection due to an error. Objectives: To provide an updated review and meta-analysis on the efficacy and safety of sildenafil for treating persistent pulmonary hypertension in neonates (PPHN). Herrera 2006 reported results at 72 hours (MD 20.98, 95% CI 14.81 to 27.15; one study, 24 participants; I2 = not applicable), showing a significant increase in PaO2 in the sildenafil group. Uslu 2011 did not include extremely preterm infants at risk for retinopathy of prematurity. Sildenafil has been used for treatment of pulmonary hypertension in adults (Kanthapillai 2004; Sastry 2004) in intravenous, oral (Ikeda 2005), and inhaled (Ichinose 2001) forms. Jones R, This type of study would require a multicentre approach. We graded the evidence as low owing to potential bias in outcome reporting/data analysis and imprecision related to a small number of participants. We roughly categorised degree of heterogeneity according to the recommendations of Higgins and coworkers (Higgins 2011). (PH), as a first line treatment choice. Evidence was downgraded due to unreported methodological features and imprecision (small sample size), 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). Ivy DD, We have presented details on risk of bias of included studies in Figure 2. Investigators reported these data in graphical format and did not provide mean and variance measures. The clinical diagnosis of pulmonary hypertension is considered when hypoxaemia is refractory to oxygen therapy or to lung recruitment strategies (partial pressure of oxygen in arterial blood (PaO2) < 55 mmHg despite fraction of inspired oxygen (FiO2) of 1.0) (Roberts 1997; Shah 2004) associated with a preductal to postductal oxygen gradient greater than 20 mmHg (WalshSukys 2000). Sildenafil for pulmonary hypertension in neonates. Kamigaki M, This situation is called persistent pulmonary hypertension of the neonate (PPHN). We used the criteria and standard methods of Cochrane and the Cochrane Neonatal Review Group (CNRG) (see the Cochrane Neonatal search strategy for specialized register). Guyatt G, We conducted a comprehensive electronic search including the Cochrane Central Register of Controlled Trials (CENTRAL 2017; Issue 3) in the Cochrane Library; MEDLINE via PubMed (1966 to 18 April 2017); Embase (1980 to 18 April 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to18 April 2017), using the following search terms: (Sildenafil[MeSH] OR sildenafil OR tadalafil OR Viagra OR Phosphodiesterase Inhibitors[MeSH] OR Phosphodiesterase V[MeSH] OR pulmonary vasodilator) AND (hypertension, pulmonary[MeSH] OR PPHN OR hypertension OR persistent fetal circulation syndrome[MeSH] OR rebound OR persistent fetal circulation syndrome), plus databasespecific limiters for randomised controlled trials (RCTs) and neonates (see Appendix 1 for full search strategies for each database). bRisk of bias due to unclear randomisation allocation and lack of clinical trial registration, aImprecise due to small sample size; only one included study, bRisk of bias due to missing data (not analysed as intent to treat), aImprecise due to very small sample size; only one included study. We assessed whether each study was free of other problems that could put it at risk of bias as: If needed, we explored the impact of the level of bias by undertaking sensitivity analyses. Outcome assessment appears to be masked, as no one was aware of treatment allocation. Before We performed planned subgroup analyses according to the criteria listed below. GA = gestational age The methodological quality of these studies ranged from low to high risk of bias. Were incomplete outcome data adequately addressed? Iacovidou N, Review authors concluded that more studies of adequate size are necessary (Kanthapillai 2004). We did not perform intentiontotreat analysis and noted that data were missing for seven neonates (five in the treatment group and two in the control group). Was allocation adequately concealed? Marsh 2004 reported severe retinopathy of prematurity following use of sildenafil in a neonate with severe pulmonary hypertension; however, another study did not report this complication (Pierce 2005). Bauer CR, Effect of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. However, additional studies are needed to compare sildenafil against existing treatment in a resourceful environment to assess its effectiveness and safety. Kanthapillai P, Investigators assessed only four out of six survivors in the sildenafil alone group at 18 months. We performed statistical analyses in accordance with recommendations of the CNRG, using RevMan 5.3 software (RevMan 2014). Sildenafil is a potent and highly selective inhibitor of PDE5 that produces pulmonary vasodilation in animal models of neonatal pulmonary hypertension, 8, 10 as well as in adults with pulmonary hypertension. Despite new advances in management of persistent pulmonary hypertension of newborn (PPHN), mortality continues to be high, ranging from 4 to 33% [1, 2]. Neonates with persistent pulmonary hypertension (PPHN) should ideally receive inhaled nitric oxide and extracorporeal membrane oxygenation. We planned to analyse clusterRCTs using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), along with an estimate of the intracluster correlation coefficient. Abman SH. We evaluated the following issues and entered the findings into the risk of bias table. Ichinose F, Outcome at 18 months of age after sildenafil therapy for refractory neonatal hypoxemia, Pediatric Academic Societies' Annual Meeting; 2005 May 1417; Washington DC, United States. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Mourani PM, Al Omar 2016 was a randomised clinical trial that evaluated sildenafil and placebo in addition to "standard care", which included iNO. At 6 to 7 hours after administration: Mean airway pressure was significantly lower in the sildenafil alone group than in the placebo group (MD 5.94, 95% CI 7.36 to 4.52 cm of H2O; two studies, 64 participants; I2 = 35% low). Penny DJ, Magnussen H. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. et al. B. Sildenafil versus no treatment, Comparison 2: sildenafil versus other pulmonary vasodilator, Subgroups: A. Sildenafil versus inhaled nitric oxide. Guy KJ, Baquero 2006 was a randomised doubleblind placebocontrolled trial. Comparison 2 Sildenafil versus active control, Outcome 3 Duration of ventilation (days). Neonatal pulmonary hypertension and persistent pulmonary hypertension of the newborn (PPHN) are terms that can be used interchangeably to describe a neonate who has cyanosis in the first few days of life in the absence of a structural congenital cardiac lesion or haemoglobinopathy ( Gersony 1984 ). Thompson JE, Oxman A, When compared with an active control (Table 2) or when used as adjuvant therapy (Table 3), sildenafil did not show improved mortality among neonates with persistent pulmonary hypertension treated with sildenafil. VargasOrigel A, The treatment team was blinded to the study arm and reported outcomes data on all randomised neonates. Previous literature reviews (Spillers 2010; Iacovidou 2012) have presented information consistent with our finding that sildenafil may be effective in PPHN when other standard treatments such as iNO are not available. Approved to treat pulmonary arterial pressure comparisons against sildenafil: placebo alone active! 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