A significant reduction in allcause mortality occurred within the first 28 days of life among the 77 recruited patients, We converted this review to new review format, 2.5 After 72 hours or at the end of treatment, 5.7 After 72 hours or at the end of treatment, 7.4 At 72 hours or at the end of treatment, 8.4 At 72 hours or at the end of treatment, 24 neonates born at 34 weeks or later with PPHN and OI > 20, iNO starting dose 20 ppm, weaning 2% to 4% every hour, 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), Random sequence generation (selection bias), Random sequence generation (information obtained from author Salama), Randomisation by sealed envelope competed by pharmacy, Blinding of participants and personnel (performance bias), Treating physicians and nurses were unaware of treatment allocation, Blinding of outcome assessment (detection bias), Respiratory therapists were unaware of treatment allocation, Data are reported on all 24 randomised neonates, 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: 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, OI was determined for all 7 participants in sildenafil group for baseline and for first 6 doses. We performed metaanalyses using Review Manager software (RevMan 2014) supplied by the Cochrane Collaboration. VargasOrigel 2010 was a randomised doubleblind placebocontrolled trial. After administration of first dose: Results show a statistically significant reduction in OI two hours after administration of the first dose of sildenafil alone compared with placebo (MD 17.14, 95% CI 27.75 to 6.53; one study, 13 participants; heterogeneity estimates not applicable). SpO2 = peripheral capillary oxygen saturation Most studies reported steady improvement in oxygenation starting from the first dose of sildenafil. For each trial, we sought information regarding the method of randomisation, and blinding and reporting of all outcomes of all infants enrolled in the trial. Neira F, B. Sildenafil versus no treatment, Comparison 2: sildenafil versus other pulmonary vasodilator, Subgroups: A. Sildenafil versus inhaled nitric oxide. Advances in our understanding of the physiology of vasoactive mediators have revealed a high concentration of phosphodiesterases in the pulmonary vasculature (Rabe 1994). Approximately 30% of neonates with PPHN fail to respond to iNO (Goldman 1996). Oxygenation index was reported for only 4 participants for the seventh dose (2 met the preset exit criteria for the study, and 1 died), No information on sequence generation was reported, Randomisation was by simple allocation of presealed numbers. Iacovidou N, After performing a revised literature search, we made a post hoc modification. Bunahia M, Evidence was downgraded due to imprecision . See Appendix 2 for a detailed description of risk of bias for each domain. The published manuscript provides data on 33 participants in the sildenafil group and 20 in the placebo group. Comparison 2 Sildenafil versus active control, Outcome 2 Time to adequate response (days). Comert S, et al. We included randomised and quasirandomised controlled trials of sildenafil for treatment of pulmonary hypertension in neonates. 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. Butt WW, 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. 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). Respiratory parameters (oxygenation index (OI) and partial pressure of oxygen in arterial blood (PaO2)) showed significant improvement in the sildenafil group when compared with the placebo group. VargasOrigel A, Data show no significant differences in duration of ventilation among neonates treated with sildenafil or placebo given adjuvant to iNO therapy (MD 1.26, 95% CI 1.32 to 3.84; one study, 24 participants; heterogeneity estimate not applicable) (Analysis 3.4). Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Blinding of outcome assessment (detection bias). Venegas ME, We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants. We acknowledge the valuable contributions made by Jennifer Spano and Collen Ovelman from the CNRG, who performed the literature searches. We reported all estimates of treatment effects with 95% confidence intervals (CIs). Fanos V, Primary outcome measures (at day 14 or until discharge): Pfizer CT.gov call centre: 18007181021, Includes a longterm followup investigation of developmental progress at 12 and 24 months. Comparison 1 Sildenafil versus placebo, Outcome 1 Pulmonary arterial pressure. Optimum dose, optimum route of administration, incidence of rebound pulmonary hypertension, and effectiveness in reducing rebound pulmonary hypertension remain unknown. Cochrane Handbook for Systematic Reviews of Interventions. Mean length of stay in hospital was 17.81 days. Three review authors (LEK, AO, PSS) used the Cochrane 'Risk of bias' tool (Higgins 2011) to independently assess risk of bias (low, high, or unclear) of all included trials for the following domains. Tasker RC, Version 5.1.0 [updated March 2011]. Review authors compared results and resolved differences. Case reports have described the efficacy of sildenafil for treatment of PPHN in neonates. At baseline: Aa DO2 was not significantly different (MD 0.99, 95% CI 11.54 to 13.51; two studies, 64 participants; I2 = 0% none). Fineman JR, Sildenafil has been studied in neonatal animal models. 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). Ethics, conscience, and science have to be balanced against limited resources, No evidence for severe retinopathy of prematurity following sildenafil. Bauer CR, An additional author (LEK) was added to this review team. This review evaluated three comparisons against sildenafil: placebo alone, active control, and placebo with iNO. As this review includes no published prospective randomised clinical trials of iloprost, we cannot confirm or disagree with these findings. A medication called sildenafil may cause lung blood vessels to relax, allowing improved blood flow and improved delivery of oxygen to all organs. Investigators reported these data in graphical format and did not provide mean and variance measures. Namachivayam P, All three studies that compared sildenafil versus placebo reported that intensive care units did not have facilities for providing highfrequency ventilation or nitric oxide therapies that have shown promise in the treatment of persistent pulmonary hypertension in neonates (PPHN). We did not apply language restrictions. We roughly categorised degree of heterogeneity according to the recommendations of Higgins and coworkers (Higgins 2011). Only one study included in this analysis (Al Omar 2016) evaluated use of an inotropic agent. Xanthos T. The use of sildenafil in the treatment of persistent pulmonary hypertension of the newborn: a review of the literature. MAS = meconium aspiration syndrome Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are not available. Was the study apparently free of other problems that could put it at high risk of bias? 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). For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. Study authors described allocation as blinded. An independent researcher prepared a computergenerated randomisation table and concealed allocation. We categorised the methods as: a. Penny DJ, Sildenafil and another pulmonary vasodilator versus another pulmonary vasodilator or placebo. We added this information to the Characteristics of included studies table. Treatment effect estimates included typical risk ratio (RR), typical risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB), or number needed to treat for an additional harmful outcome (NNTH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. whether a potential source of bias was related to the specific study design, whether the trial was stopped early owing to some datadependent process). Researchers reported these data in graphical format and did not provide mean and variance measures. Despite new advances in management of persistent pulmonary hypertension of newborn (PPHN), mortality continues to be high, ranging from 4 to 33% [1, 2]. Inhibition of phosphodiesterase5 leads to increased concentrations of cyclic adenosine monophosphate (AMP) and guanosine monophosphate (GMP) locally, which in turn leads to relaxation of pulmonary vascular smooth muscles (Humbert 2004). Physiological parameters of oxygenation (oxygenation index, partial pressure of oxygen in arterial blood (PaO2)) suggested steady improvement after the first dose of sildenafil. Sildenafil in management of persistent pulmonary hypertension of the newborn: report of two cases, PPHN: is sildenafil the new nitric? If needed, we planned to explore the impact of the level of bias by undertaking sensitivity analyses. 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). Sastry 2004 reported a slightly higher incidence of backache, headache, numbness of feet and hands, and constipation among adults who received sildenafil versus placebo for primary pulmonary hypertension. We excluded the following types of articles: letters, editorials/commentaries, reviews, lectures, and commentaries. Comparison 2 Sildenafil versus active control, Outcome 1 Allcause mortality. New citation required but conclusions have not changed, We added 2 new studies to this update and made no changes to the conclusions, New citation required and conclusions have changed, We made some changes to the conclusions. Soto R, Korones SB, They did not report changes in PaO2 or FiO2, cardiac output, and mean arterial blood pressure. {"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"}}. Lookzadeh MH, The other two studies (Herrera 2006; VargasOrigel 2010) reported that PaO2 at baseline was higher in the sildenafil group than in the placebo group (MD 8.06 mmHg, 95% CI 1.58 to 14.54 mmHg; two studies, 64 participants; I2 = 43% low). Differences in PaO2 increased over time during the first 24 hours. Blinding of participants and personnel (checking for possible performance bias). Anderson CC. Cooper SM, We have presented details on risk of bias of included studies in Figure 2. We categorised the methods as: 6. We used the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality (to meet the validity criteria) of trials. SD = standard deviation Baquero 2006 reported no grade 3 or 4 intraventricular haemorrhage in any of the infants in either group. Stocker C, 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). After administration of intervention for 36 hours (completion of therapy): Data show a statistically significant reduction in OI after administration of seven doses of sildenafil alone compared with placebo (MD 44.75, 95% CI 65.55 to 23.95; one study, eight participants; heterogeneity estimates not applicable). Overall, these studies were at low to high risk of bias, which we have summarised in Figure 3. Bolat F, Aa DO2 = alveolararterial oxygen difference Broek J, Although . Sildenafil may not be as effective in PPHN resulting from causes such as sepsis (where overproduction of nitric oxide leading to systemic vasodilation may be the major mechanism) but may be effective when PPHN has other causes such as chronic lung disease (Mesubi 2009; Mourani 2009). 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. Reyes J, Soliz A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Comparison 1 Sildenafil versus placebo, Outcome 5 Oxygenation index (absolute values). AldanaValenzuela C, Paediatr Respir Rev. Schnemann H, This study highlights the benefit of both routes of administration of sildenafil for . Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment? Itoh N, As a library, NLM provides access to scientific literature. Viagra neonatal experimentation the Pandora's box! Mourani PM, 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). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasirandomised trials. Compared with placebo, sildenafil alone was associated with a significant reduction in mortality among neonates with PPHN. Barfield CP, We would like to acknowledge the help of Dr. Cecilia Herbozo for translation of the Herrera 2006 study from Spanish. Sontag MK, Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Tyson JE, A review of the literature, Cost of inhaled nitric oxide therapy in neonates, Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Study authors reported changes in mean PAP in graphical format and did not provide mean and variance measures for metaanalysis. We included randomised and quasirandomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route, and duration of administration, in neonates with pulmonary hypertension, if investigators reported any of the prespecified outcomes. We identified {"type":"clinical-trial","attrs":{"text":"NCT01757782","term_id":"NCT01757782"}}NCT01757782 and {"type":"clinical-trial","attrs":{"text":"NCT01373749","term_id":"NCT01373749"}}NCT01373749 through ClinicalTrials.Gov and placed these studies in the awaiting status category, as published results were not yet available. 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). Objectives: To provide an updated review and meta-analysis on the efficacy and safety of sildenafil for treating persistent pulmonary hypertension in neonates (PPHN). We placed Alipour 2017 in the awaiting further information classification, as review authors did not present clear details of when outcome measures were assessed. Hromi J, For some patients, nitric oxide therapy is associated with rebound pulmonary hypertension when therapy is discontinued, as the result of suppression of endogenous nitric oxide production (Kinsella 2000). Bethesda, MD 20894, Web Policies Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Oral sildenafil was administered easily and tolerated as well as placebo and improved OI in infants with severe PPHN, which suggests that oral sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial. Studies that compared sildenafil against another medication or that used another treatment with sildenafil described no significant reduction in the number of deaths. We excluded a total of six studies (Kahveci 2014; Knig 2014; Namachivayam 2006; Sayed 2015; Steinhorn 2009; Stocker 2003), we kept four studies ({"type":"clinical-trial","attrs":{"text":"NCT01757782","term_id":"NCT01757782"}}NCT01757782; {"type":"clinical-trial","attrs":{"text":"NCT01373749","term_id":"NCT01373749"}}NCT01373749; Soliz 2009; Alipour 2017) in awaiting assessment status, and we identified one ongoing study ({"type":"clinical-trial","attrs":{"text":"NCT01720524","term_id":"NCT01720524"}}NCT01720524). Blinding of participants and personnel (performance bias). Pulmonary hypertension (PH), a condition characterized by elevated pulmonary artery pressure (PAP), is usually associated with underlying cardiac or lung disease in children. 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