Prakeshkumar S Shah1, Arne Ohlsson2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Department of
Paediatrics and Department of Health Policy, Management and Evaluation,
Rm 775A, University of Toronto, Toronto, Canada
2Departments of Paediatrics, Obstetrics and
Gynaecology and Health Policy, Management and Evaluation, University of
Toronto, Toronto, Canada
Citation example: Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD005494. DOI: 10.1002/14651858.CD005494.pub3.
Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A
University of Toronto
600 University Avenue
Toronto Ontario M5G 1XB
Canada
E-mail: pshah@mtsinai.on.ca
| Assessed as Up-to-date: | 30 April 2010 |
|---|---|
| Date of Search: | 31 December 2010 |
| Next Stage Expected: | 01 July 2013 |
| Protocol First Published: | Issue 4, 2005 |
| Review First Published: | Issue 3, 2007 |
| Last Citation Issue: | Issue 8, 2011 |
| Date / Event | Description |
|---|---|
| 18 April 2011 Updated |
This review was updated in April 2011. This update includes one new study. |
| 18 April 2011 New citation: conclusions changed |
Some changes were made to the conclusions. There was a significant reduction in all-cause mortality within the first 28 days of life among the 77 recruited patients. |
| Date / Event | Description |
|---|---|
| 11 September 2008 Amended |
Converted to new review format. |
| 27 April 2007 New citation: conclusions changed |
Substantive amendment |
Persistent pulmonary hypertension in neonates (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN is assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly and may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature has led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone.
To assess the efficacy and safety of sildenafil in the treatment of persistent pulmonary hypertension in neonates.
The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL databases were searched from their inception until December 2010; Clinicaltrials.gov web site, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction.
Randomised or quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route and duration of administration in neonates with PPHN, were included if the trial reported any of the pre-specified outcomes.
The methodological quality of the trials was assessed regarding how bias was minimized at study entry, during study intervention and at outcomes measurement. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. The I-squared (I2) test of heterogeneity was applied.
Three eligible trials that enrolled 77 infants were identified. The methodological quality of the studies indicated low-moderate risk of bias. All studies were performed in resource-limited settings where iNO and high frequency ventilation were not available at the time of study. There was significant reduction in mortality in the sildenafil group (typical RR 0.20, 95% CI 0.07 to 0.57; typical RD -0.38, 95% CI -0.60 to -0.16; Number needed to treat to benefit 3, 95% CI 2 to 6). Physiological parameters of oxygenation (oxygenation index, PaO2) suggested a steady improvement after the first dose of sildenafil. No clinically important side effects were identified.
Some babies develop persistent pulmonary hypertension of the neonate (PPHN), a condition where the pressure in the blood vessels that allows blood to flow to the lungs remains abnormally high. Persistent high pressure in these vessels leads to less blood flow to the lungs and therefore less oxygen reaching the blood and all organs of the body. Sildenafil may cause these vessels to relax and allow for improved blood flow and improved oxygen delivery to all organs. This treatment is especially useful in the settings where other treatment approaches are not available. However, in resourceful environment, further studies are needed to compare sildenafil with existing treatment for effect and safety.
Neonatal pulmonary hypertension or persistent pulmonary hypertension of the newborn (PPHN) are terms 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). The clinical diagnosis of pulmonary hypertension is considered when there is hypoxaemia refractory to oxygen therapy or lung recruitment strategies (PaO2 < 55 despite FiO2 of 1.0) (Roberts 1997; Shah 2004) associated with a preductal to postductal oxygen gradient greater than 20 mm Hg (Walsh-Sukys 2000). The echocardiographic diagnosis of PPHN is made by demonstrating the presence of extrapulmonary right to left 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). During cardiac catheterization, pulmonary hypertension is defined as pulmonary arterial pressure greater than 25 - 30 mm Hg (Adatia 2002). The incidence of pulmonary hypertension in newborns has been reported as approximately 2/1000 live births, with a reported mortality rate at various centres in the United States of 4 - 33% (Walsh-Sukys 2000). Pulmonary hypertension in the neonate can be primary (idiopathic) or secondary to pulmonary parenchymal disease (such as meconium aspiration syndrome, surfactant deficiency or alveolocapillary dysplasia), severe pulmonary hypoplasia (Adatia 2002; Gersony 1984), polycythaemia, hypoglycaemia, sepsis or maternal ingestion of prostaglandin inhibitors.
By virtue of its selective pulmonary vasodilator effects, inhaled nitric oxide (iNO) is considered the mainstay in the treatment of pulmonary hypertension in term or near term neonates (Barrington 2001). Approximately 30% of neonates with PPHN fail to respond to iNO (Goldman 1996). In some patients, nitric oxide therapy is associated with rebound pulmonary hypertension when therapy is discontinued due to suppression of endogenous nitric oxide production (Kinsella 2000). Other potential complications include the development of methaemoglobinaemia. In addition, iNO is a costly intervention (Subhedar 2002). The potential role of iNO in the treatment of preterm neonates with respiratory insufficiency is not clear (Finer 2001).
Advances in the understanding of the physiology of vasoactive mediators have revealed that there is a high concentration of phosphodiesterases in pulmonary vasculature (Rabe 1994). Inhibition of phosphodiesterase 5 leads to increased concentration of cyclic-AMP and GMP locally, which in turn leads to relaxation of pulmonary vascular smooth muscles (Humbert 2004). Phosphodiesterase 5 inhibitors include dipyridamole, zaprinast, pentoxifylline and sildenafil (Travadi 2003). Dipyridamole has a significant systemic vasodilatory effect (Dukarm 1998). Zaprinast and pentoxifylline have not been adequately studied. Sildenafil has been studied in neonatal animal models. In a neonatal pig model of pulmonary hypertension induced secondary to meconium aspiration (Shekerdemian 2002), marked improvement in pulmonary vascular resistance and cardiac output (without deterioration in systemic oxygenation) one hour after intravenous infusion of sildenafil was demonstrated compared to control animals. In a separate experiment, Shekerdemian observed improvement in pulmonary vascular resistance; however, it was associated with systemic vasodilation and deterioration of oxygenation when sildenafil (0.5 mg/kg) was administered along with 20 ppm of iNO (Shekerdemian 2004). The interaction of sildenafil with other selective pulmonary vasodilators warrants further studies.
Sildenafil has been used for the treatment of pulmonary hypertension in adults (Kanthapillai 2004; Sastry 2004). It has been used in intravenous, oral (Ikeda 2005) or inhaled (Ichinose 2001) form. In uncontrolled experiments in children, sildenafil was shown to reduce pulmonary vascular resistance (Abrams 2000; Carroll 2003; Erickson 2002) and improve exercise capacity. Uncontrolled studies of the use of sildenafil in neonates have reported improved pulmonary vascular resistance and survival (Erickson 2002; Kumar 2002). These reports have evoked a mixed reaction from the scientific community (Kumar 2002; Lewin 2002; Oliver 2002; Patole 2002). Marsh et al (Marsh 2004) reported severe retinopathy of prematurity following the use of sildenafil in a neonate with severe pulmonary hypertension; however, this complication was not reported in another study (Pierce 2005). Sildenafil use in adults is suspected to worsen proliferative diabetic retinopathy (Burton 2000; Behn 2001). Therefore, retinal vascular growth needs to be carefully observed, especially for preterm neonates. Sastry 2004 reported a slightly higher incidence of backache, headache, numbness of feet and hands, and constipation among adult patients who received sildenafil for primary pulmonary hypertension compared to placebo.
A systematic review of sildenafil for pulmonary hypertension in adults and children identified four eligible studies including 77 patients. The reviewers concluded that more studies of adequate size were necessary (Kanthapillai 2004). Neonates were not included in that review. In neonates, the disease is more prevalent and, in the majority of cases, has a different pathophysiology (failure of the natural decrease in pulmonary vascular resistance, as opposed to children and adults where pulmonary hypertension is either primary or secondary to various chronic illnesses such as collagen vascular disease, left heart disease, chronic obstructive pulmonary disease, interstitial diseases or chronic thromboembolic disorders). The following review systematically evaluates the use of sildenafil for the treatment of pulmonary hypertension in neonates.
To assess the efficacy and safety of sildenafil in the treatment of pulmonary hypertension in neonates.
Randomized or quasi-randomised controlled trials of sildenafil in the treatment of pulmonary hypertension in neonates. Studies of any route of administration (intravenous, inhaled or oral), any dose of sildenafil, and any duration of administration were considered. Crossover studies were not included due to the frequent resolution of the condition over a short period of time.
Both term and preterm infants (with a postnatal age of <28 days after reaching 40 weeks postmenstrual age [PMA]) with primary or secondary pulmonary hypertension were included for review. Studies were included if the diagnosis was based on clinical findings with or without echocardiographic confirmation. Patients with known structural heart disease (other than patent foramen ovale or patent ductus arteriosus) were excluded.
For all the haemodynamic parameters the change from baseline were planned to be assessed at 1, 2, 4, 6, 8, 12, 24 and 48 hours or at nearest times reported by the authors.
MEDLINE (1966 - December 2010) was searched using following terms:
Population:
Infant-Newborn (MeSH) OR Infant-premature (MeSH) OR Infant, Low Birth
Weight (MeSH) OR Infant, Very Low Birth Weight (MeSH) OR Infant, Small
for Gestational Age (MeSH) OR Infant, Premature, Disease (MeSH) OR
Infant, Newborn, Diseases (MeSH) OR newborn (text word) OR infant (text
word) OR neonate (text word)
Intervention: Sildenafil (MeSH) OR Viagra (text word) OR Phosphodiesterase Inhibitors (MeSH) OR Phosphodiesterase V (MeSH)
Comparison: Clinical trials (MeSH) OR
Controlled Clinical Trials (MeSH) OR randomized Controlled Trials (MeSH)
OR Random Allocation (MeSH) OR Multicenter studies (MeSH) OR Control
groups (MeSH) OR Evaluation studies (MeSH)
Outcome: Hypertension, pulmonary (MeSH) OR persistent fetal circulation syndrome (MeSH) OR rebound (text word)
All these four sub-headings were combined by "AND".
Other databases that were searched include: EMBASE (1980 - December 2010); CINAHL (1982 - December 2010); the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010) and the reference lists of identified trials, abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published electronically (2006 - 2010). We also searched Clinical trials.gov web site (March 31, 2011) for any ongoing studies. Reference lists of the identified articles were searched. Science citation was searched for quotations of any identified and accepted trial. No language restrictions were applied.
The following types of articles were excluded: letters, editorials/commentaries, reviews, lectures and commentaries.
The standard review methods of the Cochrane Neonatal Review Group (CNRG) were used to select studies for inclusion, extract data from the studies and assess the methodological quality of the studies.
All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review. Discrepancy regarding inclusion/exclusion of the studies was resolved by consensus.
Each review author extracted data separately using pre-designed data abstraction forms. The review authors compared results and resolved differences. One review author entered data into RevMan 5.1 and the other review author cross-checked the printout against his own data abstraction forms and errors were corrected by consensus.
If relevant articles were identified, the review authors obtained data from the authors where published data provided inadequate information for the review or where relevant data could not be abstracted.
Quality of included trials was evaluated independently by the two authors using risk of bias assessment tool from Cochrane Collaboration (Higgins 2011).
There were three potential answers to these questions - yes, can't tell, no
For the update in 2011, the following issues were evaluated and entered into the Risk of Bias Table:
For each included study, we categorized the risk of selection bias as:
For each included study, we categorized the risk of bias regarding allocation concealment as:
For each included study, we categorized the methods used to blind study personnel from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the study intervention):
For each included study, we categorized the methods used to blind outcome assessors from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the stud intervention). Blinding was assessed separately for different outcomes or classes of outcomes. We categorized the methods used with regards to detection bias as:
For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods with respect to the risk attrition bias as:
For each included study, we described how we investigated the risk of selective outcome reporting bias and what we found. We assessed the methods as:
For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.
The statistical analyses followed the recommendations of the Cochrane Neonatal Group. A weighted treatment effect was calculated using the RevMan 5.1 package. The treatment effect estimates included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. All estimates of treatment effects were reported with 95% confidence intervals (CI).
Heterogeneity tests including the I- squared test (I2) were performed to assess the appropriateness of pooling the data. The degree of heterogeneity was roughly categorized according to Higgins and co-workers (Higgins 2011) as 25% = low, 50% = moderate, and 75% = high.
Planned subgroup analyses were performed according to the criteria listed below.
Meta-analyses were performed using Review Manager software (RevMan 5.1) supplied by the Cochrane Collaboration. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model.
A priori subgroup analyses were planned based on:
Comparison 1: Sildenafil vs. control
Category 1: Type of control intervention
Subgroups: A. Sildenafil vs. placebo, B. Sildenafil vs. no treatment
Category 2: Gestational age
Subgroups 1. Preterm 2. Term
Comparison 2: Sildenafil vs. other pulmonary vasodilator
Category 1: Type of control intervention
Subgroups: A. Sildenafil vs. inhaled nitric oxide, B. Sildenafil vs. other pulmonary vasodilator
Category 2: Gestational age
Subgroups 1. Preterm 2. Term
Comparison 3: Sildenafil and other pulmonary vasodilator vs. other pulmonary vasodilator
Category 1: Type of control intervention
Subgroups:
A. Sildenafil and other pulmonary vasodilator vs. inhaled nitric oxide,
B. Sildenafil and nitric oxide vs. other pulmonary vasodilator, C.
Sildenafil and nitric oxide vs. placebo/no treatment
Category 2: Gestational age
Subgroups 1. Preterm 2. Term
In this update of our review (Shah 2007), we identified 232 citations, of which eight were duplicates, and 217 did not meet eligibility criteria for detailed screening (Figure 1). Of the remaining seven articles which were retrieved for full evaluation, three studies were eligible for inclusion (Baquero 2006; Herrera Torres 2006; Vargas-Origel 2010), three studies were eligible for exclusion (Namachivayam 2006; Steinhorn 2009; Stocker 2003) and one study which was kept in awaiting assessment status (Soliz 2009) because from the abstract presented at a scientific meeting, there was inadequate information to distinguish it as a separate study. Namachivayam 2006 was excluded because the age range of included patients was from 0.1 years (potentially > 1 month) and the majority (> 80%) of the patients had congenital heart disease. Steinhorn 2009 was an open label dose escalating study. Stocker 2003 was a study of infants following cardiac surgery. Our previous report included the study of Herrea et al (Herrera Torres 2006) in abstract form, which in the current version of our review is included as full report published in Spanish. For the Baquero study (Baquero 2006), data were requested regarding haemodynamic measurements before and during the intervention period, incidence of rebound hypoxaemia, incidence of intraventricular haemorrhage, length of stay and number of infants needing ECMO. Data on FiO2 before the start of therapy, mean arterial BP before the start of therapy and at 36 hours after therapy in survivors and data on number of infants with grade 3 or 4 intraventricular haemorrhage were provided by the authors. Authors reported the follow-up data from four infants (one neonatal death, one died at five months of age and one lost to follow-up) in an abstract form (Baquero 2006). Vargas-Origel 2010 published data from a total of 53 patients. They had enrolled 20 patients in the placebo group and 20 in the sildenafil group initially. After enrolment of 40 patients, their institutional ethics board precluded use of placebo and they thereafter randomised patients to sildenafil vs nitric oxide. The data in the published manuscript included 33 patients in the sildenafil and 20 in the placebo group. We contacted the authors and requested data for only the comparison of the first 40 patients (20 in the sildenafil and 20 in the placebo group). For further details see the table Characteristics of included studies.
Setting: A single centre pilot randomised double blind controlled trial in a regional NICU in Columbia. In this unit, iNO, high frequency ventilation and ECMO were not available.
Objective: To evaluate the feasibility of using oral sildenafil and to evaluate the effect of oral sildenafil on oxygenation in term and near term infants with PPHN.
Population: Term and near term (> 35.5 weeks gestation) infants with severe hypoxaemia (need for mechanical ventilation with OI > 40) and echocardiographically confirmed PPHN (presence of right to left shunt and estimated pulmonary arterial pressure > 40 mm Hg) were included.
Intervention: Patients received either oral sildenafil or placebo (diluent). The solution for sildenafil was prepared by crushing a 50 mg tablet of sildenafil in Orabase (diluent) to make a concentration of 2 mg/ml. The protocol for dosing was (1) first dose of 1 mg/kg (0.5 ml/kg) within 30 minutes of randomisation, (2) dosing every six hours (3) dose could be doubled (1 ml/kg) if the OI did not improve and blood pressure remained stable and (4) the treatment was discontinued if OI was < 20 or patient has received eight doses. Other aspects of the management of infant's care remained the same in both arms of study.
Outcomes: Changes in the oxygenation indices were reported. Mortality, change in PaO2 and mean arterial blood pressure were reported. The OI was not reported for two neonates who improved to meet the exit criteria for the study.
Recruitment: A total of 22 patients met the eligibility criteria. Out of 22 patients, two patients died (before enrolment in the study), four parents refused consent, and three parents were not approached for consent. A total of 13 patients (six in the placebo group and seven in the treatment group) were enrolled in the study. The study was terminated by the institutional review board due to the death of six patients enrolled in the study.
Follow up: Data on four survivors in the sildenafil group who were assessed at 18 months of age have been reported in abstract form.
Setting: A single centre randomised controlled study in Mexico. The centre did not have facility for administering iNO.
Objective: To compare the efficacy of oral sildenafil therapy and conventional therapy in term neonates with PPHN in a centre without iNO.
Population: Term neonates with diagnosis of PPHN and OI > 25.
Intervention: Patients were randomised to sildenafil (n = 13) 2 mg/kg via orogastric tube or distilled water (n = 11). The total duration of therapy was 72 hours. Sildenafil was administered at 2 mg/kg/dose via orogastric tube every six hourly.
Outcomes: Mortality, changes in the OI, PaO2, mean arterial blood pressure, PaCO2 and intubation days were compared.
Setting: A single centre randomised controlled trial in Mexico. In this unit, at the start of the trial iNO was not available. Inhaled nitric oxide was available during the study and the ethics board precluded the use of placebo after randomisation of 40 neonates
Objective: To evaluate the efficacy of oral sildenafil in newborns with PPHN.
Population: Term and post-term infants with PPHN diagnosed within first 48 hours who had OI > 20.
Intervention: Patients received either oral sildenafil or placebo (normal saline). The solution for sildenafil was prepared by crushing a 50 mg tablet of sildenafil in 20 ml of water. The protocol for dosing was 3 mg/kg/dose every six hours via nasogastric tube. The treatment was continued until OI was < 10. Other aspects of the management of infant's care remained the same in both arms of study.
Outcomes: Data on OI, mean airway pressure, mean arterial pressure, PaO2 and mortality on the first 40 patients randomised to sildenafil (20) and placebo (20) were provided by the authors.
Baquero 2006 was a randomised double-blind placebo controlled trial. Randomization was performed using pre-sealed envelopes. Pharmacy prepared the solution in identical containers and bedside clinicians were unaware of group assignment. Outcome assessment appears to be masked as clinicians were unaware of treatment allocation. The study was terminated early due to meeting pre-set criteria (which included hypotension, gastric intolerance or bleeding, renal failure, or death in six infants). Pre-set criteria for the discontinuation of dosing included either an OI of < 20 or administration of a maximum of eight doses. Data were compared using analysis of variance for repeated comparison of OI, blood pressure and oxygen saturation.
Herrera Torres 2006 was a randomised placebo controlled trial. Randomization method was not reported. The allocation was described as blinded. Data were compared using descriptive statistics and Student t test.
Vargas-Origel 2010 was a randomised double-blind placebo controlled trial. Randomization was generated using random number table by two nurses who were not involved in the study (information provided by the author). Pharmacy prepared the solution and bedside clinicians were unaware of group assignment. Outcome assessment appears to be masked as nurses were unaware of treatment allocation.
Graphical representation of risk of biases is shown in figures (Figure 2; Figure 3).
All three studies have now reported data on mortality. There was significant reduction in the mortality rate in sildenafil group compared to placebo group (typical RR 0.20, 95% CI 0.07 to 0.57; typical RD -0.38, 95% CI -0.60 to -0.16; Number needed to treat to benefit 3, 95% CI 2 to 6; three studies, 77 patients; I2= 39%). (Analysis 1.4)
This outcome was not reported in any of the studies.
This outcome was not reported in any of the studies.
Baquero 2006 reported these data for individual patients in a table format. These data were used to calculate OI from this study.
Herrera Torres 2006 reported that OI improved starting within the first hour of administration. The data were presented in graphical format and absolute values could not be abstracted.
No evidence of rebound hypoxaemia was noted in two patients in whom sildenafil was discontinued because of OI<20.
This outcome was not reported in any of the studies.
This outcome was not reported in any of the studies.
There was no additional mortality reported in Baquero 2006. Herrea et al did not report on this outcome (Herrera Torres 2006).
This outcome was not reported in any of the studies.
None of the studies enrolled preterm infants at risk of retinopathy of prematurity.
Baquero 2006 reported no grade 3 or 4 intraventricular haemorrhage in any of the infants in either group.
Data on neurodevelopmental follow-up was reported in an abstract form for Baquero 2006 study. Only 4 patients in the sildenafil group out of six survivors were assessed at 18 months. One patient in the sildenafil group died in the neonatal period, one died at five months of age and one was lost to follow-up. All four patients had normal neurological examination (Gessel scale of 100, 100, 100 and 111 points). They all had normal MRI, evoked potential and EEG. Their growth parameters (weight, height and head circumference) were within normal limits.
There have been case reports of the efficacy of sildenafil in the treatment of persistent pulmonary hypertension in neonates. Three very small randomised controlled trials have been performed to date which enrolled a total of 77 patients. These trials have been conducted in resource-limited settings. For all three trials, the intensive care units did not have facilities for providing high frequency ventilation or nitric oxide, therapies that have shown promise in the treatment of PPHN. The results of these three studies are interesting. Baquero (Baquero 2006) enrolled term neonates at a very high risk of mortality. The study was halted prematurely due to death in six enrolled patients. Decoding showed that 5 of the deaths occurred in the placebo group and there was a statistically significant reduction in oxygenation indices both at 24 hours and at the end of the treatment. The reduction in the absolute values of OI was evident from the first dose. Herrea (Herrera Torres 2006) enrolled moderately sick patients (OI > 25), and reported improvement in oxygenation from the first dose. Vargas-Origel 2010 enrolled 40 patients and reported improvement in mortality and physiological parameters starting from the first dose. However, it must be noted that these studies have several limitations. The number of enrolled patients is extremely small and there is inadequate reporting of various important outcomes. Having said that, it must be noted that mortality was significantly reduced in this meta-analyses (54% in control group and 20% in sildenafil group). This is clinically very significant and tempting for units in resource limited setting. However, we must realize that overall numbers are small and long-term effects are unknown.
These three studies and several case reports, including recent reports from resource limited settings (Juliana 2005; Simiyu 2006; Shivanna 2009) and resourceful settings (Steinhorn 2009) justify a call for a larger multicenter randomised controlled study. Studies of this kind could be challenging. In addition to requiring a multicenter collaboration, the studies would require that sildenafil be compared to other established therapies such as inhaled nitric oxide and/or optimal ventilatory strategy such as high frequency ventilation for PPHN. Resource limited settings could provide a platform for comparison of sildenafil to placebo and more developed countries could provide settings for comparison with other management settings. Patients at high risk of mortality or need for ECMO due to persistent hypoxaemia should be enrolled (OI > 25). Approximate rates for mortality and/or need for ECMO rates for these patients approach 50%. A clinically significant effect size would be a 10 - 20% absolute risk reduction in the rate of death and/or need for ECMO and with type 1 error of 5% and power of 80%. Required sample size for such a study would be in the range of approximately 100 to 400 patients. A multicenter approach would be required for this type of study. In resource limited settings, the mortality is higher and the required sample size could be lower. It would be very crucial to include long-term neurodevelopmental follow up aspect in any such studies as none of the studies have sufficient information for long-term effects.
Further issues to address include clear documentation of short and long-term benefits and side effects. The optimum dose, optimum route of administration, incidence of rebound pulmonary hypertension and effectiveness in the rebound pulmonary hypertension remain unanswered. Sildenafil may not be as effective in certain causes of PPHN such as sepsis (where overproduction of nitric oxide leading to systemic vasodilation may the major mechanism) and may be effective in other causes such as chronic lung disease (Mesubi 2009; Mourani 2009). Concerns regarding retinal vascular growth (Kehat 2010) and lack of convincing data in term infants may preclude the use of sildenafil in preterm infants.
Further research is needed to determine the optimum dose, safety, and route of administration. If found effective in randomised controlled trials for short term improvements, long-term data will be needed to ensure safety.
Sildenafil has a potential for improvement in physiological parameters in neonates with pulmonary hypertension. However, safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established in a large randomised trial and its use should be restricted within the context of randomised controlled trials.
Future studies are needed to evaluate safety and efficacy of sildenafil in the treatment of PPHN. The studies should be conducted both in resource limited as well as resourceful settings as different questions could be answered such as effectiveness as stand alone therapy and as an adjunct therapy. These studies will require a multicenter undertaking. Long-term neurodevelopmental follow up should be included.
We would like to thank Dr Augusta Sola for providing data on their study. We would like to acknowledge help of Dr Cecilia Herbozo for translation of Herrera Torres 2006 study from Spanish language.
A Ohlsson
| Methods | Randomised controlled trial |
|---|---|
| Participants | 13
Term neonates with persistent hypoxaemia despite mechanical ventilation
(OI >40) and echocardiographic diagnosis of PPHN were enrolled. |
| Interventions | Group 1: |
| Outcomes | Mortality |
| Notes | OI
was determined for all 7 patents in sildenafil group for baseline and
for the first 6 doses. Oxygenation index was reported only for 4
patients for the 7th dose (2 met the pre-set exit criteria for the study
and 1 patient died). |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | No information on sequence generation |
| Allocation concealment (selection bias) | Unclear risk | Randomization was by simple allocation of pre-sealed numbers. No information if the envelopes were opaque and sequentially numbered |
| Blinding (performance bias and detection bias) | Low risk | It was a blinded placebo controlled trial |
| Incomplete outcome data (attrition bias) | Low risk | Data on all enrolled patients are reported |
| Selective reporting (reporting bias) | Unclear risk | Protocol was not available to assess selective reporting |
| Other bias | Unclear risk | Small sample size and study was terminated prematurely |
| Methods | Randomised controlled trial |
|---|---|
| Participants | 24 term neonates with PPHN and OI > 25 |
| Interventions | Group 1: Sidenafil 2mg/kg via orogastric tube (duration of administration -72 hours) |
| Outcomes | Changes in OI, PaCO2, DaAO2, PaO2 Pneumothorax Death |
| Notes |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | Sequence generation not reported |
| Allocation concealment (selection bias) | Unclear risk | Reported as blinded study but no information provided |
| Blinding (performance bias and detection bias) | Low risk | Low risk for performance bias - placebo controlled . Unclear for detection bias - not reported whether assessors were blinded or not. |
| Incomplete outcome data (attrition bias) | High risk | Newborns whose data were incomplete or who were transferred to other hospitals were excluded |
| Selective reporting (reporting bias) | Unclear risk | The study was not registered in a trials registry and the study protocol was not available to us |
| Other bias | Low risk | Appears free of other bias |
| Methods | Randomised controlled trial |
|---|---|
| Participants | 40 term neonates with PPHN and OI > 20 Group 1: n=20 |
| Interventions | Group 1: Sidenafil 2mg/kg via orogastric tube 3 mg/kg/dose until OI <10 |
| Outcomes | Changes in OI, PaO2, DaAO2, PaO2, mean airway pressure Death |
| Notes | The published manuscript described 31 patients in the sildenafil group (20 randomised to placebo and another 11 who were randomised against nitric oxide). We contacted the authors and retrieved data for the first 40 infants (20 in each group). |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Unclear risk | Sequence generation not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) | Low risk | Nurses and clinicians were unaware of allocation (information provided by author) |
| Incomplete outcome data (attrition bias) | Unclear risk | Can not assess |
| Selective reporting (reporting bias) | High risk | The published report had combined data on 51 patients and it is not reported when the change in randomisation occurred. |
| Other bias | Unclear risk | Because published data include subsequent patients, it is difficult to assess other bias |
g = grams
OI= Oxygenation index
PPHN= Persistent Pulmonary Hypertension of the Newborn
| Reason for exclusion | Included patients whose age ranged from 0.1 years onwards |
|---|
| Reason for exclusion | Open-label single arm study, no randomisation |
|---|
| Reason for exclusion | Only infants after cardiac surgery were included. |
|---|
| Methods | Randomised clinical trial |
|---|---|
| Participants | 49 term neonates with PPHN and OI >25 were |
| Interventions | Randomised to placebo (n=20) and sildenafil (n=29) |
| Outcomes | OI, mean blood pressure and mean airway pressure |
| Notes | Difficult to differentiate from included studies as some authors overlap |
Sildenafil compared with placebo or other treatment for pulmonary hypertension of newborn | ||||||
Patient or population: Neonates with pulmonary hypertension Settings: Neonatal Intensive Care Unit Intervention:Sildenafil Comparison: Placebo or other treatment | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
Assumed risk | Corresponding risk | |||||
Placebo | Sildenafil | |||||
All-cause mortality |
High risk population |
RR 0.20, 95% CI 0.07, 0.57 | 77 (3) | ⊕⊕⊕⊝ | ||
432 per 1000 | 75 per 1000 | |||||
Oxygenation index (absolute values) after 24 hours of treatment |
The mean oxygenation index ranged across control groups from | The mean oxygenation index in the intervention groups was | MD -19 (95% CI -25, -14) | 76 (3) | ⊕⊕⊕⊝ | |
Change in oxygenation index - After 24 hours of treatment |
The increase in oxygenation index was by 8.5 after 24 hours of treatment | The decrease in oxygenation index was by 30 after 36 hours of treatment | MD (-39, 95% CI -57, -21) | 1 (8) | ⊕⊕⊝⊝⊝ | |
Changes in PaO2 after 24 hours of treatment |
The mean PaO2 ranged across control groups from | The mean PaO2 in the intervention groups was | MD 16 (95% CI 7, 24 mm of Hg) | 64 (2) | ⊕⊕⊕⊝ | |
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
GRADE Working Group grades of evidence | ||||||
Baquero H, Neira F, Venegas ME, Sola A, Soliz A. Outcome at 18 months of age after sildenafil therapy for refractory neonatal hypoxemia. E-PAS 2005;57:2119.
* 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;117:1077-83.
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;174:1042-7.
None noted.
Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84:E4.
Adatia I. Recent advances in pulmonary vascular disease. Current Opinion in Pediatrics 2002;14:292-7.
Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000509. DOI: 10.1002/14651858.CD000509.pub3.
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;42:523-7.
Burton AJ, Reynolds A, O'Neill D. Sildenafil (Viagra) a cause of proliferative diabetic retinopathy? Eye 2000;14:785-6. [MEDLINE: 16]
Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Archives of Disease of Childhood 2003;88:827-8. [MEDLINE: 19]
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;44:831-7.
Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000399. DOI: 10.1002/14651858.CD000399.pub2.
Gersony WM. Neonatal pulmonary hypertension: pathophysiology, classification, and etiology. Clinics in Perinatology 1984;11:517-24.
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;98:706-13.
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. New England Journal of Medicine 2004;351:1425-36.
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;29:1000-5.
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;45:286-9.
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;164:626-9.
Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary hypertension. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD003562. DOI: 10.1002/14651858.CD003562.pub2.
Kehat R, Bonsall DJ, North R, Connors B. Ocular findings of oral sildenafil use in term and near-term neonates. Journal of American Association of Pediatric Ophthalmology and Strabismus 2010;14:159-62.
Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Seminars in Perinatology 2000;24:387-95.
Kumar S. Indian doctor in protest after using Viagra to save "blue babies". British Medical Journal 2002;325:181. [MEDLINE: 5]
Lewin S. Viagra neonatal experimentation - the Pandora's box! Indian Pediatrics 2002;39:894-5.
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;88:306-7. [MEDLINE: 2]
Mesubi OO, Ashwath R, Mhanna MJ. Oral sildenafil in premature infants with pulmonary arterial hypertension secondary to bronchopulmonary dysplasia. In: E-PAS2009:615. 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;154:379-84.
Oliver J, Webb DJ. Sildenafil for "blue babies". Such unlicensed drug use might be justified as last resort. British Medical Journal 2002;325:1174.
Patole S, Travadi J. Sildenafil for "blue babies". Ethics, conscience, and science have to be balanced against limited resources. British Medical Journal 2002;325:1174.
Pierce CM, Petros AJ, Fielder AR. No evidence for severe retinopathy of prematurity following sildenafil. British Journal of Ophthalmology 2005;89:250.
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:L536-43.
Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW, Rimar S et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. New England Journal of Medicine 1997;336:605-10.
Sastry BKS, Narasimhan C, Reddy K, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension. Journal of the American College of Cardiology 2004;43:1149-53.
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;32:168-70.
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;165:1098-102.
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;55:413-8.
Shivanna B, Eichenwald EC, Stark AR. Sildenafil use in the newborn intensive care units is associated with improvement in pulmonary hypertension. In: E-PAS2009:621. 2009.
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;83:337-40.
Subhedar NV, Jauhari P, Natarajan R. Cost of inhaled nitric oxide therapy in neonates. Lancet 2002;359:1781-2.
Travadi JN, Patole SK. Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Pediatric Pulmonology 2003;36:529-35.
For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Pulmonary arterial pressure | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Baseline | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 1.10 [-7.68, 9.88] |
| 1.2 PaO2 in mm of Hg (absolute values) | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 At baseline | 2 | 64 | Mean Difference (IV, Fixed, 95% CI) | 8.06 [1.58, 14.54] |
| 1.2.2 After first dose | 2 | 64 | Mean Difference (IV, Fixed, 95% CI) | 11.09 [1.65, 20.52] |
| 1.2.3 After 6-7 hours | 2 | 63 | Mean Difference (IV, Fixed, 95% CI) | 14.28 [5.18, 23.37] |
| 1.2.4 After 24-25 hours | 2 | 57 | Mean Difference (IV, Fixed, 95% CI) | 15.28 [6.44, 24.12] |
| 1.2.5 After 72 hours or at the end of treatment | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | 20.98 [14.81, 27.15] |
| 1.3 Mean arterial blood pressure in mm of Hg | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Before initiation of therapy | 2 | 53 | Mean Difference (IV, Fixed, 95% CI) | 5.65 [2.69, 8.61] |
| 1.3.2 At the end of therapy | 2 | 40 | Mean Difference (IV, Fixed, 95% CI) | 22.70 [1.23, 44.17] |
| 1.4 All-cause mortality | 3 | 77 | Risk Difference (M-H, Random, 95% CI) | -0.38 [-0.60, -0.16] |
| 1.5 Oxygenation index (absolute values) | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 At baseline | 3 | 77 | Mean Difference (IV, Fixed, 95% CI) | -0.74 [-8.11, 6.64] |
| 1.5.2 After first dose | 3 | 77 | Mean Difference (IV, Fixed, 95% CI) | -12.53 [-18.60, -6.47] |
| 1.5.3 After 6-7 hours of treatment | 2 | 63 | Mean Difference (IV, Fixed, 95% CI) | -20.04 [-26.11, -13.97] |
| 1.5.4 After 24-25 hours of treatment | 3 | 69 | Mean Difference (IV, Fixed, 95% CI) | -19.15 [-24.52, -13.77] |
| 1.5.5 After 30 hours of treatment | 1 | 11 | Mean Difference (IV, Fixed, 95% CI) | -45.46 [-61.87, -29.05] |
| 1.5.6 After 36 hours of treatment | 1 | 8 | Mean Difference (IV, Fixed, 95% CI) | -31.75 [-45.74, -17.76] |
| 1.5.7 After 72 hours of treatment or end of study | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | -19.47 [-23.42, -15.52] |
| 1.6 Change in oxygenation index | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 After first dose | 1 | 13 | Mean Difference (IV, Fixed, 95% CI) | -17.14 [-27.75, -6.53] |
| 1.6.2 After 24 hours of treatment | 1 | 12 | Mean Difference (IV, Fixed, 95% CI) | -38.79 [-56.97, -20.61] |
| 1.6.3 After 30 hours of treatment | 1 | 11 | Mean Difference (IV, Fixed, 95% CI) | -33.08 [-50.85, -15.31] |
| 1.6.4 After 36 hours of treatment | 1 | 8 | Mean Difference (IV, Fixed, 95% CI) | -44.75 [-65.55, -23.95] |
| 1.7 Mean airway pressure | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.7.1 Baseline | 2 | 64 | Mean Difference (IV, Fixed, 95% CI) | -2.09 [-3.30, -0.88] |
| 1.7.2 At 6-7 hours | 2 | 63 | Mean Difference (IV, Fixed, 95% CI) | -5.94 [-7.36, -4.52] |
| 1.7.3 At 24-25 hours | 2 | 57 | Mean Difference (IV, Fixed, 95% CI) | -6.64 [-8.49, -4.80] |
| 1.7.4 At 72 hours | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | -8.58 [-10.37, -6.79] |
| 1.8 A-a DO2 | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.8.1 Baseline | 2 | 64 | Mean Difference (IV, Fixed, 95% CI) | 0.99 [-11.54, 13.51] |
| 1.8.2 At 6-7 hours of age | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [-27.72, 27.74] |
| 1.8.3 At 24-25 hours of age | 2 | 57 | Mean Difference (IV, Fixed, 95% CI) | 1.59 [-18.98, 22.16] |
| 1.8.4 At 72 hours | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | -18.34 [-26.59, -10.09] |
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 1 summary).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (Figure 2 summary).
