Sildenafil for pulmonary hypertension in neonates

Shah PS, Ohlsson A

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 23/05/2007
Date of last substantive update: 27/04/2007
Date of last minor update: / /
Date next stage expected 27/04/2009
Protocol first published: Issue 4, 2005
Review first published: Issue 3, 2007

Contact reviewer

Dr Prakeshkumar S Shah
Staff Neonatologist, Mount Sinai Hospital
Department of Paediatrics and Department of Health Policy, Management and Evaluation
University of Toronto
Rm 775A
600 University Avenue
Toronto
Ontario CANADA
M5G 1XB
Telephone 1: +1 416 586 4761
Telephone 2: +1 416 334 6661
Facsimile: +1 416 586 8745
E-mail: pshah@mtsinai.on.ca

Contribution of reviewers

P Shah
Protocol development
Protocol editing
Identification of trials
Writing the review
Editing the review
Collecting and entering data in Revman
Revision of review

A Ohlsson
Protocol editing
Review editing
Checking the search for trials
Identification of studies
Checking the data in Revman

Internal sources of support

Department of Paediatrics, Mount Sinai Hospital, Toronto, CANADA

External sources of support

None

What's new

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Some babies develop persistent pulmonary hypertension of the neonate (PPHN), a condition where the pressure in the blood vessel 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. However, this therapy is not adequately studied in infants and more research is needed.

Abstract

Background

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.

Objectives

To assess the efficacy and safety of Sildenafil in the treatment of persistent pulmonary hypertension in neonates.

Search strategy

MEDLINE, EMBASE, CINAHL databases were searched from their inception until March 2007; the Cochrane Central Register of Controlled Trials, the Cochrane Library, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction.

Selection criteria

Randomized or quasi-randomized 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.

Data collection & analysis

The methodological quality of the trials was assessed regarding how bias at study entry, study intervention and outcomes measurement was minimized. 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.

Main results

Two small eligible trials (one full article and one abstract) were identified. The methodological quality of the trial presented in the full article was good. Information provided in the abstract was limited. The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the Sildenafil group. One study reported what would be, if replicated, a strongly protective effect on mortality (RR 0.17, 95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported.

Reviewers' conclusions

The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials. Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.

Background

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 hemoglobinopathy (Gersony 1984). The clinical diagnosis of pulmonary hypertension is considered when there is hypoxemia 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 centers 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), polycythemia, hypoglycemia, 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 methemoglobinemia. 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.

Objectives

To assess the efficacy and safety of Sildenafil in the treatment of pulmonary hypertension in neonates.

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized 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.

Types of participants

Both term and preterm infants (with a postnatal age of 28 days after reaching 40 weeks postmenstrual age) 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.

Types of interventions

The following interventions were included:
1. Sildenafil vs. placebo or no treatment
2. Sildenafil vs. another pulmonary vasodilator
3. Sildenafil and another pulmonary vasodilator vs. another pulmonary vasodilator or placebo

Types of outcome measures

Primary outcomes:

1. Hemodynamic parameters (absolute values and change from baseline measured after the first dose, after 24 hours, after 30 hours, after 36 hours, after 42 hours, and after the end of treatment) including:
a. Pulmonary arterial pressure in mm Hg
b. Oxygenation (PaO₂) or FiO₂ requirement
c. Cardiac output in litre/kg/min
d. Mean arterial blood pressure in mm Hg
2. All-cause mortality within first 28 days of life

Secondary outcomes:

1. Changes in pulmonary vascular resistance index in Woods Unit m²(WUm²)(absolute values and change from baseline measured after the first dose, after 24 hours, after 30 hours, after 36 hours, after 42 hours, and after the end of treatment)
2. Changes in systemic vascular resistance index in WUm² (absolute values and change from baseline measured after the first dose, after 24 hours, after 30 hours, after 36 hours, after 42 hours, and after the end of treatment)
3. Changes in oxygenation index (OI = PaO₂ X FiO₂/100) (absolute values and change from baseline measured after the first dose, after 24 hours, after 30 hours, after 36 hours, after 42 hours, and after the end of treatment)
4. Rebound increase in pulmonary arterial pressure (dichotomous)
5. Decrease in cardiac output after weaning sildenafil (dichotomous)
6. Treatment with extracorporeal membrane oxygenation (ECMO) prior to discharge
7. All-cause mortality prior to discharge
8. Length of hospitalization (days)
9. Retinopathy of prematurity (among very preterm infants < 32 weeks gestation) any stage and stage 3 or more
10. Intraventricular hemorrhage (any stage and grade 3 or more)
11. Neurodevelopmental disability at 18 - 24 months (including cerebral palsy, cognitive impairment, deafness and blindness)
12. Clinically important adverse effects reported by authors (not pre-specified)
13. Any other clinically important outcome reported by authors (not pre-specified)

For all the hemodynamic 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.

Search strategy for identification of studies

MEDLINE (1966 - March 2007) 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 - March 2007); CINAHL (1982 - March 2007); the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) 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 in Pediatric Research (2001 - 2006). 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.

Methods of the review

All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review. 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. Eligible articles were assessed and data were abstracted. Discrepancy regarding inclusion/exclusion of the studies was resolved by consensus.

Quality of included trials was evaluated independently by all reviewers using the following criteria:

1. Masking of randomization
2. Masking of intervention
3. Completeness of follow-up
4. Masking of outcome assessment
There were 3 potential answers to these questions - yes, no and can't tell.

The data were compared for the outcomes outlined in the previous section as follows. A priori subgroup analyses were planned based on:
(1) gestational age (term and preterm- defined as < 37 weeks of gestation)
(2) method of diagnosis of pulmonary hypertension (clinical or echocardiographic)
(3) route of administration of Sildenafil (oral versus intravenous versus inhaled)
(4) primary or secondary cause of pulmonary hypertension.

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

RevMan 4.2.8 was used for statistical analysis. Statistical parameters included relative risk (RR), risk difference (RD), number needed to treat (NNT), number needed to harm (NNH) and weighted mean difference (WMD) when appropriate. Ninety five percent confidence intervals (CI) were reported for estimates of treatment effects. A fixed effect model was used for meta-analyses. Tests for between study heterogeneity including the I-squared (I²) test were applied to assess the appropriateness of combining studies.

Description of studies

Although several case reports of the use of sildenafil in PPHN were found, only three randomized controlled trials were identified (Baquero 2006; Herrea 2006; Namachivayam 2006). 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. Baquero (Baquero 2006) was published as a full report while the study of Herrea et al (Herrea 2006) was reported only in abstract form. For the Baquero study (Baquero 2006), data were requested regarding hemodynamic measurements before and during the intervention period, incidence of rebound hypoxemia, incidence of intraventricular hemorrhage, 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 hemorrhage 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). For the Herrea study (Herrea 2006), data on method of randomization, allocation concealment, blinding of outcome assessment, follow-up data, baseline characteristics such as gestational age, sex, and hemodynamic changes before and after the start of study, duration of study intervention, nature of placebo and route of administration were requested. However, all efforts were unsuccessful. For further details see the table Characteristics of included studies.

Baquero 2006
Setting: A single centre pilot randomized 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 hypoxemia (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 randomization, (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 enrollment 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.

Herrea 2006
Setting: A single centre randomized 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 randomized to sildenafil (n = 13) 2 mg/kg via orogastric tube or placebo (n = 11). The study is published in an abstract format and many details are not evident. The choice of placebo was not mentioned. The total duration of therapy was 72 hours. Sildenafil was administered at 2 mg/kg/dose via orogastric tube every six hourly.

Outcomes: Changes in the OI was reported in graphical format. Changes in PaO2, mean arterial blood pressure, PaCO2 and ventilation days were compared and only p values were reported.

Methodological quality of included studies

Baquero 2006 was a randomized 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.

Herrea 2006 was reported as a randomized trial. Methodologic quality assessment was not possible due to limited reporting.

Results

SILDENAFIL VS. PLACEBO (COMPARISON 01):

Primary Outcomes:

1. Hemodynamic parameters (absolute values and change from baseline)

a. Pulmonary arterial pressure in mm Hg:

Changes in pulmonary arterial pressure was not reported in either of the studies.

b. Oxygenation or FiO2 requirement:

Baquero (Baquero 2006) reported that all patients in the treatment and placebo group required 100% oxygen before the start of therapy. Baquero (Baquero 2006) reported that oxygen saturation (SaO₂) steadily improved in Sildenafil group and was statistically significantly different from baseline in Sildenafil group at 12 hours (p < 0.03) and significantly higher at 24 and 36 hours in Sildenafil group compared to placebo group (p < 0.03). Herrea (Herrea 2006) reported that PaO₂ increased in Sildenafil group compared control group and change was significant at 72 hours (p < 0.01).

c. Cardiac output in litre/kg/min:

Changes in cardiac output were not reported in either of the studies.

d. Mean arterial blood pressure in mm Hg (Outcome 01.01):

Both studies (Baquero 2006; Herrea 2006) reported no statistically significant differences in the mean arterial blood pressure between Sildenafil and placebo groups. The numerical data have not been reported. Baquero 2006 provided data on mean arterial blood pressure before starting therapy in all patients and at the end of therapy in survivors. The mean arterial blood pressure was higher in the sildenafil group compared to placebo group (MD 5, 95% CI 2, 8 mm of Hg). The values for mean arterial blood pressure after completion of therapy was available in only one of the survivors in the placebo group (45.3 mm of Hg), whereas the values in 6 survivors in the sildenafil group was (mean +SD) 43.7 + 3.3 mm of Hg.

2. All-cause mortality within first 28 days of life (Outcome 01.02):

Baquero 2006 enrolled patients with very high severity of illness (OI>40). Baquero 2006 reported a trend of protective effect on mortality favoring Sildenafil group (1/7 in the sildenafil group vs. 5/6 in the control group; RR 0.17, 95% CI 0.03, 1.09; RD -0.69, 95% CI -1.09, -0.30); however, the number of patients enrolled was small. Data regarding mortality were not reported in the abstract (Herrea 2006).

Secondary Outcomes:

1. Changes in pulmonary vascular resistance index in WUm² (absolute values and change from baseline):

This outcome was not reported in either of the studies.

2. Changes in systemic vascular resistance index in WUm² (absolute values and change from baseline):

This outcome was not reported in either of the studies.

3. Changes in oxygenation index (absolute values and change from baseline):

One study (Herrea 2006) reported on this outcome in graphical format and data could not be extracted. Baquero 2006 reported these data for individual patients in a table format. These data were used to calculate the following:

a. Oxygenation Index (absolute values) (Outcome 01.03)

1. At base line:

There was no statistically significant difference in the OI at baseline between the groups (one study, 13 patients, MD 10, 95% CI -5, 25). The baseline oxygenation indices tended to be higher in the sildenafil group.

2. After the administration of first dose:

There was trend towards lower OI in the sildenafil group compared to the placebo group, however, the difference was not statistically significantly different (one study, 13 patients, MD -7, 95% CI -18, 3).

3. After administration of intervention for 24 hours:

There was a statistically significant reduction in the OI in the sildenafil group compared to the placebo group (one study, 12 patients, MD -27, 95% CI -42, -13).

4. After administration of intervention for 30 hours:

There was a statistically significant reduction in the OI in the sildenafil group compared to the placebo group (one study, 11 patients, MD -45, 95% CI -62, -29).

5. After administration of intervention for 36 hours (completion of therapy):

There was a statistically significant reduction in the OI in the sildenafil group compared to the placebo group (one study, 11 patients, MD -32, 95% CI -46, -18).

As no measurements were available for infants who died at various intervals, there is a potential for bias in these results.

b. Changes in Oxygenation Index (Outcome 01.04):

1. After the administration of the first dose:

There was a statistically significant reduction in the OI two hours after administration of the first dose of sildenafil compared to placebo (one study, 13 patients, MD -17, 95% CI -28, -7).

2. After administration of the intervention for 24 hours:

There was a statistically significant reduction in the OI after administration of 5 doses of sildenafil (at 24 hours after administration) compared to placebo (one study, 12 patients, MD -39, 95% CI -57, -21).

3. After administration of the intervention for 30 hours:

There was a statistically significant reduction in the OI after administration of 6 doses of sildenafil (at 30 hours after administration) compared to placebo (one study, 11 patients, MD -33, 95% CI -51, -15).

4. After administration of the intervention for 36 hours (completion of therapy):

There was statistically significant reduction in the OI after administration of seven doses of sildenafil compared to placebo (one study, 11 patients, MD -45, 95% CI -66, -24). By 42 hours, one patient in the sildenafil group and two patients in the control group had died. Two patients in the control group had their OI reduced significantly prior to the last dose and were not given the last dose (according to pre-specified criteria).

Herrea 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.

4. Rebound increase in pulmonary arterial pressure or decrease in cardiac output after weaning sildenafil (dichotomous):

No evidence of rebound hypoxemia was noted in two patients in whom sildenafil was discontinued because of OI<20.

5. Need for extracorporeal membrane oxygenation (ECMO) prior to discharge:

This outcome was not reported in either of the studies.

6. Mortality prior to discharge:

There was no additional mortality reported in Baquero 2006. Herrea et al did not report on this outcome (Herrea 2006).

7. Length of hospitalization:

This outcome was not reported in either of the studies.

8. Retinopathy of prematurity (among preterm infants <32 weeks gestation):

None of the studies enrolled preterm infants at risk of retinopathy of prematurity.

9. Intraventricular hemorrhage:

Baquero 2006 reported no grade 3 or 4 intraventricular hemorrhage in any of the infants in either group.

10. Neurodevelopmental disability at 18-24 months (including cerebral palsy, cognitive impairment, deafness and blindness):

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.

11. Any clinically important outcome reported by authors (not pre-specified):

Baquero 2006 reported that the blood pressure was not affected during sildenafil therapy. The data were reported in graphical format and numerical data could not be abstracted. Herrea 2006 reported no statistically significant differences in the blood pressure between two groups.

Discussion

There have been case reports of the efficacy of sildenafil in the treatment of persistent pulmonary hypertension in neonates. Only two very small randomized controlled trials have been performed to date. These trials have been conducted in a resource-limited settings. For both 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 two 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 (Herrea 2006) enrolled moderately sick patients (OI > 25), but few data were available from this study as it has only been reported in abstract form. However, the authors' brief description of results and a graph suggested benefit of Sildenafil. 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.

These two studies and several case reports, including recent reports from resource limited settings (Juliana 2005; Simiyu 2006), justify a call for a larger multicenter randomized 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 hypoxemia 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.

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). Concerns regarding retinal vascular growth 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.

Reviewers' conclusions

Implications for practice

Safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials.

Implications for research

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.

Acknowledgements

We would like to thank Dr Augusta Sola for providing data on their study.

Potential conflict of interest

None.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Baquero 2006	Randomized controlled trial I. Masking of randomization - yes II. Masking of intervention - yes III. Masking of outcome assessment - yes IV. Completeness of follow up - Mostly, yes (Data on OI for patients who met the exit criteria were not reported - 2 patients in the sildenafil group)	13 Term neonates with persistent hypoxemia despite mechanical ventilation (OI >40) and echocardiographic diagnosis of PPHN were enrolled. Group 1: (n=7) Male:female = 4:3 Mean gestational age 38.4 (SD 2.6) weeks Mean birth weight 2803 (SD 617) g Mean OI 56 (SD 16.8) Group 2: (n=6) Male:female=3:3 Mean gestational age 37.2 (SD 1.9) weeks Mean birth weight 2710 (SD 554) g Mean OI 46 (SD 9.5)	Group 1: Sildenafil (via orogastric tube) first dose of 1 mg/kg (0.5 ml/kg), subsequent doses every 6 hours and could be doubled to 2mg/kg (1 ml/kg) if OI did not improve and the BP remained stable until patient received a maximum of 8 doses or OI improved to <20. Group 2: Same volume of placebo (orabase) first dose of 0.5 ml/kg, subsequent doses every 6 hours and could be doubled to 1 ml/kg if OI did not improve.	Mortality Changes in OI Changes in mean arterial blood pressure	OI was determined for all 7 patents in sildenafil group for basline 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). OI was determined for all 6 patients in the placebo group at baseline, after dose 1 and 2. One patient died before the third dose (measurement reported for 5 patients after 3rd dose and 4th dose); one patients died before 5th dose (measurements reported for 4 patients at dose 5, 6 and 7).	A
Herrea 2006	Randomized controlled trial I. Masking of randomization - unclear II. Masking of intervention - unclear III. Masking of outcome assessment - unclear IV. Completeness of follow up - yes	24 term neonates with PPHN and OI > 25 Group 1: n=13 Group 2: n=11	Group 1: Sidenafil 2mg/kg via orogastric tube (duration of administration not mentioned) Group 2: Placebo (not mentioned)	Changes in OI Changes in mean arterial blood pressure Duration of mechanical ventilation	Abstract only	B

g = grams
OI= Oxygenation index
PPHN= Persistent Pulmonary Hypertension of the Newborn

Characteristics of excluded studies

Study	Reason for exclusion
Namachivayam 2006	Included patients whose age ranged from 0.1 years onwards Most of the patients had associated congenital heart disease

References to studies

References to included studies

Baquero 2006 {published data only}

Baquero H, Neira F, Venegas ME, Sola A, Soliz A. Outcome at 18 months of age after sildenafil therapy for refractory neonatal hypoxemia. 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.

Herrea 2006 {published data only}

Herrea J, Castillo R, Concha E, Soliz A. Oral sildenafil treatment as an alternative to inhaled NO therapy for persistent pulmonary hypertension of the newborn. In: E-PAS2006:59:3724.3.

References to excluded studies

Namachivayam 2006 {published data only}

Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS. Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children. American Journal of Respiratory and Critical Care Medicine 2006;174:1042-7.

* indicates the primary reference for the study

Other references

Additional references

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Adatia 2002

Adatia I. Recent advances in pulmonary vascular disease. Current Opinion in Pediatrics 2002;14:292-7.

Barrington 2001

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2001. Oxford: Update software.

Behn 2001

Behn D, Potter MJ. Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the gamma-subunit of phosphodiesterase. Investigative Ophthalmology and Visual Science 2001;42:523-7.

Burton 2000

Burton AJ, Reynolds A, O'Neill D. Sildenafil (Viagra) a cause of proliferative diabetic retinopathy? Eye 2000;14:785-6.

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Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Archives of Disease of Childhood 2003;88:827-8.

Dukarm 1998

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Erickson 2002

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Finer 2001

Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. In: Cochrane Database of Systematic Reviews, Issue 2, 2001. London: Wiley Publications.

Gersony 1984

Gersony WM. Neonatal pulmonary hypertension: pathophysiology, classification, and etiology. Clinics in Perinatology 1984;11:517-24.

Goldman 1996

Goldman AP, Tasker RC, Haworth SG, Sigston PE, Macrae DJ. Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1996;98:706-13.

Humbert 2004

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Ichinose 2001

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Ikeda 2005

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Juliana 2005

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Kanthapillai 2004

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Pierce 2005

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Shekerdemian 2002

Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 2002;165:1098-102.

Shekerdemian 2004

Shekerdemian LS, Ravn HB, Penny DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatric Research 2004;55:413-8.

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Subhedar 2002

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Travadi 2003

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Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Sildenafil versus placebo
01 Mean arterial blood pressure in mm of Hg			WMD (fixed), 95% CI	Subtotals only
02 All-cause mortality	1	13	RR (fixed), 95% CI	0.17 [0.03, 1.09]
03 Oxygenation index (absolute values)			WMD (fixed), 95% CI	Subtotals only
04 Change in oxygenation index			WMD (fixed), 95% CI	Subtotals only

01 Sildenafil versus placebo

01.01 Mean arterial blood pressure in mm of Hg

01.01.01 Before initiation of therapy

01.01.02 At the end of therapy

01.02 All-cause mortality

01.03 Oxygenation index (absolute values)

01.03.01 At baseline

01.03.02 After first dose

01.03.03 After 24 hours of treatment

01.03.04 After 30 hours of treatment

01.03.05 After 36 hours of treatment

01.04 Change in oxygenation index

01.04.01 After first dose

01.04.02 After 24 hours of treatment

01.04.03 After 30 hours of treatment

01.04.04 After 36 hours of treatment

Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.