The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia Andrew James Wardle, 1 Richard Wardle, 2 Karen Luyt, 3 Robert Tulloh 4 1 University of Bristol, Bristol, UK 2 University of Leicester, Leicester, UK 3 Department of Neonatology, University of Bristol, Bristol, UK 4 Department of Paediatric Cardiology, University of Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol, UK Correspondence to Dr Robert Tulloh, Department of Paediatric Cardiology, University of Bristol, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol BS2 8BJ, UK; roberttulloh@btinternet.com RW and AW are acting as joint first authors on this project. Received 3 November 2012 Revised 1 April 2013 Accepted 3 April 2013 Published Online First 26 April 2013 To cite: Wardle AJ, Wardle R, Luyt K, et al. Arch Dis Child 2013;98: 613–617. ABSTRACT The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered. INTRODUCTION Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, most commonly affects prema- ture neonates with respiratory distress syndrome requiring mechanical ventilation or oxygen therapy. However, it can also occur when there are few signs of underlying lung pathology. 1 An estimated 13%–35% of preterm infants beyond 36 weeks postmenstrual age have BPD. Furthermore, the lack of knowledge regarding BPD’s pathology and com- plications, coupled with no consensus on best treat- ment, means significant scope remains for improved therapy. 2 One of the most important complications of BPD is pulmonary hypertension (PH). 3 Sildenafil, a phosphodiesterase-V inhibitor (PDE-Vi), has proven efficacy in PH as monotherapy and in combination with other medications; however, data regarding its specific use in BPD-induced PH (BPD-PH) remain elusive. This review outlines the utility of sildenafil in this context given currently available evidence. BPD AND PH The definition of BPD has been extensively modified since the initial description of Northway and cowor- kers in 1967. 4 Historically, the most widely accepted consensus defines BPD as a need for oxygen therapy at 36 weeks postmenstrual age in an infant older than 28-days-old. 5 More recently, a consensus workshop redefined BPD to include a severity grading system while taking into account differing postmenstrual ages, as in table 1. 6 However, exactly how BPD should be defined remains unclear. Currently, BPD incidence is approximately 30% among children born less than 1000 g. 7 Preterm infants with BPD are vulnerable to various cardio- vascular sequelae including cor pulmonale, systemic hypertension and ventricular hypertrophy. 8 It is of note that up to 37% of BPD cases are complicated by PH, 9 although the reasons for this remain unclear but presumably linked to global hypoxia. BPD-PH is the most common cause of PH due to respiratory disorders (Group 3) and is found in approximately 5% of childhood PH. 10 Earliest possible detection of BPD-PH is essential to facilitate prompt intervention and improved out- comes, especially regarding right heart failure. However, presentation can be indistinct from other respiratory conditions and therefore screening is necessary. Criteria for this have been suggested by other groups as outlined in figure 1, 3 although screening in all small for gestational age neonates is unrealistic, particularly during current economic conditions. The gold-standard PH diagnosis is defined as mean pulmonary arterial pressure ( pPA) ≥25 mm Hg at rest on cardiac catheterisation. 11 However, this is invasive and therefore Doppler echocardiography, with a tricuspid valve regurgitant jet velocity more than or equal to 2.8m/s, is a com- monly accepted screen. Additionally, PH is also recognised as a systolic pulmonary to systemic pres- sure ratio exceeding 0.5. Less widely used qualita- tive echocardiography alternatives include right atrial enlargement, septal flattening, right ventricu- lar hypertrophy or dilatation, and right ventricular ejection time into the pulmonary artery <15 ms, but their sensitivity and specificity remain question- able. Where possible (ie, infants >5 kg), diagnosis made using echocardiography should be confirmed by cardiac catheterisation, and include vasoreactivity testing to oxygen and inhaled nitric oxide (iNO). Confirmation of PH requires pulmonary vascular resistance (PVR) >3 Wood units × BSA.m 2 with capillary wedge pressures ≤15 mm Hg. This is important to distinguish PH from the hyperkinetic flows of unrepaired congenital heart disease. 12 13 Mortality Recent data based on contemporary treatments suggest BPD-PH survival rates after diagnosis of just 64% at 6 months, and 61% and 52% at 1- and 2-years, respectively. 3 PH severity is an important prognostic marker for BPD, increasing mortality fourfold. 14 That stated, prolonged sildenafil Wardle AJ, et al. Arch Dis Child 2013;98:613–617. doi:10.1136/archdischild-2012-303333 613 Review group.bmj.com on August 6, 2013 - Published by adc.bmj.com Downloaded from