Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?

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1 (2012) 32, r 2012 Nature America, Inc. All rights reserved /12 ORIGINAL ARTICLE Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits? M Nyp 1, T Sandritter 2, N Poppinga 1, C Simon 3 and WE Truog 4 1 Department of Pediatrics, Children s Mercy Hospital and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA; 2 Section of Pharmacology, Children s Mercy Hospital and Clinics, Kansas City, MO, USA; 3 Departments of Cardiology and Pediatrics, Children s Mercy Hospital and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA and 4 Department of Pediatrics, Center for Infant Pulmonary Disorders, Children s Mercy Hospitals and Clinics, University of Missouri- Kansas City School of Medicine, Kansas City, MO, USA Objective: The objective of this study is to determine the effects that sildenafil citrate has on gas exchange in infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). Study Design: A retrospective review was performed from 2005 to Infants treated with sildenafil citrate for greater than 48 h were included. Standard patient data was collected, including echocardiogram, inspired oxygen and systemic blood pressure, before and during administration of sildenafil citrate. Result: Sildenafil citrate was used in 21 preterm infants with BPDassociated PH. A significant reduction in estimated right ventricular peak systolic pressure was seen after initiation of sildenafil citrate, with the majority of infants showing no improvement in gas exchange at 48 h of treatment. Four infants died during treatment. Conclusion: Sildenafil citrate reduced estimated pulmonary artery pressures, but this reduction was not reflected in improved gas exchange within the first 48 h. (2012) 32, 64 69; doi: /jp ; published online 22 September 2011 Keywords: sildenafil; BPD; bronchopulmonary dysplasia; pulmonary hypertension; ino Introduction Pulmonary hypertension (PH) that occurs with pulmonary and airway disorders can complicate the typical course of bronchopulmonary dysplasia (BPD) in very preterm infants. 1 However, little evidence exists to support pharmacological management of PH in pulmonary disorders. 2 Correspondence: Dr M Nyp, Department of Pediatrics, Children s Mercy Hospital and Clinics, University of Missouri-Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA. mfnyp@cmh.edu Received 23 June 2011; revised 12 August 2011; accepted 18 August 2011; published online 22 September 2011 Medications that target the nitric oxide (NO) signaling pathway have been approved for use in adults, but these medications have not been approved or even extensively tested in PH that arises in infancy. Normal endothelium produces NO, which in turn activates soluble guanylate cyclase, causing increased production of cyclicguanosine monophosphate (c-gmp) in the pulmonary vascular smooth muscles. The accumulation of c-gmp within the pulmonary vascular smooth muscle cells causes relaxation and vasodilatation. The c-gmp is rapidly degraded by c-gmp-specific phosphodiesterases (PDE). The type-5 PDE is found in high concentration within the pulmonary vascular smooth muscle. The inhibition of the type-5 PDE preserves the intracellular c-gmp concentration and suppresses the ability of the pulmonary vascular smooth muscle to contract. Sildenafil citrate is a highly selective PDE-5 inhibitor. Sildenafil citrate has acute onset of action that induces clinical improvement in exercise capacity, improved cardiac output and reduction in pulmonary pressures, but has shown no change in mortality or time to lung transplant in adults with PH. 3,4 Sildenafil citrate has also been studied in PH associated with adult pulmonary parenchymal diseases like chronic obstructive pulmonary disease. Sildenafil citrate has shown improvement in hemodynamics, but also leads to impaired oxygenation at rest in these adults with chronic obstructive pulmonary disease. 5 This finding raises important implications for using sildenafil citrate in infants with BPD and PH. In neonates, sildenafil citrate has shown promise in improving gas exchange in diseases such as persistent PH of the newborn. 6,7 Sildenafil citrate has also been used in infants with BPD-associated PH, focusing on long-term treatment and improvement in hemodynamics. 8,9 However, to our knowledge, no reports have described concomitant changes in pulmonary gas exchange at initiation of sildenafil citrate in infants treated for BPD-associated PH. We report a 5-year experience of treating BPD-associated PH with sildenafil citrate.

2 65 Methods Patient selection After receiving approval from the institutional review board at Children s Mercy Hospital and Clinics (# X), we reviewed all infants for the 5-year period from January 2005 through December 2009, who were treated with sildenafil citrate. The records of all infants treated with sildenafil citrate with concurrent diagnosis of moderate/severe BPD using NIH definition were reviewed for the study. 10 Infants were excluded if they did not receive scheduled dosing of sildenafil citrate for greater than 48 h. Therapeutic courses of sildenafil citrate were considered separate if there were greater than 7 days between doses. Infants transferred to our hospital after initiation of sildenafil citrate by the referring physicians were not assessed for gas-exchange effects of sildenafil citrate, but were included in basic demographic, safety and secondary outcomes. Routine management of infants with birthweights <1500 g included supplemental O 2 to maintain S P O 2 of 88 to 93% (monitor alarm range of 85 to 95%) until post-menstrual age >37 weeks when supplemental O 2 goals are changed to S P O 2 X93% (alarm limits 85 to 100%). Assisted ventilation in <1500 g infants was used to maintain ph >7.25 and partial pressure of carbon dioxide (pco 2 ) <60 mm Hg. All assisted ventilation was done using Servo-I (Maquet, Mod # , SW , Wayne, NJ, USA). CPAP was delivered by Drager (Drager Babylog, Mod # , SW 5.00, Telford, PA, USA) or SiPAP (Viasys, Mod# 675-CFG-005, SW 2.08, Lakeland, FL, USA). Supplemental O 2 administration not assisted with positive pressure was provided by nasal canal flow by either stable flow protocol or stable O 2 protocol determined by the primary care team. Diagnosis of PH The diagnosis of suspected PH was based, in all cases, on echocardiographic criteria. Estimated right ventricular peak systolic pressure greater than half the systemic systolic blood pressure was considered to be consistent with PH. 1,8 A tricuspid regurgitation jet was measured to calculate estimated right ventricular peak systolic pressure using the Bernoulli equation and then adding the assumed right atrial pressures. 11,12 When a tricuspid regurgitation jet was not visualized, then degree of septal flattening and presence of bidirectional shunting was felt to be consistent with PH. 13 Echocardiographic assessment for PH occurred routinely in infants with BPD, still requiring fractional percentage of inhaled oxygen (FiO 2 ) >0.4 or assisted ventilation by 34 weeks postmenstrual age. All echocardiograms were performed with no change in concurrent supportive treatment. Frequency of follow-up echocardiograms was determined by the primary care team. All echocardiograms were performed by American Society of Echocardiography-certified echocardiogram technicians, using the Philips ie33 echocardiogram machine (Philips, Mod# ie33, SW , Andover, MA, USA). Echocardiograms were interpreted by staff pediatric cardiologists, independently of the care provided by the clinical team. Baseline assessment The demographic data collected and included were gender, gestational age, birthweight and race. Data collected before starting sildenafil citrate included day of life, weight, coexisting illnesses, concomitant treatment and initial dose of the medication. The respiratory support before starting sildenafil citrate was recorded, and included the type of oxygen delivery, concurrent use of inhaled NO or other inhaled or systemic medications, vasopressor support and steroid use. Respiratory severity scores (mean airway pressure FiO 2 ) were calculated to assess respiratory support for infants requiring assisted mechanical ventilation, as infants typically lacked arterial access. 14 Respiratory severity scores (RSS) were calculated using the highest mean airway pressure and FiO 2 within the 24 h before starting sildenafil citrate, and then at 24 and 48 h. Supplemental FiO 2 in infants not requiring positive pressure were calculated using nasal flow, and FiO 2 delivered based on infant s weight using previously reported estimates. 15 We evaluated the effects of sildenafil citrate on gas exchange at 24 and 48 h to minimize the role other medication adjustments may have on gas exchange at later time points. Previous data suggest that sildenafil citrate has a rapid onset of action, which is evident in treatment of neonatal persistent pulmonary arterial hypertension. 8,9 FiO 2 requirement and highest capillary pco 2 within the 24 h before starting, 24 h after starting and 48 h after starting sildenafil citrate were also recorded. Data collected after starting sildenafil citrate included changes in respiratory support, duration of sildenafil citrate use and reason for discontinuation. Duration of treatment was arbitrarily divided into three categories: acute 2 to 7 days; intermediate 8 to 31 days; and chronic >30 days. For infants who died, the number of days on sildenafil citrate and autopsy findings were recorded. Definition of response We considered a 20% absolute reduction in estimated right ventricular peak systolic pressures as clinically significant. Only echocardiograms with estimated right ventricular peak systolic pressures were used in descriptive analysis, whereas subjective findings of degree of septal flattening and shunt direction were recorded, but not analyzed. We also considered a 20% absolute reduction in RSS in the first 48 h as clinically significant. In infants in whom RSS were not calculated, because they were not being treated with positive airway pressure, an absolute decline in FiO 2 by 20% in the first 48 h was considered to be a clinically significant improvement in oxygenation. Safety was assessed by documenting adverse events during treatment with sildenafil citrate, including new onset sepsis, opening of a patent ductus arteriosus, and onset of necrotizing

3 66 Sildenafil citrate, BPD and pulmonary gas exchange enterocolitis. Systemic blood pressure readings were reviewed for hypotension (>15% decline in mean pressure monitored by cuff). Statistical analysis The null hypothesis was that reduction in right ventricular peak systolic pressures with sildenafil citrate would have no effect on pulmonary gas exchange. Non-parametric data are expressed as medians with ranges. All statistical analyses were conducted using SPSS version 18 (Chicago, IL, USA). Student s paired t-test, Fisher s exact test or Mann Whitney U-test were used as appropriate in the statistical analysis, with P<0.05 reported as significant. A post hoc power analysis showed an 80% power to detect a 20% reduction in estimated right ventricular peak systolic pressure with the number of patients available and using the s.d. obtained in our study. Results Patient population Sildenafil citrate therapy was initiated in 21 in-patient infants with concurrent diagnosis of moderate/severe BPD (Table 1). In all cases, the indication for treatment was PH. There were 24 treatment courses of sildenafil citrate in the 21 infants. Baseline measurements Echocardiographic findings in all infants before initiation of sildenafil citrate therapy demonstrated evidence of PH (septal flattening and ductal shunting). Eighteen of the infants demonstrated estimated right ventricular peak systolic pressure by tricuspid regurgitation jet with overall median estimated pressure of 65 mm Hg (range 38 to 100). Four infants (18%) had pulmonary/systemic artery pressures >1.0. Eleven of the patients Table 1 Patient demographics Patients 21 Sex, male (%) 11 (52) Median gestational age at birth, weeks (range) 27 (23 33) No. less than or equal to 26 weeks (%) 9 (43) Median birth weight, in grams (range) 641 ( ) No. less than 600 g (%) 8 (47) Birthweight classification LGA (%) 1 (5) AGA (%) 8 (38) SGA (%) 9 (42) Race Caucasian (%) 10 (50) African American (%) 9 (42) Others (%) 2 (8) Abbreviations: AGA, appropriate for gestational age; LGA, large for gestational age; SGA, small for gestational age. were receiving inhaled-no (ino) at the time of initiation of sildenafil citrate. None of the infants had echocardiographic evidence of a patent ductus arteriosus before starting sildenafil citrate. Baseline data are summarized in Table 2. Dose of sildenafil citrate Sildenafil citrate was started at an oral dose between 0.25 to 0.5 mg kg 1 per day, given every 6 h and titrated to systemic effects in systemic blood pressure or clinical reduction in respiratory support. The titration of sildenafil citrate was accomplished by increasing dosing by 0.25 to 0.5 mg kg per dose or increasing the daily dose by 0.25 to 0.5 mg kg 1 per day to a maximum dose of 6mgkg 1 per day. Effects of sildenafil citrate on gas exchange Sildenafil citrate was initiated at a median age of 167 days (range 83 to 307) with a median post-menstrual age of 49 weeks (range Table 2 Baseline measurements Median day of life when sildenafil citrate was started 167 (82 307) PMA when sildenafil citrate was started, weeks 49 (37 71) Weight in grams 4125 ( ) No. of infants with weight < 10% for corrected GA (%) 13 (62) Mean cuff systemic pressure 63 (40 86) Estimated right ventricular peak systolic pressure by echocardiogram, mm Hg No. of infants with suprasystemic estimated right ventricular peak systolic pressure by echocardiogram (%) 65 (38 100) 4 (19) Respiratory support CPAP (%) 3 (14) CMV (%) 14 (67) Nasal cannula (%) 4 (19) Medication at time sildenafil citrate was started ino (%) 11 (52) No. of acute responders* 8 Systemic steroids (%) 9 (41) Inhaled steroids (%) 10 (50) Milrinone (%) 4 (18) Median respiratory severity score 5.2 (3 12) Median FiO 2 requirement 0.45 (0.22 1) Median peak pco 2 24 h before starting sildenafil 58 (43 78) citrate, in mm Hg Abbreviations: CMV, conventional mechanical ventilation; CPAP, continuous positive airway pressure; FiO 2, fractional percentage of inhaled oxygen; GA, gestational age; ino, inhaled nitric oxide; pco 2, partial pressure of carbon dioxide; PMA, post-menstrual age. *Acute responder was defined as either PaO 2 improved from < 50 mm Hg to greater than 80 mm Hg, or a reduction in FiO 2 requirements by 20% after starting inhaled nitric oxide.

4 67 37 to 71). Ten infants underwent follow-up echocardiogram after starting sildenafil citrate with calculated right ventricular peak systolic pressure by tricuspid regurgitation jet (Figure 1; Supplementary Information). Seven of these infants showed a reduction in median estimated right ventricular peak systolic pressure to 53 mm Hg (range 35 to 58; P-value 0.01). All seven infants demonstrated a >20% reduction of estimated right ventricular peak systolic pressures. Three infants showed a >20% reduction in RSS; three infants demonstrated an increased RSS. The overall baseline median RSS was 5.2 (range 3 to 9; Figure 2), and was 5.8 (range 3.2 to 11.7) and 5.2 (range 2.8 to 12.8) at 24 and 48 h after initiation of sildenafil citrate, respectively. In the infants in whom RSS were not calculated, no infants showed a >20% reduction in FiO 2 requirement, whereas two infants showed a >20% increase in FiO 2 requirement. There was no statistical difference in capillary pco 2 after starting sildenafil citrate, with baseline median pco 2 58 mm Hg (range 43 to 78 mm Hg) and median pco 2 at 48 h of 56 mm Hg (range 36 to 80 mm Hg). Figure 2 Effects of sildenafil citrate on respiratory severity scores (RSS) in infants with suspected pulmonary hypertension (PH). Infants who were receiving mechanical ventilation without arterial access had RSS calculated (mean airway pressure (MAP) fractional inspired oxygen (FiO 2 )) using the highest FiO 2 and MAP 24 h before starting sildenafil citrate, at 24 and 48 h after starting sildenafil citrate treatment. The median RSS is represented by the black dotted line. There was no clinically significant reduction in median RSS after starting sildenafil citrate; 5.2 versus 5.8 versus 5.2 (P-value ¼ not significant (NS)). The other lines represent changes in RSS at the given time points. Figure 1 Effects of sildenafil citrate on echocardiogram estimated right ventricular peak systolic pressure in infants with suspected pulmonary hypertension (PH). Estimated right ventricular peak systolic pressures by echocardiogram closest to starting sildenafil citrate were used as the baseline measurement. Follow-up estimated right ventricular peak systolic pressures by echocardiogram occurring within 28 days were used as the follow-up measurement. The median right ventricular peak systolic pressure is represented by the black dotted line. There was a clinically significant reduction in median echocardiographic pressure after starting sildenafil citrate; 65 versus 53 mm Hg (P-value 0.01). The other lines represent individual changes in estimated right ventricular peak systolic pressures. Outcomes There were a total of four deaths (19%) in the infants; the median days on sildenafil citrate for non-survivors were 77 days (8 to 135). Two of the deaths occurred in the infants who showed a >20% reduction in RSS within the first 48 h. Autopsy findings in one infant were compatible with severe BPD showing interstitial fibrosis and pulmonary arterial medial thickening; two other infants died of hypoxic respiratory failure, but did not have consent for autopsy. The fourth death occurred in an infant placed in hospice care after sustaining a neurological injury following cardiopulmonary arrest, which occurred before the initiation of sildenafil citrate. One infant developed systemic hypotension at the sildenafil citrate dose of 0.5 mg kg 1 per day, which required discontinuation of sildenafil citrate therapy. Sildenafil citrate was then tolerated at 0.5 mg kg 1 per day when it was restarted 3 days later and was titrated to a dose of 4 mg kg 1 per day. None of infants had documented changes in clinical sepsis, opening of a patent ductus arteriosus, or onset of necrotizing enterocolitis. Comparison of inhaled NO before starting of sildenafil Baseline estimated right ventricular peak systolic pressures were not different in the infants treated concurrently with ino before starting sildenafil citrate 65 versus 71 mm Hg (P ¼ 0.72). There were no differences in median RSS or FiO 2 between the groups in response

5 68 Table 3 Comparison of infant on ino when sildenafil citrate was started Concurrent ino use (11) No ino before sildenafil citrate (10) P-value Baseline Mean cuff systemic pressure, mm Hg 62 (43 73) 64 (40 86) 1.0 FiO ( ) 0.43 ( ) 1.0 Respiratory severity score 5.5 (3 12) 5.2 ( ) 1.0 pco 2 58 (51 71) 58 (43 78) 1.0 Estimated RVP, mm Hg 65 (38 74) 71 (44 100) h of sildenafil citrate Mean cuff systemic pressure, mm Hg 56 (40 70) 70 (56 96) 1.0 FiO ( ) 0.4 (0.25 1) 1.0 Respiratory severity score 5.7 ( ) 5 ( ) pco 2 59 (36 80) 53 (41 72) Estimated RVP after starting sildenafil citrate, mm Hg 40 (25 58) 55 (40 65) Abbreviations: FiO 2, fractional inspired oxygen; ino, inhaled nitric oxide; pco 2, partial pressure of carbon dioxide; RVP, right ventricular pressure. to sildenafil citrate (Table 3). No infants were started on ino therapy after initiation of sildenafil citrate. Discussion We reported a significant reduction in estimated right ventricular peak systolic pressure by echocardiogram after starting sildenafil citrate. We found that infants both treated simultaneously with ino and sildenafil citrate, and infants treated with only sildenafil citrate had similar reductions in estimated right ventricular peak systolic pressure. The reductions observed in estimated right ventricular peak systolic pressures did not correlate with improvement in measured FiO 2 or pco 2 during the first 48 h of treatment with sildenafil citrate. We found that only 3 of the 21 infants showed an improvement in gas exchange, whereas the majority of infants (18 of the 21 infants) showed no improvement, in either RSS or FiO 2, during the first 48 h following treatment with sildenafil citrate. The mechanism by which sildenafil citrate might be associated with improved gas exchange in infants includes increased blood flow through functional lung parenchyma, leading to acute improvement in ventilation perfusion (V/Q) matching. The failure to improve gas exchange could have occurred due to decreased pulmonary vascular resistance not associated with increased pulmonary blood flow or a change in distribution of pulmonary blood to low V/Q areas, resulting in no net benefit for gas exchange. The poor response within the first 48 h may be due to inhibition of hypoxic vasoconstriction at baseline, a mechanism leading to more V/Q mismatch, which may resolve over time, leading to the clinical improvement seen in longer-term treatment with sildenafil citrate previously reported. 10 The initial dose and titration of sildenafil citrate within the first 48 h were highly variable with dosing of sildenafil citrate ranging between 1 to 4 mg kg 1 per day at 48 h. These doses were below the maximum dose of 6 mg kg 1 per day and may have contributed to lack of improvement in oxygenation seen in this study. Furthermore, the lack of strict O 2 weaning protocols and higher SpO 2 targets may have had a role in falsely elevating the RSS and FiO 2 at 24 and 48 h after starting sildenafil citrate. Nine infants (42%) were small of gestation age at birth, whereas 13 (62%) were small for gestation age at initiation of sildenafil citrate. Recent data would suggest small for gestational age is an independent risk factor in the development of BPD-associated PH. 16 It is unknown if the relationship between the poor weight gains in these infants was a cause of, or the effect of, poor lung development, leading to the development of BPD-associated PH. The overall mortality rate in this current report was 4/21 (19%), with deaths occurring at a median of 77 days (8 to 135 days) on sildenafil citrate. Infants who develop BPD-associated PH have been reported to have a mortality rate that reaches 50% by 2 years following the diagnosis, with 36% of deaths occurring within the first 6 months. 1 The mortality rate was lower than the rates reported for infants who developed BPD-associated PH, but we only looked at infants during their first 12 months. The question remains if treatment of the PH associated with severe BPD leads to a reduction in this mortality rate. Adult data suggest that treatment of PH associated pulmonary parenchymal disease does not affect disease progression or mortality. There are many differences between the mechanism of pulmonary injury and parenchymal damage that occur in infants with BPD-associated PH, when compared with adults with chronic obstructive pulmonary disease-associated PH, which make it difficult to

6 69 assume equal outcomes. Longer courses of sildenafil citrate may improve aveolarization of the lung parenchyma. Animal studies suggest sildenafil may attenuate lung-growth failure in hyperoxia, 17,18 but the effects on lung growth in term or preterm human infants are unknown. These growth-promoting effects of sildenafil citrate imply a different mechanism of action, leading to improved vascular growth instead of direct pulmonary vasodilatation. Others have addressed sildenafil citrate used to treat BPDassociated PH. Mourani et al., 8 in a retrospective study, evaluated the long-term effects of sildenafil citrate on infants with chronic lung disease, which included 18 infants with BPD-associated PH. Krishnan et al., 19 in a case series, which included four infants with BPD, reported treating six infants with chronic lung disease with a combination of bosentan and sildenafil citrate. Humpl et al., 20 in an open-label single drug study, evaluated sildenafil citrate therapy for neonatal PH, which included one infant with BPD-associated PH. Caputo et al., 21 in a case report, describe treating one infant with sildenafil citrate for BPD-associated PH. The present report adds to this published experience and represents the largest group of infants treated with sildenafil citrate for BPD-associated PH to date. Including the BPD patients from the previous articles, the total number is 45, with an overall 18% mortality. Although our study was limited by the overall low number of patients and the indirect measurement of PH pressures by echocardiogram, we did study a population of infants requiring a wide range of respiratory support at baseline. Our findings suggest that sildenafil citrate does lead to reduction of estimated peak systolic right ventricular pulmonary pressures in BPD-associated PH. However, pulmonary gas exchange did not improve at 48 h in the majority of patients. Two of the infants, who showed an improvement in pulmonary oxygen exchange within 48 h of starting sildenafil citrate, died. Sildenafil citrate should be used cautiously in infants with BPDassociated PH as a rescue therapy, even with the possibility of longer-term benefits of sildenafil citrate on lung growth. Prospective studies of sildenafil citrate in infants with BPDassociated PH should stratify for severity of altered pulmonary gas exchange to indentify any long-term gas exchange benefits, as well as hemodynamic benefits. Conflict of interest The authors declare no conflict of interest. References 1 Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: Clinical features and outcomes in the surfactant era. Pediatrics 2007; 120(6): Kulik TJ, Rhein LM, Mullen MP. 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