Eur J Pediatr DOI 10.1007/s00431-015-2515-7
ORIGINAL ARTICLE
Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety Kenneth Tan & Mohan B. Krishnamurthy & Josie L. O’Heney & Eldho Paul & Arvind Sehgal
Received: 25 August 2014 / Revised: 26 February 2015 / Accepted: 5 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (±SD) gestation age and birth weight of 25.6 (±1.3) weeks and 631 (±181)g, respectively. Six Communicated by Patrick Van Reempts K. Tan : M. B. Krishnamurthy : J. L. O’Heney : A. Sehgal Monash Newborn, Monash Children’s Hospital, Melbourne, Australia K. Tan e-mail: [email protected] M. B. Krishnamurthy e-mail: [email protected]
(27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing ≥20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had ‘severe’ BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE±0.05) to 0.42 (SE±0.03) (p=0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 ± 3.3 to 63.2 ± 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted. Conclusion: Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.
E. Paul Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia e-mail: [email protected]
What is known: • Sildenafil is used to treat severe bronchopulmonary dysplasiaassociated pulmonary hypertension, and pharmacologic effects make it a suitable drug. • Improvement in echocardiographic parameters has been shown, though many infants were on additional pulmonary vasodilators. What is new: • Pulmonary and systemic echocardiographic parameters improved with sildenafil as the sole pulmonary vasodilator. • It also highlights accompanying clinical improvements, tolerance, and long-term outcomes.
A. Sehgal (*) Monash Children’s Hospital, Monash University, 246, Clayton Road, Clayton, Melbourne, VIC 3168, Australia e-mail: [email protected]
Keywords Cardiac . Echocardiography . Efficacy . Sildenafil . Safety
J. L. O’Heney e-mail: [email protected] K. Tan : A. Sehgal Department of Pediatrics, Monash University, Melbourne, Australia
Eur J Pediatr
Abbreviations ANZNN Australia and New Zealand Neonatal Network BPD Bronchopulmonary dysplasia CPAP Continuous positive airway pressure cGMP Cyclic guanosine monophosphate FS Fractional shortening iNO Inhaled nitric oxide IQR Interquartile IVS Interventricular septal IUGR Intrauterine growth restriction PAH Pulmonary artery hypertension PVD Pulmonary vascular disease PVR Pulmonary vascular resistance RVETc Right ventricular ejection time RVSP Right ventricular systolic pressure TPV Time to peak velocity TRJVmax Tricuspid regurgitation jet velocity
Introduction Infants with severe bronchopulmonary dysplasia (BPD) and accompanying pulmonary artery hypertension (PAH) are at risk of increased morbidity and mortality. It also contributes to increased health-care utilisation (need for mechanical ventilation and home oxygen) and a significantly increased length of hospital stay [23]. It is estimated that between 17 and 37 % of extremely low birth weight infants with BPD will have some degree of PAH [5, 22]. Khemani et al. [13] studied cross-sectional follow-up data at a median of 5.2 months (range, 0.1–98 months) after the diagnosis of PAH at a median age of 10.9 months (range, 5.1–101 months). Sixteen subjects (38 %) died during the follow-up period, the majority (13/16, 81 %) within 2 months after the diagnosis. In 14 of those who died, pulmonary hypertension was determined to be a significant contributor. Bhat et al. [5] noted that amongst extremely low birth weight infants, 26 (18 %) were diagnosed with PAH at any time during hospitalisation and 9 (6.2 %) by initial screening (early PAH). Importantly, 11.7 % were identified later (late PAH), suggesting a disease which evolves. Sildenafil is commonly used to treat BPD-associated PAH. Sildenafil acts by modulating cyclic guanosine monophosphate (cGMP) pathway by way of inhibiting phosphodiesterase V enzyme which augments vasodilatation and suppresses smooth muscle proliferation. It also preserves lung angiogenesis and decreases pulmonary vascular resistance (PVR), right ventricular hypertrophy and medial wall thickness in newborn rats [15]. Its property of reducing pulmonary inflammatory response and fibrin deposition and attenuating airway reactivity makes it a particularly attractive and physiologically relevant option in BPD-associated PAH [6]. Given its multi-factorial potential in modulating the disease physiology, sildenafil is being increasingly used in managing ex-
preterm infants with BPD-associated PAH. Untreated, the pulmonary pressures would remain elevated for years, potentially affecting the quality of life and the overall development of the child. Given the pharmacological efficacy of sildenafil in reducing pulmonary pressures and, hence, the potential to improve outcomes, we reviewed our data set to assess the therapeutic efficacy and safety profile of sildenafil therapy.
Methods After obtaining approval from the institution’s research ethics board, we reviewed medical records and archived images of all the infants treated with sildenafil during the period 2004 to 2012. In the infants born
ORIGINAL ARTICLE
Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety Kenneth Tan & Mohan B. Krishnamurthy & Josie L. O’Heney & Eldho Paul & Arvind Sehgal
Received: 25 August 2014 / Revised: 26 February 2015 / Accepted: 5 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (±SD) gestation age and birth weight of 25.6 (±1.3) weeks and 631 (±181)g, respectively. Six Communicated by Patrick Van Reempts K. Tan : M. B. Krishnamurthy : J. L. O’Heney : A. Sehgal Monash Newborn, Monash Children’s Hospital, Melbourne, Australia K. Tan e-mail: [email protected] M. B. Krishnamurthy e-mail: [email protected]
(27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing ≥20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had ‘severe’ BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE±0.05) to 0.42 (SE±0.03) (p=0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 ± 3.3 to 63.2 ± 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted. Conclusion: Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.
E. Paul Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia e-mail: [email protected]
What is known: • Sildenafil is used to treat severe bronchopulmonary dysplasiaassociated pulmonary hypertension, and pharmacologic effects make it a suitable drug. • Improvement in echocardiographic parameters has been shown, though many infants were on additional pulmonary vasodilators. What is new: • Pulmonary and systemic echocardiographic parameters improved with sildenafil as the sole pulmonary vasodilator. • It also highlights accompanying clinical improvements, tolerance, and long-term outcomes.
A. Sehgal (*) Monash Children’s Hospital, Monash University, 246, Clayton Road, Clayton, Melbourne, VIC 3168, Australia e-mail: [email protected]
Keywords Cardiac . Echocardiography . Efficacy . Sildenafil . Safety
J. L. O’Heney e-mail: [email protected] K. Tan : A. Sehgal Department of Pediatrics, Monash University, Melbourne, Australia
Eur J Pediatr
Abbreviations ANZNN Australia and New Zealand Neonatal Network BPD Bronchopulmonary dysplasia CPAP Continuous positive airway pressure cGMP Cyclic guanosine monophosphate FS Fractional shortening iNO Inhaled nitric oxide IQR Interquartile IVS Interventricular septal IUGR Intrauterine growth restriction PAH Pulmonary artery hypertension PVD Pulmonary vascular disease PVR Pulmonary vascular resistance RVETc Right ventricular ejection time RVSP Right ventricular systolic pressure TPV Time to peak velocity TRJVmax Tricuspid regurgitation jet velocity
Introduction Infants with severe bronchopulmonary dysplasia (BPD) and accompanying pulmonary artery hypertension (PAH) are at risk of increased morbidity and mortality. It also contributes to increased health-care utilisation (need for mechanical ventilation and home oxygen) and a significantly increased length of hospital stay [23]. It is estimated that between 17 and 37 % of extremely low birth weight infants with BPD will have some degree of PAH [5, 22]. Khemani et al. [13] studied cross-sectional follow-up data at a median of 5.2 months (range, 0.1–98 months) after the diagnosis of PAH at a median age of 10.9 months (range, 5.1–101 months). Sixteen subjects (38 %) died during the follow-up period, the majority (13/16, 81 %) within 2 months after the diagnosis. In 14 of those who died, pulmonary hypertension was determined to be a significant contributor. Bhat et al. [5] noted that amongst extremely low birth weight infants, 26 (18 %) were diagnosed with PAH at any time during hospitalisation and 9 (6.2 %) by initial screening (early PAH). Importantly, 11.7 % were identified later (late PAH), suggesting a disease which evolves. Sildenafil is commonly used to treat BPD-associated PAH. Sildenafil acts by modulating cyclic guanosine monophosphate (cGMP) pathway by way of inhibiting phosphodiesterase V enzyme which augments vasodilatation and suppresses smooth muscle proliferation. It also preserves lung angiogenesis and decreases pulmonary vascular resistance (PVR), right ventricular hypertrophy and medial wall thickness in newborn rats [15]. Its property of reducing pulmonary inflammatory response and fibrin deposition and attenuating airway reactivity makes it a particularly attractive and physiologically relevant option in BPD-associated PAH [6]. Given its multi-factorial potential in modulating the disease physiology, sildenafil is being increasingly used in managing ex-
preterm infants with BPD-associated PAH. Untreated, the pulmonary pressures would remain elevated for years, potentially affecting the quality of life and the overall development of the child. Given the pharmacological efficacy of sildenafil in reducing pulmonary pressures and, hence, the potential to improve outcomes, we reviewed our data set to assess the therapeutic efficacy and safety profile of sildenafil therapy.
Methods After obtaining approval from the institution’s research ethics board, we reviewed medical records and archived images of all the infants treated with sildenafil during the period 2004 to 2012. In the infants born
