sildenafil-citrate and Bronchopulmonary-Dysplasia

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Cardiac Catheterization; Cardiac Surgical Procedures; Echocardiography; Endothelin Receptor Antagonists; Heart Failure; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Magnetic Resonance Imaging; Nitric Oxide; Oxygen Inhalation Therapy; Prostaglandins I; Sildenafil Citrate; Tomography, X-Ray Computed; Tricuspid Valve Insufficiency; Vascular Resistance; Vasodilator Agents

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions. Many drugs remain inadequately tested and no new drugs have been approved in more than 25 years for BPD prevention or therapy. More progress is needed in defining appropriate end points based on the pathophysiology of BPD and postdischarge chronic pulmonary insufficiency of prematurity and to develop effective new drugs. In addition, much work is needed to better define perinatal factors, early postnatal findings, and physiologic phenotypes or endotypes.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bronchodilator Agents; Bronchopulmonary Dysplasia; Caffeine; Diuretics; Female; Humans; Infant, Newborn; Infant, Premature; Insulin-Like Growth Factor I; Mesenchymal Stem Cell Transplantation; Nitric Oxide; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pregnancy; Prenatal Care; Progesterone; Progestins; Pulmonary Surfactants; Sildenafil Citrate; Vitamin A; Vitamins

While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.

Topics: Administration, Inhalation; Biomarkers; Bronchodilator Agents; Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Lung; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Respiration, Artificial; Respiratory Insufficiency; Sildenafil Citrate; Vasodilator Agents

Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension.. MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near-term infants with pulmonary hypertension or premature infants at risk for BPD or with BPD-associated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool.. Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n = 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher right-sided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension.. There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed.

Topics: Administration, Inhalation; Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nitric Oxide; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

The survival of great number of extremely premature newborn babies is associated with increased risk of damage of the newborn lung and development of chronic lung disease/Broncopulmonary dysplasia. The lower the gestational age and weight, the greater the frequency of BPD. The disease leads to impairment of the normal alveolization and vascularization of the premature lung. There are new theories for the pathogenesis of BPD and new staging of the disease. These changes lead to new therapeutic strategies.

Topics: Antihypertensive Agents; Birth Weight; Bronchodilator Agents; Bronchopulmonary Dysplasia; Epoprostenol; Female; Gestational Age; Humans; Infant, Newborn; Lung; Milrinone; Nitric Oxide; Pregnancy; Sildenafil Citrate; Vasodilator Agents

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.

Topics: Bronchopulmonary Dysplasia; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Pulmonary hypertension is a deadly complication of bronchopulmonary dysplasia, the most common pulmonary morbidity of prematurity. Despite these catastrophic consequences, no evidence-based therapies are available for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults. Preclinical models suggest a beneficial effect of sildenafil on premature lungs through improved alveolarization and preserved vascular development. Sildenafil may therefore prevent the development of pulmonary hypertension associated with lung disease of prematurity by reducing pulmonary vascular remodeling and lowering pulmonary vascular resistance; however, clinical trial evidence is needed. The present study, supported by the National Institutes of Health's National Heart Lung and Blood Institute, will generate safety, pharmacokinetics, and preliminary effectiveness data on sildenafil in a population of premature infants with severe bronchopulmonary dysplasia at risk for pulmonary hypertension.. We have designed a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety trial of sildenafil in premature infants with severe bronchopulmonary dysplasia. We will randomize 120 premature infants < 29 weeks gestational age with severe bronchopulmonary dysplasia at 32-40 weeks postmenstrual age in a dose-escalating approach 3:1 (sildenafil: placebo) sequentially into each of 3 cohorts at ~ 30 clinical sites. Participants will receive up to 34 days of study drug, followed by 28 days of safety monitoring. The primary outcome will be safety as determined by incidence of hypotension. Secondary outcomes will include pharmacokinetics and preliminary effectiveness of sildenafil based on presence or absence of pulmonary hypertension diagnosed by echocardiography at the end of treatment period.. Sildenafil is a promising intervention to prevent the development of pulmonary hypertension in premature infants with bronchopulmonary dysplasia. Clinical trials of sildenafil specifically designed for premature infants are urgently needed. The current study will make substantial contributions to scientific knowledge of the safety of sildenafil in premature infants at risk for pulmonary hypertension. Results from the study will be used by investigators to inform the design of a pivotal efficacy trial.. ClinicalTrials.gov NCT04447989 . Registered 25 June 2020.

Topics: Bronchopulmonary Dysplasia; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Sildenafil Citrate

Bronchopulmonary dysplasia (BPD) is the need for oxygen therapy at 36 weeks postmenstrual age (PMA). Sildenafil has been shown to enhance the lung alveolarization and vascularization in newborn animal models after lung injury and has possible therapeutic potential for the prevention of BPD.. To perform a proof-of-concept, Phase II, pilot randomized, double-blind, clinical trial to study the efficacy of sildenafil in preventing BPD, in postnatal (< 24 h), extremely and very preterm infants.. No significant differences were observed between the sildenafil and placebo study groups in mortality at 36 weeks PMA (10% vs 20%, p = 1), respiratory support at 36 weeks (30% vs 25%, p = 0.57), and side effects (0% vs 0%). For all other secondary outcomes, no significant differences were detected.. While not associated with side effects, off-label oral sildenafil did not demonstrate benefits in the prevention of BPD or death in the extreme and very preterm infants. Future studies of dosing and efficacy that target different regimens of sildenafil are warranted before sildenafil is recommended for the prevention of BPD.

Topics: Bronchopulmonary Dysplasia; Double-Blind Method; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Pilot Projects; Pre-Exposure Prophylaxis; Proof of Concept Study; Risk Factors; Sildenafil Citrate; Vasodilator Agents

Sildenafil has been shown to preserve alveolar growth and lung angiogenesis in a rat model of bronchopulmonary dysplasia. We conducted a proof-of-concept randomised controlled pilot study to assess the feasibility of oral sildenafil treatment in extremely preterm infants with evolving bronchopulmonary dysplasia.. Preterm infants <28 weeks gestational age were eligible if they were mechanically ventilated on day 7 of life. Infants were randomised to a 4-weeks course of either oral sildenafil (3 mg/kg/day) or placebo solution. Pre-discharge cardiorespiratory outcomes and medication side effects were collected.. Twenty infants were randomised, 10 received sildenafil (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98)) and 10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147)). One infant in the sildenafil group did not receive treatment because of an early pneumoperitoneum. Two infants did not complete the study (transferred out). Of the remaining seven treated infants, three died (two from respiratory-related causes). One infant in the control group died from a non-respiratory cause. Sildenafil did not reduce length of invasive (median 688 versus 227 h) or non-invasive ventilation (median 1609 versus 1416 h). More infants in the sildenafil group required postnatal steroid treatment. One infant developed hypotension following sildenafil administration and was excluded after three doses.. In this pilot study, oral sildenafil treatment did not improve any short-term respiratory outcomes in extremely preterm infants.

Topics: Bronchopulmonary Dysplasia; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Feasibility Studies; Female; Gestational Age; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Male; Pilot Projects; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The use of pulmonary vasodilator therapy in children born preterm is largely unknown. Our aim was to map prescription patterns in children with bronchopulmonary dysplasia in Sweden.. This was a descriptive national registry-based study of children <7 years who had been prescribed a pulmonary vasodilator during 2007-2017, were born preterm and classified as having bronchopulmonary dysplasia. Information on prescriptions, patient characteristics and comorbidities were retrieved from the Swedish Prescribed Drug Register and linked to other national registers.. The study included 74 children, 54 (73%) born at 22-27 weeks' gestation and 20 (27%) at 28-36 weeks. Single therapy was most common, n = 64 (86.5%), and sildenafil was prescribed most frequently, n = 69 (93%). Bosentan, iloprost, macitentan and/or treprostinil were used mainly for combination therapies, n = 10 (13.5%). Patent ductus arteriosus or atrial septal defect were present in 29 (39%) and 25 (34%) children, respectively, and 20 (69%) versus 3 (12%) underwent closure. Cardiac catheterisation was performed in 19 (26%) patients. Median duration of therapy was 4.6 (1.9-6.8, 95% CI) months. Mortality was 9%.. Preterm children with bronchopulmonary dysplasia were prescribed pulmonary vasodilators, often without prior catheterisation. Sildenafil was most commonly used. Diagnostic tools, effects, and drug safety need further evaluation.

Topics: Bronchopulmonary Dysplasia; Child; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Infant, Premature; Outpatients; Sildenafil Citrate; Vasodilator Agents

Extremely low gestational age newborns (ELGANs) represent an especially vulnerable population. Herein, we aimed to determine incidence and severity of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) in extremely immature ELGANs (gestational age: 23. In this prospective observational cohort study, we assessed BPD-PH by means of several echocardiography markers and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 3 and 12 months of chronological age. In addition, we analyzed incidence and efficacy of pharmacologic treatment for BPD-PH.. At 3 months 15/34 ELGANs had echocardiographic evidence of BPD-PH, while at 12 months of age 6/34 still had PH. PH-targeted therapy consisted of sildenafil monotherapy in 11 and dual oral combination therapy (sildenafil and macitentan) in four ELGANs at 3 and 12 months.. 44% (15/34) of ELGANs developed BPD-PH. All received PH-targeted pharmacotherapy at 3 months, leading to hemodynamic improvements at 12 months in most infants.

Topics: Adult; Biomarkers; Bronchopulmonary Dysplasia; Child; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Premature; Infant, Newborn; Pregnancy; Prospective Studies; Sildenafil Citrate; Young Adult

To evaluate the cost-utility of catheterization-obligate treatment in preterm infants with pulmonary hypertension, as compared with empiric initiation of sildenafil based on echocardiographic findings alone.. A Markov state transition model was constructed to simulate the clinical scenario of a preterm infant with echocardiographic evidence of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD) and without congenital heart disease under consideration for the initiation of pulmonary vasodilator therapy via one of two modeled treatment strategies-empiric or catheterization-obligate. Transitional probabilities, costs and utilities were extracted from the literature. Forecast quality-adjusted life-years was the metric for strategy effectiveness. Sensitivity analyses for each variable were performed. A 1000-patient Monte Carlo microsimulation was used to test the durability of our findings.. The catheterization-obligate strategy resulted in an increased cost of $10 778 and 0.02 fewer quality-adjusted life-years compared with the empiric treatment strategy. Empiric treatment remained the more cost-effective paradigm across all scenarios modeled through one-way sensitivity analyses and the Monte Carlo microsimulation (cost-effective in 98% of cases).. Empiric treatment with sildenafil in infants with pulmonary hypertension associated with BPD is a superior strategy with both decreased costs and increased effectiveness when compared with catheterization-obligate treatment. These findings suggest that foregoing catheterization before the initiation of sildenafil is a reasonable strategy in preterm infants with uncomplicated pulmonary hypertension associated with BPD.

Topics: Bronchopulmonary Dysplasia; Cardiac Catheterization; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Sildenafil Citrate

Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants.. Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016.. Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge.. The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.

Topics: Bronchopulmonary Dysplasia; Drug Utilization; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Meconium Aspiration Syndrome; Retrospective Studies; Sildenafil Citrate; Vasodilator Agents

To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil.. A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review.. There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2  weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02.. In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving.

Topics: Adolescent; Bronchopulmonary Dysplasia; Child; Child, Preschool; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Sildenafil Citrate; Tadalafil; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high.. The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program.. ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed.. In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20).. An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge.

Topics: Birth Weight; Bronchopulmonary Dysplasia; Echocardiography; Female; Germany; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Intensive Care Units, Neonatal; Logistic Models; Male; Risk Factors; Severity of Illness Index; Sildenafil Citrate

To assess whether sildenafil is associated with worsening retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants (≤1500 g) with bronchopulmonary dysplasia (BPD).. This retrospective case-control study included VLBW infants admitted to the neonatal intensive care unit between January 1, 2006, and December 31, 2012. Each infant treated with sildenafil was assigned 3 unexposed controls matched for gestational age, birth weight, and BPD diagnosis. Severe ROP was defined as stage ≥3 ROP. Worsening ROP was defined as increased stage of ROP within 8 weeks + 4 days after initiation of sildenafil or matched postmenstrual age.. Twenty-three exposed infants and 69 matched controls met the inclusion criteria for the study (mean birth weight, 715 ± 210 g; mean gestational age, 25 ± 1 weeks). The mean postmenstrual age at sildenafil treatment was 42 ± 8 weeks. Exposed infants had more days of respiratory support (mean, 208 ± 101 days vs 102 ± 33 days; P < .001). Exposed infants had a higher prevalence of severe ROP (26% [6 of 23] vs 7% [5 of 69]; OR, 6.4; 95% CI, 1.2-32.9; P = .026). Five exposed infants and 2 unexposed infants had severe ROP before starting sildenafil and were excluded from the analysis for worsening ROP. The rate of worsening ROP did not differ significantly between exposed infants and unexposed infants ((41% [7 of 17] vs 24% [12 of 51]; OR, 8.4; 95% CI, 0.9-78.6; P = .061).. Although sildenafil treatment was not statistically significantly associated with worsening of ROP, the raw difference in ROP rate is concerning. Larger studies are warranted to confirm this finding.

Topics: Bronchopulmonary Dysplasia; Case-Control Studies; Disease Progression; Dose-Response Relationship, Drug; Female; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Male; Phosphodiesterase 5 Inhibitors; Retinopathy of Prematurity; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Visual Acuity

Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Guanylate Cyclase; Hyperoxia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Mice; Mice, Inbred C57BL; Oxygen; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Pulmonary Artery; Signal Transduction; Sildenafil Citrate; Vascular Remodeling

When bronchopulmonary dysplasia (BPD) is complicated by pulmonary hypertension (PH), morbidity and mortality are significantly increased. BPD-associated PH is not included in the current indications for PH medications. However, limited data demonstrate hemodynamic improvement and decreased mortality with PH-specific treatment. This report describes our 6-year experience treating BPD-associated PH with PH medications, mainly sildenafil.. The medical records of 20 infants diagnosed with BPD-associated PH at a tertiary pediatric pulmonary hypertension clinic in 2008-2014 were reviewed. Clinical improvement was defined as a decrease in Ross functional class by at least one degree. PH severity was classified by echocardiography as mild, moderate, or severe. Hemodynamic improvement was defined as a decrease in PH severity by at least one level.. Eighteen out of 20 patients were treated with PH medications: 12 sildenafil, 5 sildenafil and bosentan, and 1 bosentan. Median follow-up time was 2 years. Mean functional class significantly decreased from 3.2 ± 0.9 at diagnosis to 1.7 ± 0.9 at the last follow-up. Improvement in functional class was observed in 15/16 children (94%). Moderate or severe PH was found in 13/18 children (72%) at diagnosis, and in three (17%, all moderate PH) at the last follow-up. Improvement in PH class by echocardiography was demonstrated in 14/18 children (78%). The survival rate was 95%.. Treatment of BPD complicated by PH with PH-specific medications, mainly sildenafil, is associated with improvement in both clinical and hemodynamic parameters and a low mortality rate. Pediatr Pulmonol. 2017;52:77-83. © 2016 Wiley Periodicals, Inc.

Topics: Antihypertensive Agents; Bosentan; Bronchopulmonary Dysplasia; Child, Preschool; Drug Therapy, Combination; Echocardiography; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Treatment Outcome

To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants.. We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003 to 2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil before first eye exam to three nonexposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression.. Of the 57 815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 nonexposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs nonexposed groups (17/81 (21%) vs 38/243 (16%), P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed vs nonexposed infants (odds ratio=1.46, 95% confidence interval=0.76 to 2.82, P=0.26).. We did not observe an association between risk of severe ROP and sildenafil exposure before first eye exam in this cohort of premature infants.

Topics: Bronchopulmonary Dysplasia; Diagnostic Techniques, Ophthalmological; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Premature; Infant, Very Low Birth Weight; Male; Medical Records, Problem-Oriented; Retinopathy of Prematurity; Risk Assessment; Risk Factors; Sildenafil Citrate; Statistics as Topic; United States; Vasodilator Agents

This study had 2 goals: (1) to identify clinical and demographic characteristics associated with sildenafil exposure for infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH); and (2) to characterize hospital-specific treatment frequency, age at first administration, and length of sildenafil treatment.. This retrospective cohort study used data from the Pediatric Health Information System to determine variables associated with sildenafil exposure and between-hospital variations in sildenafil utilization patterns. The study included infants with BPD-PH who were discharged between January 1, 2006, and December 31, 2013.. Within 36 US pediatric hospitals, 3720 infants were diagnosed with BPD, of whom 598 (16%) also had a diagnosis of PH (BPD-PH). Among infants with BPD-PH, 104 infants (17%) received sildenafil. The odds for sildenafil treatment among infants born between 25 and 26 weeks' gestational age (GA) and <24 weeks' GA, respectively, were 2.26 (95% confidence interval [CI]: 1.20-4.24) and 3.21 (95% CI: 1.66-6.21) times those of infants born at 27 to 28 weeks' GA. Severity of BPD correlated with sildenafil exposure, with adjusted odds ratios (ORs) for moderate BPD (OR: 3.03 [95% CI: 1.03-8.93]) and severe BPD (OR: 7.56 [95% CI: 2.50-22.88]), compared with mild BPD. Greater rates of sildenafil exposure were observed among small for GA neonates (OR: 2.32 [95% CI: 1.21-4.46]). The proportion of infants with BPD-PH exposed to sildenafil varied according to hospital (median: 15%; 25th-75th percentile: 0%-25%), as did the median duration of therapy (52 days; 25th-75th percentile: 28-109 days).. The odds of sildenafil treatment were greatest among the most premature infants with severe forms of BPD. The frequency and duration of sildenafil exposure varied markedly according to institution. Patient-centered trials for infants with BPD-PH are needed to develop evidence-based practices.

Topics: Bronchopulmonary Dysplasia; Cohort Studies; Female; Gestational Age; Hospitals, Pediatric; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Male; Needs Assessment; Outcome and Process Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Practice Patterns, Physicians'; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; United States

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant, Extremely Premature; Infant, Newborn; Outcome Assessment, Health Care; Sildenafil Citrate; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Topics: Acute Disease; Administration, Inhalation; Bronchopulmonary Dysplasia; Cardiac Catheterization; Chronic Disease; Consensus; Constriction, Pathologic; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Lung Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Pulmonary Veins; Sildenafil Citrate; Tomography, X-Ray Computed

The objective of this study is to assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH).. Data were collected from six infants receiving sildenafil for the treatment of PH and plasma samples were collected at the time of routine laboratory blood draws. The echocardiography results were assessed for improvement in right ventricular (RV) hypertension following sildenafil treatment.. The median (range) sildenafil and DMS concentrations were 27.4 ng ml(-1) (2.6 to 434.0) and 105.5 ng ml(-1) (3.6 to 314.0), respectively. The median metabolite-to-parent ratio was higher in infants receiving co-medications that can induce cytochrome P450 (CYP) enzymes (5.2 vs 0.7). The echocardiography results showed improvement in RV hypertension for the majority of infants (5/6).. The concentrations of sildenafil and DMS were within the previously observed ranges. Our results suggest that caution may be warranted when CYP-related co-medications are administered during sildenafil treatment for PH.

Topics: Bronchopulmonary Dysplasia; Echocardiography; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Premature; Male; North Carolina; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Ventricular Function, Right

Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants remains a serious concern and continues to cause significant morbidity despite improvements in both quality of life and survival for patients. One of the potential agents that might help is sildenafil citrate, a phosphodiesterase-V inhibitor used a first line therapy for idiopathic PH. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. The evidence and current knowledge is presented for sildenafil alone and in combination with other disease modifying agents to treat PH in the presence of BPD. We have previously suggested that sildenafil appears to be safe and possibly effective in this condition. We present the evidence that if continued until PH resolution, there might be reduced mortality in this debilitating disease.

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant; Sildenafil Citrate; Vasodilator Agents

Topics: Bronchopulmonary Dysplasia; Echocardiography; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome

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 (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.. Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.

Topics: Blood Pressure; Bronchopulmonary Dysplasia; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate; Time Factors; Treatment Outcome; Ventricular Function, Left

Sildenafil, a phosphodiesterase-5 inhibitor, is a controversial treatment option for pulmonary arterial hypertension (PAH), a significant complication of bronchopulmonary dysplasia (BPD). The objective of this study was to evaluate the use of sildenafil in infants with PAH secondary to BPD. This was a retrospective review of medical records of all premature infants with PAH associated with BPD treated with sildenafil between January 2009 and May 2013 in a level 3 neonatal intensive care unit. The primary outcomes were clinical response (20 % decreases in respiratory support score or oxygen requirements) and echocardiographic response (20 % decrease in tricuspid regurgitation gradient or change of at least 1° of septal flattening). Twenty-three infants were included in the study. Significant echocardiographic and clinical responses were, respectively, observed in 71 and 35 % of cases. Most clinical responses were observed in the first 48 h of treatment, and the median time to an echocardiographic response was of 19 days. The median dose of sildenafil used was 4.4 mg/kg/day, with a median time to reach the maximum dose of 9 days. Transient hypotension was the primary reported side effect, and it was observed in 44 % of our study population. Sildenafil treatment in patients with PAH secondary to BPD was associated with an echocardiographic improvement in the majority of patients, whereas clinical improvement was observed in a minority of patients. Many infants presented with transient hypotension during the course of the treatment. Further prospective studies are required to better assess safety and efficacy of this treatment in this population.

Topics: Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Echocardiography; Female; Humans; Hypertension, Pulmonary; Hypotension; Infant; Infant, Newborn; Intensive Care, Neonatal; Male; Oxygen; Phosphodiesterase 5 Inhibitors; Respiratory Rate; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Tricuspid Valve Insufficiency

Sildenafil, a phospohodiesterase-5 inhibitor, is widely used to treat pulmonary hypertension in infants with bronchopulmonary dysplasia despite a lack of evidence to support either safety or efficacy and US FDA advice against its use.

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature.

Topics: Bosentan; Bronchopulmonary Dysplasia; Hernia, Diaphragmatic; Humans; Hypertension, Pulmonary; Infant, Newborn; Milrinone; Nitric Oxide; Piperazines; Prostaglandins; Purines; Signal Transduction; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance

Sildenafil is occasionally used as rescue treatment for preterm infants with severe bronchopulmonary dysplasia and pulmonary arterial hypertension. In adults, sildenafil treatment has been associated with several ophthalmological adverse effects, including nonarteritic ischaemic optic neuropathy. We reviewed the effect of sildenafil on retinopathy of prematurity (ROP) in very preterm infants.. Retrospective case-control study. Infants born <30 weeks gestation who had received sildenafil during their hospitalisation were included. A control group matched for gestation, birth weight, gender, and place of birth was identified from the departmental database. For every sildenafil case, three matched controls were studied. Baseline data, sildenafil therapy data, results of eye examinations and respiratory data were analysed.. 17 infants received sildenafil between 2004 and 2010. The median duration of sildenafil treatment was 52 days. Baseline characteristics were similar between groups. The odds ratio for an increase in ROP stage in the group treated with sildenafil was 1.35 (95% confidence interval 0.39-4.62, P-value 0.63). One infant in each group required laser treatment.. Sildenafil treatment did not affect ROP progression or increase the need for laser treatment in this cohort.

Topics: Bronchopulmonary Dysplasia; Case-Control Studies; Disease Progression; Humans; Infant, Newborn; Infant, Premature; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retinopathy of Prematurity; Sildenafil Citrate; Sulfones

Bronchopulmonary dysplasia (BPD) is a major cause of morbidity in premature infants receiving oxygen therapy. Currently, sildenafil is being examined clinically to improve pulmonary function in patients with BPD. Based on the pharmacological action of sildenafil, the elevation of cyclic guanosine 3',5'-monophosphate (cGMP) in lung tissue is considered to underlie its beneficial effects, but this mechanism is not understood at the molecular level. Here, we examined the possibility that sildenafil helps the pulmonary system adapt to hyperoxic stress. To induce BPD, fetal rats were exposed to LPS before delivery, and neonates were exposed to hyperoxia, followed by intraperitoneal injections of sildenafil. Alveolarization was impaired in rats exposed to hyperoxia, and alveolarization significantly recovered with sildenafil. An immunohistochemical examination revealed that sildenafil effectively increased vascular distribution in lung tissue. Furthermore, the oxygen sensor hypoxia-inducible factor (HIF)-1/2α and the angiogenic factor vascular endothelial growth factor (VEGF) were highly expressed in the lungs of sildenafil-treated rats. In human small-airway epithelial cells, HIF-1/2α and its downstream genes, including VEGF, were confirmed to be induced by sildenafil at both the protein and mRNA levels. Mechanistically, cGMP in airway cells accumulated after sildenafil treatment because of interfering phosphodiesterase Type 5, and subsequently cGMP activated HIF-mediated hypoxic signaling by stimulating the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog 1 (AKT)-mammalian target of rapamycin (mTOR) pathway. This study provides a better understanding about the mode of action for sildenafil, and suggests that HIF can be a potential target for treating patients with BPD.

Topics: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Bronchopulmonary Dysplasia; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Female; Humans; Hypoxia-Inducible Factor 1; Infant, Newborn; Lung; Neovascularization, Physiologic; Phosphatidylinositol 3-Kinases; Piperazines; Pregnancy; Proto-Oncogene Proteins c-akt; Purines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sildenafil Citrate; Sulfones; TOR Serine-Threonine Kinases; Up-Regulation; Vascular Endothelial Growth Factor A

Bronchopulmonary dysplasia (BPD) of very preterm infants is a multifactorial chronic lung disease and its incidence has not decreased despite improvements in neonatal intensive care, including lung protective strategies. Pulmonary hypertension (PH) can complicate the course of BPD. Mortality in infants with BPD-associated PH is thought to be very high, but its incidence is unknown and a standard diagnostic and therapeutic strategy has not been well defined. In this article, we will first describe the current knowledge on the BPD-associated PH and the current treatments available for this pathology. We will then present the HTP-DBP Study, carried out in Paris (France) starting in 2012. The diagnosis of PH is suspected on echocardiographic criteria, but cardiac catheterization is considered the gold standard for diagnosis and evaluation of the severity of PH. Moreover, pulmonary vasoreactivity testing is used to guide the management of patients with PH. The pathogenesis of BPD-associated PH is poorly understood and even less is known about appropriate therapy. Today, optimizing ventilation and reducing the pulmonary vascular tone with specific pulmonary vasodilatator drugs are the main goals in treating HTP-associated DBP. Animal studies and a few clinical studies suggest that medications targeting the nitric oxide (NO) signaling pathway (NO inhalation, oral sildenafil citrate) could be effective treatments for BPD-associated PH, but they have not been approved for this indication. The HTP-DBP study is a French multicenter prospective observational study. The objective is to evaluate the frequency of BPD-associated PH, to describe its physiopathology, its severity (morbidity and mortality), and the effectiveness of current treatments.

Topics: Administration, Inhalation; Bronchodilator Agents; Bronchopulmonary Dysplasia; Cardiac Catheterization; Familial Primary Pulmonary Hypertension; France; Humans; Hypertension, Pulmonary; Incidence; Infant, Extremely Premature; Infant, Newborn; Nitric Oxide; Piperazines; Positive-Pressure Respiration; Prospective Studies; Purines; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

A 23-week-old baby, born at 26(+2) weeks, presented to the hospital with critical respiratory failure, which was impossible to stabilize. She had unstable oxygen saturations between 35% and 95%. A presumptive diagnosis of bronchopulmonary dysplasia with associated pulmonary hypertensive crisis was made. In the absence of inhaled nitric oxide, 2 oral doses of 1 mg/kg sildenafil were given, with a dramatic improvement 30 to 45 minutes later. Her oxygenation index fell from 43 to 14. She made a full recovery and was discharged from the hospital 2 weeks later.

Topics: Administration, Oral; Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Arrest; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Intubation, Gastrointestinal; Oxygen; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Respiratory Insufficiency; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Bronchopulmonary Dysplasia; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

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).. A retrospective review was performed from 2005 to 2009. 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.. Sildenafil citrate was used in 21 preterm infants with BPD-associated 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.. Sildenafil citrate reduced estimated pulmonary artery pressures, but this reduction was not reflected in improved gas exchange within the first 48  h.

Topics: Bronchopulmonary Dysplasia; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Gas Exchange; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Topics: Bronchopulmonary Dysplasia; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones

While new pharmacological approaches have been demonstrated to effectively manage PH in adults, few reports have addressed PH treatment in neonates and infants. This case report describes the successful management of severe PH secondary to bronchopulmonary dysplasia, respiratory syncytial virus infection, and hypoxia in a preterm 4-month-old with the long-term use of orally administered sildenafil and inhaled iloprost.

Topics: Administration, Inhalation; Administration, Oral; Bronchopulmonary Dysplasia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Infant; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Respiratory Syncytial Virus Infections; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Bronchopulmonary dysplasia is a common adverse outcome of very premature babies treated with long-lasting ventilation and oxygen therapy. Infants with bronchopulmonary dysplasia may develop pulmonary arterial hypertension. We report on severe bronchopulmonary dysplasia in a preterm infant who developed secondary, symptomatic and progressively severe pulmonary arterial hypertension. He was treated with sildenafil for 12 months, with complete resolution of pulmonary arterial hypertension. Eighteen months after therapy discontinuation, the patient was asymptomatic, and his systolic pulmonary artery pressure was normal. Routine use of sildenafil in preterm infants with bronchopulmonary dysplasia and secondary pulmonary arterial hypertension could be the future; large studies should confirm this report.

Topics: Antihypertensive Agents; Blood Pressure; Bronchopulmonary Dysplasia; Drug Administration Schedule; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Ultrasonography; Vasodilator Agents

To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy.. We conducted a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms.. Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis.. These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.

Topics: Blood Pressure; Bronchopulmonary Dysplasia; Echocardiography; Female; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome

Chronic lung disease (CLD) is often complicated by chronic pulmonary vascular changes and pulmonary hypertension (PH) in young children. Current therapies for severe PH in such patients, including oxygen, inhaled nitric oxide, and parenteral prostacyclin, are often suboptimal, cumbersome, and expensive. Recently, oral endothelin receptor blockers and phosphodiesterase-5 inhibitors have been used successfully to control and reverse pulmonary vascular disease in idiopathic PH, but the use and efficacy of these agents in pediatric CLD have not been previously reported. We report a series of six children with CLD and severe PH treated with bosentan (six of six) and sildenafil (four of six). Vascular reactivity was assessed by cardiac catheterization prior to and after 6 months of therapy. Serial echocardiography was also used to assess response. Patients have been treated for 2.1-2.9 years (mean, 2.53 years). Response to therapy has included improvement in oxygenation, symptoms, echocardiographic parameters, and hemodynamics by cardiac catheterization. Transiently elevated liver enzymes were noted associated with viral respiratory infections in two subjects; no other adverse effects were noted. Three patients with large cardiac right-to-left shunts prior to therapy had subsequent shunt reversal, two of whom underwent shunt closure later. Oral therapy with bosentan alone or in combination with sildenafil improves PH in patients with CLD over a period of 3-4 years.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Bronchopulmonary Dysplasia; Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

We report the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension refractory to inhaled nitric oxide treatment, maximal ventilatory support and conventional vasodilator therapy. Sildenafil was prepared as a liquid suspension by the method of trituration and administered via an orogastric tube to the patient. Forty-eight hours after sildenafil treatment, echocardiography revealed that the tricuspid incompetence was substantially diminished and the contractility of both ventricles improved, indicating a marked reduction in pulmonary arterial pressure. Oral sildenafil treatment was continued for 6 months until complete resolution of pulmonary arterial hypertension, and oxygen supplement was weaned off. There was no adverse effect during the treatment period. Oral sildenafil may be useful in reducing pulmonary vascular resistance and can be considered for treatment of severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia.

Topics: Administration, Oral; Bronchopulmonary Dysplasia; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents