sildenafil-citrate and Persistent-Fetal-Circulation-Syndrome

Persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem characterized by refractory and severe hypoxemia secondary to elevated pulmonary vascular resistance resulting in right-to-left extrapulmonary shunting of deoxygenated blood. PPHN is associated with diverse cardiopulmonary disorders and a high early mortality rate for infants with severe PPHN. Surviving infants with PPHN have an increased risk of long-term morbidities. PPHN physiology can be categorized by (1) maladaptation: pulmonary vessels have normal structure and number but have abnormal vasoreactivity; (2) excessive muscularization: increased smooth muscle cell thickness and increased distal extension of muscle to vessels that are usually not muscularized; and (3) underdevelopment: lung hypoplasia associated with decreased pulmonary artery number. Treatment involves adequate lung recruitment, optimization of cardiac output and left ventricular function, and pulmonary vasodilators such as inhaled nitric oxide. Infants who fail to respond to conventional therapy should be evaluated for lethal lung disorders including alveolar-capillary dysplasia, T-box transcription factor 4 gene, thyroid transcription factor-1, ATP-binding cassette A3 gene, and surfactant protein diseases.

Topics: Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Infant; Infant, Newborn; Infant, Premature; Lung; Milrinone; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Pulmonary Alveoli; Pulmonary Surfactants; Risk; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Humans; Infant, Newborn; Off-Label Use; Persistent Fetal Circulation Syndrome; Randomized Controlled Trials as Topic; Sildenafil Citrate; Tadalafil

Although persistent pulmonary hypertension of the newborn (PPHN) and infantile hypertrophic pyloric stenosis (HPS) are both well-known diseases that occur in early infancy, PPHN complicated by HPS is rare. As nitric oxide (NO) is an important mediator of biological functions, on both the vascular endothelium and smooth muscle cells, the decreased production of NO might play a role in the pathogenesis of both PPHN and HPS. We present the case of a neonate who developed HPS following PPHN, including a detailed review on research published to date, and we discuss the pathogenesis of PPHN and HPS.. A female neonate born at 38 weeks of gestation, weighing 3140 g, developed PPHN due to meconium aspiration syndrome. Intensive treatment with high frequency oscillations and inhaled NO were initiated, and sildenafil and bosentan were added. She gradually recovered. At 15 days of age, the patient developed recurrent vomiting after feeding and the diagnosis of HPS was made. Intravenous atropine therapy was started at 20 days of age, but the efficacy was clinically unsatisfactory. The coadministration with transdermal nitroglycerin improved the symptoms, and oral feeding was successfully re-introduced.. Our patient recovered from both PPHN and HPS using NO-related medications. A decrease in NO synthesis is likely to be a common pathway for PPHN and HPS.

Topics: Antihypertensive Agents; Atropine; Bosentan; Bronchodilator Agents; Female; High-Frequency Ventilation; Humans; Infant, Newborn; Meconium Aspiration Syndrome; Muscarinic Antagonists; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Persistent Fetal Circulation Syndrome; Pyloric Stenosis, Hypertrophic; Sildenafil Citrate; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) represents a challenging condition associated with significant morbidity. A successful transition from intrauterine to extrauterine life is contingent on adequate pulmonary vasodilation. Several pathophysiologies contribute to the failure of this cascade and may result in life-threatening hypoxia and acidosis in the newborn. Management includes optimal respiratory support, adequate sedation and analgesia, and support of vascular tone and cardiac function. Pulmonary vasodilation has the potential to overcome the cycle of hypoxia and acidosis, improving outcome in these infants. Oxygen and inhaled nitric oxide represent the foundation of therapy. Tertiary pulmonary vasodilators represent a greater challenge, selecting between therapies that include prostanoids, sildenafil, and milrinone. Variable levels of evidence exist for each agent. Thorough review of available data informing efficacy and adverse effects contributes to the development of an informed approach to neonates with refractory PPHN.

Topics: Bosentan; Humans; Infant, Newborn; Milrinone; Nitric Oxide; Oxygen Inhalation Therapy; Persistent Fetal Circulation Syndrome; Prostaglandins; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

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

Persistent pulmonary hypertension of the newborn (PPHN) is a surprisingly common event in the neonatal intensive care unit, and affects both term and preterm infants. Recent studies have begun to elucidate the maternal, fetal and genetic risk factors that trigger PPHN. There have been numerous therapeutic advances over the last decade. It is now appreciated that oxygen supplementation, particularly for the goal of pulmonary vasodilation, needs to be approached as a therapy that has risks and benefits. Administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of disease and duration of hospital stay. Milrinone may have specific benefits as an 'inodilator', as prolonged exposure to iNO plus oxygen may activate phosphodiesterase (PDE) 3A. Additionally, sildenafil and hydrocortisone may benefit infants exposed to hyperoxia and oxidative stress. Continued investigation is likely to reveal new therapies such as citrulline and cinaciguat that will enhance NO synthase and soluble guanylate cyclase function. Continued laboratory and clinical investigation will be needed to optimize treatment and improve outcomes.

Topics: Administration, Inhalation; Disease Management; Extracorporeal Membrane Oxygenation; Humans; Hydrocortisone; Infant, Newborn; Milrinone; Nitric Oxide; Oxygen Inhalation Therapy; Persistent Fetal Circulation Syndrome; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a serious and potentially fatal condition, characterized by hypoxemia due to increased pulmonary vascular resistance (PVR) with resultant shunting of pulmonary blood to the systemic circulation. Inhaled nitric oxide (iNO) has been considered a revolutionary treatment of PPHN. Data show that the use of iNO has reduced the need of ECMO in neonates with severe PPHN, while in moderate PPHN, iNO administration has been associated with a significant decrease in ventilatory support and prevented progression to severe PPHN. Not all neonates respond to iNO therapy though, and phosphodiesterase (PDE) inhibitors with their potent vasodilator properties have evolved as an alternative therapy or as an adjunct to the treatment of PPHN with iNO. There are ten families of PDE isoenzymes. PDE 5 is particularly prevalent in vascular smooth muscle (VSM) and PDE 5 inhibitors, such as sildenafil, have been used in clinical practice. This review provides a comprehensive account of existing data in the literature, from animal and clinical studies, on the use of sildenafil for the treatment of PPHN. Sildenafil may also have a role as a single mode of therapy, since in resource-limited settings the cost of iNO is a serious concern.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Humans; Infant, Newborn; Nitric Oxide; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Bosentan; Child; Citrulline; Drug Therapy, Combination; Endothelium, Vascular; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Muscle Contraction; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Piperazines; PPAR gamma; Prostaglandins; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasoconstriction; Ventricular Function, Right

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening neonatal pathology resulting from poor hemodynamic and respiratory transition to extrauterine life. Inhaled nitric oxide (iNO) is a current, commonly used treatment of PPHN. However, some infants with PPHN do not respond to iNO therapy. Because of the significant morbidity and mortality associated with PPHN, it is useful to look at other possible therapies. This article explores the use of sildenafil in the treatment of PPHN, either as a supplement to iNO or as an alternative to iNO. Current research, including a case study, is reviewed. An emphasis is placed on the administration and efficacy of sildenafil in synergy with, and in lieu of, current iNO therapy in the treatment of PPHN.

Topics: Bronchodilator Agents; Drug Therapy, Combination; Evidence-Based Practice; Humans; Infant, Newborn; Intensive Care, Neonatal; Neonatal Nursing; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Risk Factors; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN), is defined as a failure of the pulmonary vasculature to relax at birth and consequently of the normal adaptation to extra uterine life of the fetal heart/lung system, resulting in hypoxemia. This condition, occurs in about 1-2 newborns per 1000 live births and despite significant improvements in treatment it is associated with substantial infant mortality and morbidity. Over the years wider application of inhaled nitric oxide (iNO) therapy and improved ventilation strategies including surfactant, high-frequency oscillatory ventilation has led to a decrease in the need for invasive life-sustaining therapies such as extracorporeal membrane oxygenation (ECMO). Mortality rate varies from 10 to 20 % of affected newborns in developed countries, but it is much higher when PPHN is refractory to the above reported therapies or when they are not available. As a consequence, development of new therapeutic strategies for severe PPHN is crucial. In particular, recent studies seem to show that sildenafil, a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance may be a useful therapeutic adjunct to critically ill neonates with PPHN.

Topics: Administration, Inhalation; Humans; Infant, Newborn; Milrinone; Nitric Oxide; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones

Persistent pulmonary hypertension of the newborn (PPHN) is a cardiopulmonary disorder characterized by systemic arterial hypoxemia secondary to elevated pulmonary vascular resistance with resultant shunting of pulmonary blood flow to the systemic circulation. PPHN is a serious illness that becomes progressively worse and is sometimes fatal. Management of the disease includes treatment of underlying causes, sedation and analgesia, maintenance of adequate systemic blood pressure, and ventilator and pharmacologic measures to increase pulmonary vasodilatation, decrease pulmonary vascular resistance, increase blood and tissue oxygenation, and normalize blood pH. Inhaled nitric oxide (NO) has been one of the latest measures to successfully treat PPHN. If all other treatments fail, extracorporeal membrane oxygenation (ECMO) can be used. Recently, preclinical and clinical studies have demonstrated the utility of the selective inhibitor of phosphodiesterase type 5 (PDE5), sildenafil, in decreasing pulmonary hypertension (HP). Sildenafil was first employed to offset rebound pulmonary hypertension in infants upon withdrawal of NO treatment. Later, several case reports demonstrated the effectiveness of sildenafil in the treatment of PPHN. Two randomized blinded studies with sildenafil in infants with PPHN were published in 2006. In both studies, the patients treated with sildenafil showed a steady improvement in pulse oxygen saturation over time. Likewise, the frequency death was lower in the groups treated with sildenafil. Recent evidence shows the utility of sildenafil in the treatment of PPHN. However, since existing data are limited there is an urgent need for multicenter blinded, placebo controlled, randomized trials.

Topics: Animals; Humans; Infant, Newborn; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Topics: Administration, Oral; Humans; Infant, Newborn; Patient Selection; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with multiple causes, with an incidence of 0.43-6.8/1,000 live births and a mortality of 10-20%. Survivors have high morbidity in the forms of neurodevelopmental and audiological impairment, cognitive delays, hearing loss, and a high rate of rehospitalization. The optimal approach to the management of PPHN remains controversial. Inhaled nitric oxide (iNO) is currently regarded as the gold standard therapy, but with as many as 30% of cases failing to respond, has not proven to be the single magic bullet. Given the complex pathophysiology of the disease, any such magic bullet is unlikely. A number of recent studies have suggested a role for specific phosphodiesterase (PDE) inhibitors in the management of PPHN. Sildenafil, a specific PDE5 inhibitor, appears the most promising of such agents. We aim to review the current status and limitations of iNO and the potential of PDE inhibitors in the management of PPHN. The reasons why caution is warranted before specific PDE5 inhibitors like sildenafil are labelled as potential magic bullets for PPHN will be discussed. The need for randomized-controlled trials to determine the safety, efficacy, and long-term outcome following treatment with sildenafil in PPHN is emphasized.

Topics: Dipyridamole; Endothelium-Dependent Relaxing Factors; Humans; Infant, Newborn; Nitric Oxide; Pentoxifylline; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Purinones; Sildenafil Citrate; Sulfones

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a condition caused by failure of pulmonary vascular adaptation at birth, resulting in severe hypoxia. Several therapeutic modalities are being tried in developing countries where established therapies (inhaled nitric oxide and extracorporeal membrane oxygenation) are widely unavailable. This study aimed to assess the efficacy of milrinone versus sildenafil as available alternative therapeutics in treating PPHN. Forty neonates (>34 weeks) admitted to neonatal intensive care units with evidence of PPHN were randomly allocated to receive either oral sildenafil (0.5-2 mg/kg/6 hours) or intravenous milrinone (0.25-0.75 mic/kg/min). Primary outcomes included improvements in systolic pulmonary artery pressure and oxygen saturation index (OSI) at 24 and 48 hours after treatment. Secondary outcomes included the duration of hospitalization and mechanical ventilation. The ClinicalTrials identifier is NCT04391478. Both groups showed significant improvement in the post-treatment hemodynamic variables compared with pretreatment levels ( P < 0.05 for all parameters). Systolic pulmonary artery pressure and OSI values significantly improved in both study groups compared with baseline ( P < 0.001). The 24-hour and 48-hour post-treatment OSI values were much lower in the milrinone group than those in the sildenafil group ( P < 0.05). The length of hospital stay was significantly shorter in the milrinone group than that in the sildenafil group ( P < 0.05). There were no significant differences in the duration of mechanical ventilation, incidence of intracranial hemorrhage and pulmonary hemorrhage, or mortality between the 2 groups ( P > 0.05). In conclusion, milrinone and sildenafil are effective and well-tolerated in neonates with PPHN, particularly when inhaled nitric oxide and extracorporeal membrane oxygenation are not available. Milrinone is superior to sildenafil in improving oxygenation without lowering blood pressure parameters.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Milrinone; Nitric Oxide; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN.. Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related.. IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

Topics: Administration, Inhalation; Double-Blind Method; Endothelium-Dependent Relaxing Factors; Female; Humans; Infant, Newborn; Infusions, Intravenous; Male; Nitric Oxide; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

Inhaled nitric oxide (iNO) is the standard therapy for infants with persistent pulmonary hypertension of the newborn (PPHN). Recently, sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator.. To assess the effectiveness of adding sildenafil as an early adjunctive therapy together with iNO when treating newborns with PPHN and/or hypoxemic respiratory failure.. This is a randomized placebo trial on newborns with gestational age > 34 weeks, postnatal age < 48 hours, and diagnosed with PPHN (oxygen index (OI) ≥ 20). Newborns were randomized to two groups: Group A- received oral sildenafil and iNO, and group B- received placebo and iNO. Initial and follow up echocardiography were performed over 14 days period.. A total of 24 newborns were recruited; 13 of them received sildenafil in addition to iNO and 11 received iNO and placebo. The most common causes of PPHN were meconium aspiration syndrome, pneumonia, and RDS. At the starting point, OI was marginally higher in the intervention group without statistical significance (29 vs 28). There were no differences between the two groups regarding surfactant administration, incidence of pneumothoraces, and the underlying causes of PPHN. Sildenafil or placebo treatment started within 12 hours after starting iNO (8 vs 6 hours).. Early use of oral sildenafil next to iNO in cases of PPHN was tolerated well by newborns and it did not show significant adverse effects. Further studies with a larger sample size is needed to assess its effecacy.

Topics: Administration, Oral; Double-Blind Method; Feasibility Studies; Female; Humans; Infant, Newborn; Infant, Premature; Male; Nebulizers and Vaporizers; Nitric Oxide; Persistent Fetal Circulation Syndrome; Prospective Studies; Qatar; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

The aim of this prospective, randomized and controlled study was to compare the clinical efficacy of intravenous magnesium sulfate (MgSO₄) and oral sildenafil therapies with persistent pulmonary hypertension of the newborn. A total of 34 infants in the MgSO₄ group and 31 infants in the sildenafil group completed the study. The time to reach the adequate clinical response [defined as oxygen index (OI) level of <15, a pulmonary artery pressure of < 20 mmHg) was significantly shorter in the sildenafil group (p = 0.002). Duration of mechanical ventilation was longer and the number of the patients requiring inotropic support was higher in the MgSO₄ group (p = 0.001 and p = 0.002, respectively). Although among two groups the difference in OI > 5 as speculated in our hypothesis could only be found at 36 h of the treatment, sildenafil was more effective than MgSO₄ in the treatment of persistent pulmonary hypertension of the newborns with regard to time to adequate clinical response, duration of mechanical ventilation and support requirement with inotropic agents.

Topics: Administration, Oral; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Injections, Intravenous; Intensive Care Units; Magnesium Sulfate; Male; Oxygen; Persistent Fetal Circulation Syndrome; Piperazines; Prospective Studies; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We evaluated the effectiveness of sildenafil in the treatment of neonatal pulmonary hypertension. We performed a double-blind randomized clinical trial in 51 full-term infants with persistent pulmonary hypertension confirmed by Doppler echocardiography. Patients were divided in two groups: 20 infants in group A received placebo when the oxygenation index was >20, and 31 infants in group B received 3 mg/kg of oral sildenafil every 6 hours. Arterial blood gases were taken at 1, 4, 7, 13, 19, and 25 hours after treatment was started. Main outcome measures were oxygenation changes, time on mechanical ventilation, and mortality. Both groups were comparable in general variables as well as in illness severity. We observed better oxygenation parameters after 7 hours of sildenafil treatment, but no significant changes were found in the placebo group. Mortality was higher in the placebo group (40%) than in those infants who received sildenafil (6%; P = 0.004), although no difference was found in time on mechanical ventilation between groups. Our results confirm that sildenafil may be a useful adjuvant therapy for term infants with pulmonary hypertension in centers lacking inhaled nitric oxide and extracorporeal membrane oxygenation.

Topics: Combined Modality Therapy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Male; Oxygen Inhalation Therapy; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The phosphodiesterase 5 inhibitor sildenafil is a potential therapeutic option in the treatment of persistent pulmonary hypertension of the newborn (PPHN) and neonatal hypoxemia. In this open-label trial, 36 term neonates with PPHN or hypoxemia were administered intravenous sildenafil for up to 7 days starting within 72 h of birth. A mixed-effects pharmacokinetic model that included two-compartment disposition of sildenafil and its metabolite and an effect of postnatal age on sildenafil clearance was used to describe plasma concentration-time data of parent and metabolite. Allometrically scaled sildenafil clearance increased threefold from the first day after birth to values similar to those in adults by the first week. Volume of distribution of sildenafil in neonates was fourfold higher than in adults, resulting in a longer terminal half-life in neonates (48-56 h) compared to adults. Increase in sildenafil clearance in the early postnatal period likely reflects maturation of CYP-mediated N-demethylation.

Topics: Biological Availability; Female; Half-Life; Humans; Infant, Newborn; Infusions, Intravenous; Male; Metabolic Clearance Rate; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones

To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN).. This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days.. Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 +/- 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO.. IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses.

Topics: Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Male; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Pilot Projects; Piperazines; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Persistent pulmonary hypertension (PPHN) occurs in as many as 6.8 of 1000 live births. Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are not available. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance.. Our goal was to evaluate the feasibility of using oral sildenafil and its effect on oxygenation in PPHN.. This study was a proof-of-concept, randomized, masked study in infants >35.5 weeks' gestation and <3 days old with severe PPHN and oxygenation index (OI) >25 admitted to the NICU (Hospital Niño Jesús, Barranquilla, Colombia). The sildenafil solution was prepared from a 50-mg tablet. The first dose (1 mg/kg) or placebo was given by orogastric tube <30 minutes after randomization and every 6 hours. Preductal saturation and blood pressure were monitored continuously. OI was calculated every 6 hours. The main outcome variable was the effect of oral sildenafil on oxygenation. Sildenafil or placebo was discontinued when OI was <20 or if there was no significant change in OI after 36 hours.. Six infants with an OI of >25 received placebo, and 7 received oral sildenafil at a median age of 25 hours. All infants were severely ill, on fraction of inspired oxygen 1.0, and with similar ventilatory parameters. Intragastric sildenafil and placebo were well tolerated. In the treatment group, OI improved in all infants within 6 to 30 hours, all showed a steady improvement in pulse oxygen saturation over time, and none had noticeable effect on blood pressure; 6 of 7 survived. In the placebo group, 1 of 6 infants survived.. Oral sildenafil was administered easily and tolerated as well as placebo and improved OI in infants with severe PPHN, which suggests that oral sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial.

Topics: Administration, Oral; Blood Pressure; Double-Blind Method; Female; Humans; Infant, Newborn; Male; Oxygen; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Pilot Projects; Piperazines; Purines; Sildenafil Citrate; Sulfones; Survival Rate; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs).. A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed.. There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation.. We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

Topics: Administration, Inhalation; Humans; Hypertension, Pulmonary; Infant, Newborn; Intensive Care Units, Neonatal; Nitric Oxide; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Surveys and Questionnaires; Vasodilator Agents

The prevalence of persistent pulmonary hypertension of newborn (PPHN) has been estimated 1.9/1000 live births. Although the efficacy of inhaled nitric oxide and extracorporeal membrane oxygenation in PPHN is well established but it is difficult to administer and monitor in resource limited countries. Owing to this, other treatment options need to be evaluated.. Total 82 newborns were enrolled. Fifty-two patients improved after 48 h so were continued on same treatment. Sildenafil dose was increased in 30 (37.9%) patients whose PO. The results of our study show effectiveness of oral Sildenafil in treating PPHN. The overall improvement observed in the patients was overwhelming. Combination of Sildenafil with Bosentan is beneficial in patients who did not respond on Sildenafil alone.

Topics: Bosentan; Child; Humans; Infant, Newborn; Nitric Oxide; Persistent Fetal Circulation Syndrome; Prospective Studies; Sildenafil Citrate; Tertiary Care Centers; Vasodilator Agents

While advanced therapies for severe persistent pulmonary hypertension of the newborn (PPHN) such as inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are standard treatments in high-income countries, these therapies are often unavailable in resource-limited settings such as middle-income countries. However, there are small clinical trials illustrating the efficacy of sildenafil at reducing mortality in PPHN. This analysis sought to determine the cost-utility of enteral sildenafil for the treatment of severe PPHN.. A Markov-state transition model was constructed for the two clinical approaches to compare costs, clinical outcomes, and quality of life: (1) "conventional," (2) "sildenafil." The impact of sildenafil was modeled as a relative risk modifier of the conventional strategy's mortality risk. Transitional probabilities, costs, and utility metrics were extracted from the literature. Sensitivity analyses for each model input as well as 100-patient Monte Carlo simulations were used to test the durability of the model conclusion.. The sildenafil strategy was cost-effective for upper but not lower middle-income countries with an incremental cost-effectiveness ratio of $2,339 per quality-adjusted life year. This conclusion was durable across a wide-range of model assumptions; the sildenafil strategy only failed to meet criteria for cost-effectiveness when sildenafil therapy had a mortality relative risk efficacy of >0.89, if life expectancy in that country is <40 years, or if the lifetime forecasted costs of a survivor's life was quite high.. Enteral sildenafil is a cost-effective intervention for severe PPHN for upper middle-income countries where ECMO and iNO are not available.. · PPHN is a common life-threatening condition in newborns.. · Sildenafil improves survival of PPHN.. · Sildenafil is cost-effective for upper-middle income countries..

Topics: Cost-Benefit Analysis; Developing Countries; Health Care Costs; Humans; Income; Infant, Newborn; Models, Biological; Persistent Fetal Circulation Syndrome; Quality of Life; Quality-Adjusted Life Years; Sildenafil Citrate; Vasodilator Agents

About 10% of term neonates present with respiratory distress at birth. The most common aetiologies include transient tachypnoea of the newborn, pneumonia and meconium aspiration syndrome (MAS). Hyaline membrane disease (HMD) in a term infant occurs either as primary HMD, secondary surfactant deficiency or congenital surfactant dysfunction. A detailed history supported with appropriate radiological and laboratory investigations can help a clinician reach a diagnosis. We report a case of surfactant dysfunction disorder which presented as severe MAS and persistent pulmonary hypertension of the newborn. In the infant described, the significant history of a sibling death with severe neonatal respiratory disease led us to think of diffuse developmental lung diseases especially surfactant dysfunction syndromes. Exome sequencing detected a heterozygous missense variation in exon 21 of the ATP binding cassette protein member 3 (

Topics: ATP-Binding Cassette Transporters; Bronchodilator Agents; Diagnosis, Differential; Fatal Outcome; Humans; Infant, Newborn; Lung Diseases, Interstitial; Male; Meconium Aspiration Syndrome; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Surfactants; Respiration, Artificial; Sildenafil Citrate; Vasodilator Agents

Premature preterm rupture of membranes (PPROM) is reported to be associated with high rates of neonatal mortality and morbidity. Sildenafil has been used in infants with persistent pulmonary hypertension of newborn (PPHN) due to congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD). Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator. This case report illustrates the use of early sildenafil for PPHN and right ventricular dysfunction in an unusual setting of lung and renal hypoplasia.. A male infant was born at 37 weeks with a birth weight of 2840 g. Rupture of membranes developed at approximately 24 weeks of gestational age (GA). Bilateral small kidneys (< 2 standard deviations below average) were detected on ultrasound (US) examination at 30 weeks of gestation. The baby developed pneumothorax and pulmonary hypertensive crisis towards the end of the first day. An echocardiogram showed a dilated right ventricle, moderate right ventricular systolic dysfunction, hypoplastic pulmonary arteries and a large patent ductus arteriosus with bidirectional flow. The patient was sedated, paralyzed, and inhaled nitric oxide was administered to decrease the pulmonary resistance. In anticipation of persistent pulmonary hypertension due to the hypoplastic lungs and small calibre of pulmonary arteries, sildenafil was started on day of life (DOL) 5 at a dosage of 0.25 mg/kg/dose Q8H and gradually increased to 2 mg/kg/dose Q8H on DOL 9. The patient was finally extubated on DOL 7 and weaned off of non-invasive respiratory support on DOL 26. Sildenafil was gradually weaned beginning on DOL 21 and discontinued on DOL 48. Repeat echocardiogram assessment at 3 months showed complete resolution of PHT and right ventricular dilatation.. We describe the early use of sildenafil in treating pulmonary hypertension associated with lung and renal hypoplasia in a non-CDH patient. Following this treatment the patient made a full recovery from right ventricular dysfunction.

Topics: Antihypertensive Agents; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Kidney; Lung; Male; Persistent Fetal Circulation Syndrome; 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

We report significant hypotension and prerenal failure in an extremely preterm infant following two doses of oral sildenafil that warranted discontinuation of the drug and treatment with inotropes. Blood pressure and urine output normalized after 24 h of withdrawal of the oral drug. Sildenafil should be used cautiously in extremely preterm infants early in the neonatal course, where there is limited data on its efficacy and safety.

Topics: Acidosis, Lactic; Administration, Oral; Female; Humans; Hypotension; Infant, Extremely Premature; Infant, Newborn; Kidney; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

Despite recent treatment modalities, mortality from persistent pulmonary hypertension (PPHN) remains significant. In instances where infants do not respond to inhaled nitric oxide (iNO), oral sildenafil could hold promise as a selective pulmonary vasodilator. Further studies are still needed to explore its efficacy and safety in newborns with PPHN.. To validate the efficacy of oral sildenafil on oxygenation and its short-term safety in newborns with persistent pulmonary hypertension.. A total of 27 newborns ≥36 weeks gestational age were admitted to NICU with oxygenation index (OI) ≥15 and confirmed diagnosis of PPHN with echocardiography. Oral sildenafil given at a dose of 1-2 mg/kg every 6 hours. We monitored improvement in oxygenation, safety and short-term outcomes.. Among 27 newborns, oral sildenafil was efficacious in 21 patients (78%) with reduction of OI from 34.9 ± 9.6 to 13 ± 3.2 (p <  0.001), increase of PaO2 from 42.4 ± 13.5 to 78 ± 11.5 mmHg (<0.001), and reduction of FiO2 from 1.0 ± 0 to 0.3 ± 0.06 (<0.001). OI decreased by 6.3 % from baseline after the first dose of sildenafil and continued to decrease with subsequent doses. In 6 patients (22%) sildenafil did not work; 5/6 patients (18%) transferred to another tertiary NICU and one patient (4%) died of sepsis. None of the patients had significant systemic hypotension.. Oral sildenafil is a promising pulmonary vasodilator in patients with PPHN, particularly in medical facilities with no available iNO and ECMO. It is well tolerated with no significant short term complications.

Topics: Administration, Oral; Blood Pressure; Bronchodilator Agents; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth, seen in about 2/1000 live born infants. While it is mostly seen in term and near-term infants, it can be recognized in some premature infants with respiratory distress or bronchopulmonary dysplasia. Most commonly, PPHN is secondary to delayed or impaired relaxation of the pulmonary vasculature associated with diverse neonatal pulmonary pathologies, such as meconium aspiration syndrome, congenital diaphragmatic hernia, and respiratory distress syndrome. Gentle ventilation strategies, lung recruitment, inhaled nitric oxide, and surfactant therapy have improved outcome and reduced the need for extracorporeal membrane oxygenation (ECMO) in PPHN. Newer modalities of treatment discussed in this article include systemic and inhaled vasodilators like sildenafil, prostaglandin E1, prostacyclin, and endothelin antagonists. With prompt recognition/treatment and early referral to ECMO centers, the mortality rate for PPHN has significantly decreased. However, the risk of potential neurodevelopmental impairment warrants close follow-up after discharge for infants with PPHN.

Topics: Administration, Inhalation; Alprostadil; Asphyxia Neonatorum; Endothelium-Dependent Relaxing Factors; Epoprostenol; Extracorporeal Membrane Oxygenation; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Infant, Newborn; Meconium Aspiration Syndrome; Nitric Oxide; Oxygen Inhalation Therapy; Persistent Fetal Circulation Syndrome; Piperazines; Pulmonary Surfactants; Purines; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Intravenous sildenafil treatment has recently shown promising results and good tolerability in the treatment of refractory pulmonary hypertension (PH) in term and near-term neonates, while comparable data in preterm infants are still lacking. However, for critically ill preterm infants suffering from PH refractory to conventional treatment, sildenafil may represent a last treatment resort.. We reviewed the records of 6 critically ill extremely preterm infants who had suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment.. To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome.. 4/6 patients showed resolution of severe PH with full reversal of ductal shunt direction into pure left-to-right shunt within 82 ± 35 h after sildenafil start. Remarkably, 2/6 patients developed pulmonary hemorrhage at a time point when significant improvement of PH had already taken place, both of them survived. Overall 4/6 patients died, two deaths were related to treatment-refractory PH.. Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of ductal shunt. Accordingly, sildenafil should be restricted to most severe and refractory cases in this population.

Topics: Female; Hemorrhage; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Infusions, Intravenous; Intensive Care Units, Neonatal; Lung Diseases; Male; Persistent Fetal Circulation Syndrome; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is the most serious condition that causes high mortality in term and post term infants. The authors have an experience of using high frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) for treatment of this condition with a good result. However, due to high cost of iNo, other pulmonary vasodilators have been use. Sildenafil had some side effects of systemic hypotension. Thus, inhaled iloprost was introduced for treatment of PPHN at our institute.. To evaluate the outcome of inhaled iloprost for the treatment of PPHN.. This was a retrospective study. The data from medical records of newborns, diagnosed as persistent pulmonary hypertension of the newborn and had received inhaled iloprost from October 1st, 2008-October 31st, 2012, were reviewed.. Nineteen cases of PPHN treated with inhaled iloprost were reviewed. Male to female ratio was 1.3 7:1 (11:8). Mean birth weight and gestational age of these patients were 2,997 ± 531.63 grams and 37.9 ± 2.51 weeks, respectively. Meconium aspiration syndrome was the leading underlying cause of this condition. The mortality rate in this study was 21% (4 from 19 cases). After the addition of inhaled iloprost, the oxygen index (OI) in the survivor group decreased significantly at one hour after treatment (from 32.89 to 22.06, 18.76, 13. 76 at 1, 6, 12 hours, respectively). Oxygen saturation (SpO2) continued increasing after treatment in the survivor group (from 82.40% to 92.20%, 95.00%, 95.80% at 1, 6, 12 hours, respectively) with significant difference at one hour. There was a significant difference of OI and SpO2 between the survivor and non-survivor groups after treatment. Low Apgar score at 5 minutes and early diagnosis of PPHN were found statistically significant different in the non-survivor compared to the survivor groups.. Inhaled iloprost could be used as an alternative treatment of PPHN without side effects of systemic hypotension.

Topics: Administration, Inhalation; Drug Administration Schedule; Female; High-Frequency Ventilation; Humans; Iloprost; Infant, Newborn; Lung; Male; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Thailand; Time Factors; Vasodilator Agents

The case is described herein of a patient with alveolar capillary dysplasia with double-outlet right ventricle and duodenal atresia who survived for a remarkably long time. The newborn girl was born at a gestational age of 36 weeks and weighed 1926 g. One min after delivery the Apgar score was 4. The patient had persistent pulmonary hypertension (PH) and needed nitric oxide inhalation and i.v. epoprostenol all through her life. Although other oral medications for PH were tried, they could not be used in practice because of gastrointestinal complications. The patient died on the 237 th day of life as a result of worsening PH associated with infection.

Topics: Administration, Inhalation; Bosentan; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Fatal Outcome; Female; Follow-Up Studies; Humans; Infant, Newborn; Nitric Oxide; Persistent Fetal Circulation Syndrome; Piperazines; Platelet Aggregation Inhibitors; Pulmonary Alveoli; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Vasodilator Agents

The use of sildenafil has become a common practice in neonatal intensive care unit on clinical ground, because opinion by Pediatric Cardiologist is usually not available especially in peripheral centers. We consider it essential to share our experience that severe pulmonary arterial hypertension can be due to some unusual hemodynamics or extremely rare structural causes which do not require pulmonary vasodilator therapy.

Topics: Diagnosis, Differential; Echocardiography; Female; Humans; Infant; Infant, Newborn; Male; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Over the last few years, sildenafil is increasingly being used in the neonatal ICU for a variety of indications. The use is even more so in the developing world due to the limited availability of nitric oxide and extracorporeal membrane oxygenation (ECMO). There are still no clear cut guidelines for its use. At present the drug appears relatively safe and effective when other treatment options have been optimized. However, the use of sildenafil must be monitored and reported. Due to its easy availability and ease of administration we must guard against its inappropriate use.

Topics: Humans; Infant, Newborn; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Premature infants with preterm premature rupture of membranes (PPROM) are at high risk of severe respiratory failure because of lung hypodysplasia associated with persistent pulmonary hypertension of the newborn (PPHN). We describe the clinical course of a 28-week gestation infant with PPROM from the 20th week and prolonged oligohydramnios before delivery, who developed refractory hypoxia treated with oral bosentan as adjunct therapy to inhaled nitric oxide (iNO) and oral sildenafil. Conclusion Our experience suggests that bosentan can be used in the premature infant with PPHN after PPROM. To the best of our knowledge, this is the first report of bosentan treatment in a premature infant.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Despite the recent advances, the clinical approach to persistent pulmonary hypertension of the newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of nitric oxide and high-frequency ventilation. However, not all the neonates with PPHH are responsive to this clinical approach. Recent studies have proposed the use of sildenafil, a phosphodiesterase 5 inhibitor, in refractory forms of PPHN. The aim of this study is to review the cases and the clinical approach of PPHN in the Neonatal Intensive Care Unit of Meyer Children Hospital in the year 2009 and to discuss the possible role of sildenafil in the management of PPHN.

Topics: Antihypertensive Agents; Gestational Age; Humans; Infant, Newborn; Length of Stay; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Infant, Newborn; Infusions, Parenteral; Male; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Administration, Oral; Fatal Outcome; Female; Humans; Infant, Newborn; Male; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Blood Pressure; Humans; Infant, Newborn; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The authors report one case of persistent pulmonary hypertension that had hypoxia although receiving treatment with high frequency oscillation, inotropic drugs, blood transfusion, and oral sildenafil for pulmonary vasodilatation. The patient developed hypotension after two doses of oral sildenafil and no response to high dose of inotropic drugs. So aerosolized iloprost was given via endotracheal tube and oxygen saturation improved within 10 minutes. Oxygen was weaned at 36 hours after treatment with this drug and no any side effect was found.

Topics: Female; High-Frequency Ventilation; Humans; Hypotension; Iloprost; Infant, Newborn; Intubation, Intratracheal; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Failure; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) remains an important cause of mortality and morbidity in the term neonate. Preliminary but limited data suggest that there may be a role for sildenafil in the treatment of PPHN. We report the successful treatment of PPHN caused by pulmonary hypoplasia in a patient with spondyloepiphyseal dysplasia congenita.

Topics: Female; Humans; Infant, Newborn; Osteochondrodysplasias; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Administration, Oral; Humans; Infant, Newborn; Male; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Ethics, Medical; Human Experimentation; Humans; Infant, Newborn; Persistent Fetal Circulation Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Persistent pulmonary hypertension secondary to meconium aspiration syndrome is an important cause of morbidity and mortality in the neonatal population. We investigated the use of the phosphodiesterase-5 inhibitor sildenafil, in its intravenous form, as a pulmonary vasodilator in a model of meconium aspiration syndrome. Pulmonary hypertension was induced in 18 piglets, by endotracheal instillation of human meconium, 6 piglets subsequently received an infusion of intravenous sildenafil for 2 hours, 6 received inhaled nitric oxide for 2 hours, and 6 control animals received no additional intervention. Meconium aspiration increased pulmonary vascular resistance by 70%, and increased oxygenation index by over 100%. Pulmonary vascular resistance remained elevated for the remainder of the study period in control animals. Inhaled nitric oxide reduced the pulmonary vascular resistance by 40% after 2 hours of treatment; intravenous sildenafil completely reversed the increase in pulmonary vascular resistance within 1 hour of commencing the infusion. Neither agent had an effect on systemic hemodynamics. Sildenafil also increased cardiac output by 30%, but while doing so did not adversely influence oxygenation. Intravenous sildenafil is a selective and highly effective pulmonary vasodilator, which is at least as effective as inhaled nitric oxide, in this model of neonatal persistent pulmonary hypertension.

Topics: Administration, Inhalation; Animals; Hemodynamics; Humans; Infant, Newborn; Infusions, Intravenous; Meconium Aspiration Syndrome; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Swine; Vascular Resistance; Vasodilator Agents