sildenafil-citrate and Meconium-Aspiration-Syndrome

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

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

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

This study was performed to examine the effectiveness and safety of oral sildenafil and inhaled iloprost in term newborns with persistent pulmonary hypertension of the newborn (PPHN).. Oral sildenafil and inhaled iloprost were administered to 27 and 20 neonates, respectively, for treatment of persistent pulmonary hypertension. All patients were term infants at 37 gestational weeks or older. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea. Sildenafil citrate was administered via an oral feeding tube. Iloprost was administered endotracheally to patients on mechanical ventilation using a jet nebulizer.. Iloprost appeared to be more effective than sildenafil in the treatment of PPHN with regard to time to adequate clinical response, ventilatory parameters, duration of drug administration, duration of mechanical ventilation, duration of return to normal values of respiratory failure indices, use of MgSO4 as a second vasodilator and requirement for support with inotropic agents. We observed no side effects on blood pressure or homeostasis in any of the patients in the iloprost group. Systemic hypotension was significantly elevated in the sildenafil group. Four and three infants died of PPHN in the sildenafil and iloprost groups, respectively. Pulmonary systolic arterial pressure decreased to normal levels in the remaining 40 patients, and they were discharged from hospital.. We suggested that inhaled iloprost may be a safe and effective treatment choice in newborn infants with persistent pulmonary hypertension. In cases where treatment with inhaled iloprost, ECMO or INO is not possible, oral sildenafil can be an alternative therapy option in the treatment of PPHN.

Topics: Administration, Oral; Female; Humans; Hypertension, Pulmonary; Hypoxia-Ischemia, Brain; Iloprost; Infant, Newborn; Male; Meconium Aspiration Syndrome; Nebulizers and Vaporizers; Pneumonia; Retrospective Studies; Sildenafil Citrate; Tachypnea; 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

Meconium aspiration syndrome causes respiratory failure after birth and in vivo monitoring of pulmonary edema is difficult. The objective of the present study was to assess hemodynamic changes and edema measured by transcardiopulmonary thermodilution in low weight newborn piglets. Additionally, the effect of early administration of sildenafil (2 mg/kg vo, 30 min after meconium aspiration) on this critical parameter was determined in the meconium aspiration syndrome model. Thirty-eight mechanically ventilated anesthetized male piglets (Sus scrofa domestica) aged 12 to 72 h (1660 ± 192 g) received diluted fresh human meconium in the airway in order to evoke pulmonary hypertension (PHT). Extravascular lung water was measured in vivo with a PiCCO monitor and ex vivo by the gravimetric method, resulting in an overestimate of 3.5 ± 2.3 mL compared to the first measurement. A significant PHT of 15 Torr above basal pressure was observed, similar to that of severely affected humans, leading to an increase in ventilatory support. The vascular permeability index increased 57%, suggesting altered alveolocapillary membrane permeability. Histology revealed tissue vessel congestion and nonspecific chemical pneumonitis. A group of animals received sildenafil, which prevented the development of PHT and lung edema, as evaluated by in vivo monitoring. In summary, the transcardiopulmonary thermodilution method is a reliable tool for monitoring critical newborn changes, offering the opportunity to experimentally explore putative therapeutics in vivo. Sildenafil could be employed to prevent PHT and edema if used in the first stages of development of the disease.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Extravascular Lung Water; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung; Male; Meconium Aspiration Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Sus scrofa; Thermodilution; Time Factors; Vasodilator Agents

There has been recent interest in the use of the phosphodiesterase-5 inhibitor sildenafil for treating pulmonary hypertension. We examined the interaction between inhaled nitric oxide (iNO) and i.v. sildenafil in 12 piglets with acute pulmonary hypertension and lung injury secondary to meconium aspiration. Six animals (controls) received no intervention after meconium instillation, and six received iNO (20 ppm) from 120 min, with the addition at 240 min of an i.v. sildenafil infusion (2 mg/kg over 2 h). Meconium instillation increased mean pulmonary artery (PA) pressure from 16.0 +/- 3.1 to 24.8 +/- 4.6 mm Hg (p < 0.01) and pulmonary vascular resistance (PVR) from 0.047 +/- 0.008 to 0.089 +/- 0.027 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.01). Oxygenation index increased from 3 +/- 0.8 to 8.3 +/- 3.0 (p < 0.01). There were no further changes beyond 120 min in controls. iNO reduced PA pressure and PVR to baseline values, without influencing oxygenation. The addition of sildenafil further reduced PA pressure, tended to increase the cardiac output, and reduced PVR from 0.049 +/- 0.02 to 0.028 +/- 0.01 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.05). Sildenafil lowered the systemic blood pressure and systemic vascular resistance and produced profound arterial hypoxemia, reducing arterial Po(2) from 69 +/- 23 mm Hg to 49 +/- 15 mm Hg, despite substantial increases first in inspired oxygen fraction and subsequently in mean airway pressures. Consequently, the oxygenation index increased by 13.9 +/- 4.8 (p = 0.01). When given in addition to iNO, sildenafil at a dose of >0.5 mg/kg produced profound pulmonary vasodilation, but this was coupled with an unacceptable deterioration in oxygenation and systemic vasodilation in this model of pulmonary hypertension with acute parenchymal lung disease.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Drug Interactions; Humans; Infant, Newborn; Infusions, Intravenous; Meconium Aspiration Syndrome; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine

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