Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia.

BACKGROUND: Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH. METHODS: Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16-20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed. RESULTS: The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242-0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-3.7) µm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-4.9) µm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-15.2) µm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-9.4) µm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5-15.4) µm versus 8.5 (95% CI 7.1-9.3) µm]. Pulmonary arterial wall thickness was also decreased in the former group. CONCLUSIONS: In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.

Psychosocial parental support programs and short-term clinical outcomes in extremely low-birth-weight infants.

OBJECTIVE: To describe the association between an individualized psychosocial parental support (PPS) program and short-term clinical outcomes of extremely low-birth-weight (ELBW) infants admitted to the neonatal intensive care unit (NICU). METHODS: Medical records of ELBW infants (<1000 g) hospitalized in the NICU at Miami Children's Hospital between July 2006 and June 2008 were reviewed. Outborn infants admitted during their first 72 h of life and discharged home were included. Parents were divided in two groups according to their participation status in the PPS program. Neonatal outcomes in both groups were compared. RESULTS: Forty-one infants were included (n = 41). Mean gestational age was 26.7±2 weeks, and birth weight was 860±125 g. Median length of stay (LOS) was 96 days (quartile range: 76-112 days). PPS was provided to 33.3% of these infants' parents. The median LOS in the PPS group was significantly lower than in control group (86 vs. 99 days; p < 0.05). No other differences in short-term neonatal outcomes were found. CONCLUSIONS: The addition of individualized psychosocial parent support programs to standard care in the NICU may reduce LOS in surviving infants discharged home. Further larger and randomized prospective studies are needed.

Significant weight loss in breastfed term infants readmitted for hyperbilirubinemia.

BACKGROUND: Weight loss of greater than 7% from birth weight indicates possible feeding problems. Inadequate oral intake causes weight loss and increases the bilirubin enterohepatic circulation. The objective of this study was to describe the association between total serum bilirubin (TSB) levels and weight loss in healthy term infants readmitted for hyperbilirubinemia after birth hospitalization. METHODS: We reviewed medical records of breastfed term infants who received phototherapy according to TSB levels readmitted to Caja Petrolera de Salud Clinic in La Paz, Bolivia during January 2005 through October 2008. RESULTS: Seventy-nine infants were studied (64.6% were males). The hyperbilirubinemia readmission rate was 5% among breastfed infants. Term infants were readmitted at a median age of 4 days. Mean TSB level was 18.6 +/- 3 mg/dL. Thirty (38%) had significant weight loss. A weak correlation between TSB levels and percent of weight loss was identified (r = 0.20; p < 0.05). The frequency of severe hyperbilirubinemia (> 20 mg/dL) was notably higher among infants with significant weight loss (46.7% vs. 18.4%; p < 0.05). The risk of having severe hyperbilirubinemia was approximately 4 times greater for infants with significant weight loss (OR: 3.9; 95% CI: 1.4-10.8; p < 0.05). CONCLUSIONS: Significant weight loss could be a useful parameter to identify breastfed term infants at risk of severe hyperbilirubinemia either during birth hospitalization or outpatient follow-up visits in settings where routine pre-discharge TSB levels have not been implemented yet.

Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study.

BACKGROUND: 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. OBJECTIVE: Our goal was to evaluate the feasibility of using oral sildenafil and its effect on oxygenation in PPHN. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of aerosolized milrinone during drug-induced pulmonary hypertension in lambs.

We tested whether aerosolized milrinone in lambs selectively reduces drug-induced acute pulmonary hypertension without reducing the mean systemic blood pressure (MSBP). Seven, 2-3-week-old lambs were anesthetized (50 mg/kg ketamine), paralyzed (0.1 mg/kg vecuronium bromide) and mechanically ventilated. A femoral artery, pulmonary artery, and jugular vein were catheterized for continuous monitoring of MSBP, mean pulmonary artery pressure, periodic gas-exchange analyses, and determination of cardiac output by thermodilution technique. An Airlife Misty nebulizer was used in a dry state to establish a stable baseline of an inspired fraction of oxygen (FiO(2)) at 0.21. Acute pulmonary hypertension with hypoxemia was then induced by increasing the mean pulmonary artery pressure up to 30-35% of the MSBP using 2-6 microg/kg/min of Thromboxane A(2) mimetic (U-46619), intravenously. The lambs were then subjected to 15 min of saline nebulization without milrinone followed by 30 min saline nebulization with a relatively high concentration of milrinone (10 mg/ml, total dose of 40 mg). Aerosolized milrinone had no effect on systemic or pulmonary artery pressure during combined acute pulmonary hypertension and hypoxemia. We speculate that our nebulization procedures failed to deliver sufficient amount of milrinone for producing a detectable hemodynamic effect.

Methemoglobinemia in an infant receiving nitric oxide after the use of eutectic mixture of local anesthetic.

High levels of methemoglobinemia can cause tissue hypoxia and cyanosis. We report the case of a 7-month-old girl with pulmonary dysplasia receiving inhaled nitric oxide who had cyanosis caused by methemoglobinemia after prolonged use of a eutectic mixture of local anesthetics cream.