Search

Objectives To describe the demographics, clinical characteristics and referral patterns of premature infants to a regional level IV neonatal intensive care unit (NICU); to determine the prevalence and predictors of back-transport of infants [less than or equal to] 32 weeks gestational age in a level IV NICU; for infants not back-transported closer to maternal residence, determine the length of stay beyond attainment of clinical stability. Methods Data (2010-2014) from the Children's Hospital Neonatal Database and individual chart review for infants [less than or equal to] 32 weeks admitted to a level IV NICU whose maternal residence was outside the metro area were included. Bivariate associations of maternal and infant characteristics with back-transport were estimated using two-sample t tests and Fisher's exact test. Multivariable logistic regression was used to measure independent predictors of back-transport. Clinical stability was defined as the attainment of full volume enteral feedings and low flow nasal cannula. Results A total of 223 infants were eligible for analysis; of whom 26% were back-transported after acute care. In the adjusted analysis, insurance status, distance from maternal residence and gestational age were significantly associated with back-transport. For infants not back-transported closer to maternal residence, median length of stay in the level IV NICU beyond attainment of clinical stability was 28.5 days. Conclusion for Practice Predictors of back-transport include private insurance, greater distance of maternal residence from NICU and younger gestational age. Many preterm infants admitted to a regional NICU for acute care remained hospitalized in a level IV NICU after achieving clinical stability, for which care in a NICU closer to maternal residence may be appropriate., Author(s): Stephanie L. Bourque [sup.1] , Claire Levek [sup.1] , Diane L. Melara [sup.1] , Theresa R. Grover [sup.1] , Sunah S. Hwang [sup.1] Author Affiliations: (Aff1) 0000 0001 0703 [...]

Objective The aim of this study was to describe the use, duration, and intercenter variation of analgesia and sedation in infants with congenital diaphragmatic hernia (CDH). Study Design This is a retrospective analysis of analgesia, sedation, and neuromuscular blockade use in neonates with CDH. Patient data from 2010 to 2016 were abstracted from the Children's Hospitals Neonatal Database and linked to the Pediatric Health Information System. Patients were excluded if they also had non-CDH conditions likely to affect the use of the study medications. Results A total of 1,063 patients were identified, 81% survived, and 30% were treated with extracorporeal membrane oxygenation (ECMO). Opioid (99.8%), sedative (93.4%), and neuromuscular blockade (87.9%) use was common. Frequency of use was higher and duration was longer among CDH patients treated with ECMO. Unadjusted duration of use varied 5.6-fold for benzodiazepines (median: 14 days) and 7.4-fold for opioids (median: 16 days). Risk-adjusted duration of use varied among centers, and prolonged use of both opioids and benzodiazepines ≥5 days was associated with increased mortality (p < 0.001) and longer length of stay (p < 0.001). Use of sedation or neuromuscular blockade prior to or after surgery was each associated with increased mortality (p ≤ 0.01). Conclusion Opioids, sedatives, and neuromuscular blockade were used commonly in infants with CDH with variable duration across centers. Prolonged combined use ≥5 days is associated with mortality. Key Points Use of analgesia and sedation varies across children's hospital NICUs. Prolonged opioid and benzodiazepine use is associated with increased mortality. Postsurgery sedation and neuromuscular blockade are associated with mortality. [ABSTRACT FROM AUTHOR]

Objective  Infants with congenital diaphragmatic hernia (CDH) require multiple invasive interventions carrying inherent risks, including central venous and arterial line placement. We hypothesized that specific clinical or catheter characteristics are associated with higher risk of nonelective removal (NER) due to complications and may be amenable to efforts to reduce patient harm. Study Design  Infants with CDH were identified in the Children's Hospital's Neonatal Database (CHND) from 2010 to 2016. Central line use, duration, and complications resulting in NER are described and analyzed by extracorporeal membrane oxygenation (ECMO) use. Results  A total of 1,106 CDH infants were included; nearly all (98%) had a central line placed, (average of three central lines) with a total dwell time of 22 days (interquartile range [IQR]: 14–39). Umbilical arterial and venous lines were most common, followed by extremity peripherally inserted central catheters (PICCs); 12% (361/3,027 central lines) were removed secondary to complications. Malposition was the most frequent indication for NER and was twice as likely in infants with intrathoracic liver position. One quarter of central lines in those receiving ECMO was placed while receiving this therapy. Conclusion  Central lines are an important component of intensive care for infants with CDH. Careful selection of line type and location and understanding of common complications may attenuate the need for early removal and reduce risk of infection, obstruction, and malposition in this high-risk group of patients. Key Points Central line placement near universal in congenital diaphragmatic hernia infants. Mean of three lines placed per patient; total duration 22 days. Clinical patient characteristics affect risk. [ABSTRACT FROM AUTHOR]

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble gnanylate cyclase (sGC) activity. Cinacignat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heine or heine-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 [+ or -] 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1-100 [micro]g over 10 rain) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with IH-[l,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinacignat-induced pulmonary vasodilation by > 120%. The pulmonary vasodilator effect of cinacignat was prolonged, decreasing pulmonary vascular resistance for > 1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinacignat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinacignat may have therapeutic potential for severe neonatal pulmonary hypertension. BAY 58-2667; cGMP; nitric oxide; persistent pulmonary hypertension of the newborn; pulmonary hypertension

Respiratory distress syndrome (RDS) secondary to preterm birth and surfactant deficiency is characterized by severe hypoxemia, lung injury, and impaired production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Since hypoxia-inducible factors (HIFs) mediate the effects of both NO and VEGF in part through regulation by prolyl-hydroxylase-containing domains (PHDs) in the presence of oxygen, we hypothesized that HIF-1[alpha] and -2[alpha] in the lung are decreased following severe RDS in preterm neonatal lambs. To test this hypothesis, fetal lambs were delivered at preterm gestation (115-day gestation, term = 145 days; n = 4) and mechanically ventilated for 4 h. Lambs developed respiratory failure characterized by severe hypoxemia despite treatment with mechanical ventilation with high inspired oxygen concentrations. Lung samples were compared with nonventilated control animals at preterm (115-day gestation; n = 3) and term gestation (142-day gestation; n = 3). We found that HIF-1[alpha] protein expression decreased (P < 0.05) and PHD-2 expression increased (P < 0.005) at birth in normal term animals before air breathing. Compared with age-matched controls, HIF-1[alpha] protein and HIF-2[alpha] protein expression decreased by 80% and 55%, respectively (P < 0.005 for each) in preterm lambs with RDS. Furthermore, VEGF mRNA was decreased by 40%, and PHD-2 protein expression doubled in RDS lambs. We conclude that pulmonary expression of HIF-1[alpha], HIF-2[alpha], and the downstream target of their regulation, VEGF mRNA, is impaired following RDS in neonatal lambs. We speculate that early disruption of HIF and VEGF expression after preterm birth and RDS may contribute to long-term abnormalities in lung growth, leading to bronchopulmonary dysplasia. lung development; neonatal lung injury; vascular endothelial growth factor doi:10.1152/ajplung.00372.2006.

Mechanisms that maintain high pulmonary vascular resistance (PVR) in the fetal lung are poorly understood. Activation of the Rho kinase signal transduction pathway, which promotes actin-myosin interaction in vascular smooth muscle cells, is increased in the pulmonary circulation of adult animals with experimental pulmonary hypertension. However, the role of Rho kinase has not been studied in the fetal lung. We hypothesized that activation of Rho kinase contributes to elevated PVR in the fetus. To address this hypothesis, we studied the pulmonary hemodynamic effects of brief (10 min) intrapulmonary infusions of two specific Rho kinase inhibitors, Y-27632 (15-500 [micro]g) and HA-1077 (500 [micro]g), in chronically prepared late-gestation fetal lambs (n = 9). Y-27632 caused potent, dose-dependent pulmonary vasodilation, lowering PVR from 0.67 [+ or -] 0.18 to 0.16 [+ or -] 0.02 mmHg x [ml.sup.-1] x [min.sup.-1] (p < 0.01) at the highest dose tested without lowering systemic arterial pressure. Despite brief infusions, Y-27632-induced pulmonary vasodilation was sustained for 50 rain. HA-1077 caused a similar fall in PVR, from 0.39 [+ or -] 0.03 to 0.19 [+ or -] 0.03 (P < 0.05). To study nitric oxide (NO)-Rho kinase interactions in the fetal lung, we tested the effect of Rho kinase inhibition on pulmonary vasoconstriction caused by inhibition of endogenous NO production with nitro-L-arginine (L-NA; 15-30 mg), a selective NO synthase antagonist. L-NA increased PVR by 127 [+ or -] 73% above baseline under control conditions, but this vasoconstrictor response was completely prevented by treatment with Y-27632 (P < 0.05). We conclude that the Rho kinase signal transduction pathway maintains high PVR in the normal fetal lung and that activation of the Rho kinase pathway mediates pulmonary vasoconstriction after NO synthase inhibition. We speculate that Rho kinase plays an essential role in the normal fetal pulmonary circulation and that Rho kinase inhibitors may provide novel therapy for neonatal pulmonary hypertension. Y-27632; fasudil; nitric oxide; persistent pulmonary hypertension of the newborn; newborn

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy. pulmonary hypertension of the newborn; lung; vasodilator; pulmonary vascular reactivity; direct soluble guanylate cyclase activator

VEGF signaling inhibition decreases alveolar and vessel growth in the developing lung, suggesting that impaired VEGF signaling may contribute to decreased lung growth in bronchopulmonary dysplasia (BPD). Whether VEGF treatment improves lung structure in experimental models of BPD is unknown. The objective was to determine whether VEGF treatment enhances alveolarization in infant rats after hyperoxia. Two-day-old Sprague-Dawley rats were placed into hyperoxia or room air (RA) for 12 days. At 14 days, rats received daily treatment with rhVEGF-165 or saline. On day 22, rats were killed. Tissue was collected. Morphometrics was assessed by radial alveolar counts (RAC), mean linear intercepts (MLI), and skeletonization. Compared with RA controls, hyperoxia decreased RAC (6.1 [+ or -] 0.4 vs. 11.3 [+ or -] 0.4, P < 0.0001), increased MLI (59.2 [+ or -] 1.8 vs. 44.0 [+ or ] 0.8, P < 0.0001), decreased nodal point density (447 [+ or -] 14 vs. 503 [+ or -] 12, P < 0.0004), and decreased vessel density (11.7 [+ or -] 0.3 vs. 18.9 [+ or -] 0.3, P < 0.001), which persisted despite RA recovery. Compared with hyperoxic controls, rhVEGF treatment after hyperoxia increased RAC (11.8 [+ or -] 0.5, P < 0.0001), decreased MLI (42.2 [+ or -] 1.2, P < 0.0001), increased nodal point density (502 [+ or -] 7, P < 0.0005), and increased vessel density (23.2 [+ or -] 0.4, P < 0.001). Exposure of neonatal rats to hyperoxia impairs alveolarization and vessel density, which persists despite RA recovery, rhVEGF treatment during recovery enhanced vessel growth and alveolarization. We speculate that lung structure abnormalities after hyperoxia may be partly due to impaired VEGF signaling. bronchopulmonary dysplasia; lung development; vascular endothelial growth factor; angiogenesis

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEG[F.sub.165] inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEG[F.sub.165] would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension, rhVEG[F.sub.165] or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment, rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEG[F.sub.165] preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN. pulmonary development; persistent pulmonary hypertension of the newborn; angiogenesis; recombinant human vascular endothelial growth factor

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl- 12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 [+ or -] 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 [+ or -] 12% vs. 2 [+ or -] 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension. fetus; N-methylsufonyl-12,12-dibromododec-11-enamide; ductus arteriosus; 20-hydroxyeicosatetraenoic acid; nitric oxide synthase

Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41-2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41-2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125-130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41-2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% (P < 0.01). Prolonged infusion of BAY 41-2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41-2272 was not attenuated by [N.sup.[omega]]-nitro-L-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41-2272 was more prolonged. We conclude that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41-2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production. physiology; lung; vasodilator

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical disorder characterized by abnormal vascular structure, growth, and reactivity. Disruption of vascular growth during early postnatal lung development impairs alveolarization, and newborns with lung hypoplasia often have severe pulmonary hypertension. To determine whether pulmonary hypertension can directly impair vascular growth and alveolarization in the fetus, we studied the effects of chronic intrauterine pulmonary hypertension on lung growth in fetal lambs. We performed surgery, which included partial constriction of the ductus arteriosus (DA) to induce pulmonary hypertension (PH, n = 14) or sham surgery (controls, n = 13) in fetal lambs at 112-125 days (term = 147 days). Tissues were harvested near term for measurement of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), mean linear intercepts (MLI), wall thickness, and vessel density of small pulmonary arteries. Chronic DA constriction caused RVH (P < 0.0001), increased wall thickness of small pulmonary arteries (P < 0.002), and reduced small pulmonary artery density (P < 0.005). PH also reduced alveolarization, causing a 27% reduction in RAC and 20% increase in MLI. Furthermore, prolonged DA constriction (21 days) not only decreased RAC and increased MLI by 30% but also caused a 25% reduction of lung-body weight ratio. We conclude that chronic PH reduces pulmonary arterial growth, decreases alveolar complexity, and impairs lung growth. We speculate that chronic hypertension impairs vascular growth, which disrupts critical signaling pathways regulating lung vascular and alveolar development, thereby interfering with alveolarization and ultimately resulting in lung hypoplasia. lung development; angiogenesis; persistent pulmonary hypertension of the newborn; lung hypoplasia

Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGF[alpha]- and [beta]-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124-128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGF[alpha]- and [beta]-receptor proteins compared with age-matched controls (P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% (P < 0.05) and right ventricular hypertrophy (RVH) by 66% (P < 0.02). Lung PDGF[alpha]- and [beta]-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH. smooth muscle; NX1975; aptamer

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function And modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7-10 days after ductus arteriosus ligation (132-140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits [VEGF.sub.165]. Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of [VEGF.sub.165] mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.

Objective To avoid preventable consequences of perinatal hepatitis B infection, all infants should be given hepatitis B vaccine (HBV) within 24 hours of birth if birth weight is ≥2 kg and at 30 days of life or at discharge if <2 kg, to provide highest seroprotection rates while ensuring universal vaccination prior to discharge. We aimed to achieve timely HBV administration in >80% of eligible infants in both birthweight groups and decrease infants discharged home without receiving HBV to <1% over an 18-month period and sustain results for an additional 15 months. Methods Data were collected from June 2016 to May 2020 in a level III neonatal intensive care unit. A multidisciplinary team identified barriers and interventions through Plan-Do-Study-Act cycles from September 2017 to February 2019: using pharmacists as champions, overcoming legal barriers, staff education and best practice alerts (BPAs) embedded in electronic health records. Statistical process control (SPC) p charts were used to evaluate the primary outcome measure, monthly percentage of infants receiving timely HBV administration stratified by birthweight categories (≥2 and <2 kg). For infants receiving HBV outside the time frame, absolute difference of timeliness was calculated. Results Mean timely HBV administration improved from 45% to 95% (≥2 kg) and from 45% to 85% (<2 kg) with special cause variation in SPC charts. Infants discharged without receiving HBV decreased from 4.6% to 0.22%. Of those given HBV outside the recommended time frame, median absolute time between recommended and actual administration time decreased significantly: from 3.5 days (IQR 1.6, 8.6) to 0.3 day (IQR 0.1, 0.8) (p<0.001) in ≥2 kg group and from 6 days (IQR 1, 15) to 1 day (IQR 1, 6.5) (p=0.009) in <2 kg group. Conclusions Using a multidisciplinary approach, we significantly improved and sustained timely HBV administration and nearly eliminated infants discharged home without receiving HBV. Pharmacists as champions and BPAs were critical to our success. [ABSTRACT FROM AUTHOR]

Prolonged infusions of 17[Beta]-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182, 780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] [change in PVR -30 [+ or -] 6% (CTRL) vs. + 10 [+ or -] 13%, (ICI), P [is less than] 0.05] without reducing the vasodilator response to ventilation with high [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] [change in PVR, -73 [+ or -] 3% (CTRL) vs. -77 [+ or -] 4%, (ICI); P = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P [is less than] 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation. prostacyclin; prostacyclin synthase; cyclooxygenase; newborn

Grover, Theresa R., Robyn L. Rairigh, Jeanne P. Zenge, Steven H. Abman, and John P. Kinsella. Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb. Am J Physiol Lung Cell Mol Physiol 278: L779-L784, 2000.--As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO ([I.sub.NO]) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO ([I.sub.CO]) may have similar effects on the perinatal lung. To determine whether [I.sub.CO] can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of [I.sub.CO] on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired [O.sub.2] fraction [is less than] 0.10) to maintain a constant fetal arterial [PO.sub.2]. After 60 min (baseline), the lambs were treated with [I.sub.CO] [5-2,500 parts/million (ppm)]. Comparisons were made with [I.sub.NO] (5 and 20 ppm) and combined [I.sub.NO] (5 ppm) and [I.sub.CO] (100 and 2,500 ppm). We found that [I.sub.CO] did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose [I.sub.NO] decreased PVR by 47% (P [is less than] 0.005). The combination of [I.sub.NO] and [I.sub.CO] did not enhance the vasodilator response to [I.sub.NO]. To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that [I.sub.CO] does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus. nitric oxide; heme oxygenase; persistent pulmonary hypertension of the newborn; pulmonary hypertension

Parker, Thomas A., D. Dunbar Ivy, Henry L. Galan, Theresa R. Grover, John P. Kinsella, and Steven H. Abman. Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 278: L374-L381, 2000.--Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes, in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol ([E.sub.2]) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of [E.sub.2] (10 [micro] g; [E.sub.2] group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the [E.sub.2]-treated group (2.43 [+ or -] 0.79 vs. 1.48 [+ or -] 0.26 mmHg [multiplied by] [ml.sup.1.min], control vs. [E.sub.2], P [is less than] 0.05). During the subsequent delivery study, PVR was lower in the [E.sub.2]-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% [O.sub.2]. During mechanical ventilation after delivery, arterial partial [O.sub.2] pressure was higher in [E.sub.2] animals than controls (41 [+ or -] 11 vs. 80 [+ or -] 35 Torr, control vs. [E.sub.2], P [is less than] 0.05). Morphometric studies of hypertensive vascular changes revealed that [E.sub.2] treatment decreased wall thickness of small pulmonary arteries (59 [+ or -] 1 vs. 48 [+ or -] 1%, control vs. [E.sub.2], P [is less than] 0.01). We conclude that chronic [E.sub.2] treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs. pulmonary circulation; persistent pulmonary hypertension of the newborn; fetus; lamb

Background: Growth and nutrition are critical in neonatal care. Whether feeding guidelines improve growth and nutrition and reduce morbidity is unknown.Purpose: Feeding guidelines for very low birth-weight (VLBW) infants were implemented in our neonatal intensive care unit (NICU) to start and achieve full enteral feeds sooner, and increase weight gain over the first month.Methods: Feeding guidelines for VLBW infants were implemented in January 2014, stratified by birth weight (<750, 750-1000, and 1000-1500 g). After trophic feedings, enteral feedings were advanced by 20 to 30 mL/kg/d.Data were analyzed for 2 years prior (baseline) and 6 months after (guideline) guidelines were implemented and included days to initiation of enteral feeds, days on total parenteral nutrition (TPN), and weight gain over the first month. Potential concomitant factors that could affect feeding tolerance were examined including indomethacin or dopamine treatment, delivery room cardiopulmonary resuscitation, and growth restriction.Results: A total of 95 infants with a birth weight of less than 1500 g were included (59 baseline and 36 guideline). Days to start enteral feeds decreased by 47% (P < .01) and days on TPN decreased by 25% (16 days vs 11 days; P < .01). Weight gain over the first month of life increased by 15% (p < .05). Dopamine and indomethacin use decreased during the study period, and small for gestational age infants were overrepresented in the guideline group.Implications For Practice/research: Establishment of feeding guidelines for VLBW infants in our NICU reduced the days to start feeds and days on TPN while increasing weight gain over the first month. Improving growth and nutrition and reducing need for TPN in this vulnerable population may ultimately prevent infection and improve neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]