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To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). Six-year linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants. A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χ2, p = 0.17. Clinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

Objective To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. Study design Data from the Children’s Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. Results Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (

BACKGROUND The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight

To describe the association between echocardiographic measures of pulmonary vascular disease and time to respiratory improvement among infants with Type I severe bronchopulmonary dysplasia (sBPD).We measured the pulmonary artery acceleration time indexed to the right ventricular ejection time (PAAT/RVET) and right ventricular free wall longitudinal strain (RVFWLS) at 34-41 weeks' postmenstrual age. Cox-proportional hazards models were used to estimate the relationship between the PAAT/RVET, RVFWLS, and the outcome: days from 36 weeks' postmenstrual age to room-air or discharge with oxygen (≤0.5 L/min).For 102 infants, the mean PAAT/RVET and RVFWLS were 0.27 ± 0.06 and -22.63 ± 4.23%. An abnormal measurement was associated with an increased time to achieve the outcome (PAAT/RVET: 51v24, p 0.0001; RVFWLS; 62v38, p = 0.0006). A normal PAAT/RVET was independently associated with a shorter time to outcome (aHR = 2.04, 1.11-3.76, p = 0.02).The PAAT/RVET may aid in anticipating timing of discharge in patients with type I severe BPD.

Background Cumulative supplemental oxygen (CSO) and cumulative mean airway pressure (CMAP) are associated with bronchopulmonary dysplasia (BPD) in preterm infants, but their relationships to white matter injury (WMI) and neurodevelopment have not been evaluated. Methods Preterm infants

To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH).Six-year linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants.A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χClinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH. Six years linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used to describe associations between prenatal/perinatal factors, clinical outcomes, echocardiographic findings and PH medications (PHM), during hospitalization and at discharge. Of 1106 CDH infants from 23 centers, 62.8% of infants received PHM, and 11.6% of survivors were discharged on PHM. Survivors discharged on PHM more frequently had intrathoracic liver, small for gestational age, and low 5 min APGARs compared with those discharged without PHM (p

BACKGROUND In addition to substantial medical and surgical intervention, neonates with congenital diaphragmatic hernia often have concurrent concerns for acquired infection. However, few studies focus on infection and corresponding antimicrobial utilization in this population. METHODS The Children's Hospital Neonatal Database was queried for congenital diaphragmatic hernia infants hospitalized from January 2010 to February 2016. Patient charts were linked to the Pediatric Health Information Systems database. Descriptive clinical data including delivery history, cultures sent, diagnosed infection, antimicrobial use and outcomes were reported. RESULTS A total of 1085 unique patients were identified after data linkages; 275 (25.3%) were born at

To assess whether cord blood biomarkers associated with placental maternal vascular underperfusion (MVU) are predictive of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH).Premature infants enrolled in a longitudinal cohort study were randomly sampled from 4 gestational age strata (n?=?190, range 23-36 weeks). Fifteen factors from a human angiogenesis panel were measured in cord blood using multiplex immunoassay. Multivariate linear regression was used to compare biomarker levels according to placental histologic MVU, taking into account acute/chronic inflammation and fetal vascular pathology. Biomarkers associated with MVU were further evaluated in the subgroup of extremely low gestational age infants (gestational age ? 28 weeks; n?=?48), and measured by enzyme-linked immunoassay in an additional 39 infants to determine associations with BPD (defined using the National Institutes of Health workshop criteria) and PH (identified by echocardiogram at 36 weeks of gestation).Cord blood placental growth factor (PIGF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor-A were decreased with MVU (P??.003), and decreased with BPD-PH (P??.05). The findings were validated for PIGF and G-CSF in 39 additional extremely low gestational age infants. In the combined group (n?=?87), PIGF was decreased in infants with BPD-PH (n?=?21) versus controls without PH (median 3 pg/mL [IQR 2-7] vs median 15 pg/mL [IQR 6-30], respectively; P??.001). G-CSF was similarly decreased with BPD-PH (median, 55 pg/mL [IQR 38-85] vs median 243 pg/mL [IQR 48-1593], respectively; P?=?.001). Receiver operator curve analysis revealed that decreased PIGF and G-CSF were predictive of BPD-PH (area under the curve 0.83 and 0.76, respectively).Cord blood angiogenic factors that are decreased with placental MVU may serve as predictors of BPD-PH.

Appropriate post-natal growth remains a mainstay of therapeutic goals for infants with CDH, with the hypothesis that optimizing linear growth will improve survival through functional improvements in pulmonary hypoplasia. However, descriptions of growth and the effect on survival are limited in affected infants.Describe in-hospital weight gain related to survival among infants with CDH.Children's Hospitals Neonatal Database (CHND) identified infants with CDH born ≥34weeks' gestation (2010-14). Exclusion criteria were: admission age7days, death/discharge age14days, or surgical CDH repair prior to admission. Weight gain velocity (WGV: g/kg/day) was calculated using an established exponential approximation and the cohort stratified by Q1:25%ile, Q2-3: 25-75%ile, and Q4:75%ile. Descriptive measures and unadjusted Kaplan-Meier analyses describe the implications of WGV on mortality/discharge.In 630 eligible infants, median WGV was 4.6g/kg/day. After stratification by WGV [Q1: (n=156;3.1g/kg/day); Q2-3 (n=316; 3.1-5.9g/kg/day), and Q4 (n=158,5.9g/kg/day)] infants in Q1 had shortest median length of stay, less time on TPN and intervention for gastro-esophageal reflux relative to the other WGV strata (p0.01 for all). Unadjusted survival estimates revealed that Q1 [hazard ratio (HR)=9.5, 95% CI: 5.7, 15.8] and Q4 [HR=2.9, 95% CI: 1.7, 5.1, p0.001 for both] WGV were strongly associated with NICU mortality relative to Q2-3 WGV.Variable WGV is evident in infants with CDH. Highest and lowest WGV appear to be related to adverse outcomes. Efforts are needed to develop nutritional strategies targeting optimal growth.

Objective To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). Study design Infants with sBPD in the Children’s Hospitals Neonatal Database who had echocardiograms 34–44 weeks’ postmenstrual age (PMA) were included. SP and RVSP were categorized normal, abnormal (flattened/bowed SP or RVSP > 40 mmHg) or missing. Results Of 1157 infants, 115 infants (10%) died. Abnormal SP or RVSP increased mortality (SP 19% vs. 8% normal/missing, RVSP 20% vs. 9% normal/missing, both p

To predict mortality or length of stay (LOS)109 days (90th percentile) among infants with congenital diaphragmatic hernia (CDH).We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010 to 2014. Infants born34 weeks gestation with CDH admitted at 22 participating regional neonatal intensive care units were included; patients who were repaired or were at home before admission were excluded. The primary outcome was death before discharge or LOS109 days. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants.The median gestation and age at referral in this cohort (n=677) were 38 weeks and 6 h, respectively. The primary outcome occurred in 242 (35.7%) infants, and was distributed between mortality (n=180, 27%) and LOS109 days (n=66, 10%). Regression analyses showed that small for gestational age (odds ratio (OR) 2.5, P=0.008), presence of major birth anomalies (OR 5.9, P0.0001), 5- min Apgar score ⩽3 (OR 7.0, P=0.0002), gradient of acidosis at the time of referral (P0.001), the receipt of extracorporeal support (OR 8.4, P0.0001) and bloodstream infections (OR 2.2, P=0.004) were independently associated with death or LOS109 days. This model performed well in the validation cohort (area under curve (AUC)=0.856, goodness-of-fit (GF) χ(2), P=0.16) and acted similarly even after omitting extracorporeal support (AUC=0.82, GF χ(2), P=0.05).Six variables predicted death or LOS ⩾109 days in this large, contemporary cohort with CDH. These results can assist in risk adjustment for comparative benchmarking and for counseling affected families.

The development of pulmonary hypertension (PH) is a serious complication of bronchopulmonary dysplasia (BPD) among infants born at extremely low gestational ages. Bronchopulmonary dysplasia-associated PH is characterized by persistent pulmonary vasoconstriction, progressive right heart dysfunction, and an increased risk of death. We have shown previously that certain placental vascular lesions are associated with BPD-associated PH. Further evaluation of the villous and vascular morphometry of these placentas is warranted. Using digital image analysis (DIA), we compared villous and vascular morphometric parameters of placentas from infants with and without BPD-associated PH. We conducted a case-control study of placentas from 14 infants born at ≤28 weeks' gestational age (GA). Cases with PH ( N = 7) and non-PH controls ( N = 7) were identified using echocardiogram screening at 36 weeks' corrected GA. Central parenchymal sections from each placenta were stained for CD31. Digital image analysis was used to measure vessel and villous capillary number, perimeter, diameter, and area. Mean villous vascularity (number of vessels per villus) was calculated for each patient. Mean vessel and villous number as well as area were similar between the two groups. Villous vascularity was decreased in placentas from infants who ultimately had PH disease compared to non-PH controls (5.5 ± 1.0 vs 7.1 ± 1.6; P < 0.05). Placental villous vascularity is decreased in infants with BPD-associated PH. Further studies should assess whether placental morphometric markers may allow clinicians to better predict BPD and provide earlier and more targeted management.

The aim of this study is to characterize medical and surgical therapies and short-term outcomes in infants with congenital diaphragmatic hernia (CDH).Retrospective analysis of CDH infants admitted to 27 children's hospitals submitting data to Children's Hospital Neonatal Database (CHND) from 2010 to 2013, stratified by gestational age, birth weight, and survival.A total of 572 infants were identified, 508 (89%) born ≥ 34 weeks' gestation and ≥ 2 kg. More mature infants had higher APGAR scores, shorter duration of mechanical ventilation, and were more likely to receive extracorporeal membrane oxygenation (ECMO). Overall, mortality for the cohort was 29%, with mortality lower in infants born ≥ 34 weeks' gestation and ≥ 2 kg (26 vs. 50%, p 0.01). Nonsurvivors were more likely to receive treatment with high-frequency oscillatory ventilation (HFOV), vasopressors, pulmonary vasodilators, and ECMO, and to have associated major congenital anomalies than survivors. In hospital morbidity and complications were relatively uncommon among survivors.Infants with CDH have a high risk of morbidity and mortality, and for preterm infants with CDH those risks are amplified. Patterns of respiratory and circulatory support appeared to be different for survivors. In addition to established data registries, this consortium of regional neonatal intensive care units provides a new collaborative effort to describe short-term outcomes for infants referred with CDH.

In recent decades, survival of children with complex congenital heart disease has improved considerably. Specifically, children with a variety of congenital heart defects resulting in ‘single ventricle’ physiology can now undergo palliative surgery that allows survival beyond the neonatal period, and in many cases into adulthood, despite having a single functional ventricular pumping chamber supplying both the pulmonary and systemic circulation. Our growing understanding of the functionally univentricular heart has resulted in freedom from Fontan failure of >50% at 25 years post-Fontan. Yet there is still a fair amount of knowledge to be gained, specifically as it relates to the pulmonary circulation in this group of patients. Knowledge gaps relate not only to the pulmonary circulation after Fontan operation, but also at each stage of the single ventricle surgical palliation, including the native physiology prior to any intervention. The pulmonary circulation is affected by multiple issues related to the single ventricle, including specific details of the anatomy unique to each patient, any intervention(s) undertaken, and potential complications such as aortopulmonary collaterals, protein losing enteropathy, plastic bronchitis, venovenous collaterals, pulmonary arteriovenous fistulae, ventricular dysfunction, pulmonary venous stenosis, and more. This chapter will review the current knowledge with regard to the pulmonary circulation in the single ventricle patient, primarily after the Fontan operation. Additionally, it is our hope to help the practitioner assess the pulmonary circulation in the single ventricle patient; we will also discuss the evidence behind and approach to treatment strategies in order to optimize the pulmonary circulation in this complex group of patients.

Neonates with chronic respiratory failure have uncertain prognosis and can face significant treatment burden. As the trajectory of the illness becomes more concerning, consultation with a pediatric palliative service should be considered, especially as therapeutic options shift from standard to "innovative." Benefits include as follows: supporting emotionally conflicted providers and parents, maintaining transparency in determination of goals, and balancing medical progress with each individual patient's and family's best interests.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy, and BPD-associated pulmonary hypertension (PH) is a serious complication that can negatively impact later childhood health. There is growing evidence that lung injury leading to BPD and PH is due to chronic fetal hypoxia-ischemia. The purpose of this study was to investigate whether placental pathologic changes of maternal vascular underperfusion (MVU) are associated with BPD, and further increased with PH.We conducted a 5-year retrospective cohort study of premature infants born ≤28 weeks. BPD was defined as persistent oxygen requirement at 36 weeks corrected gestational age. PH was identified using a standardized algorithm of echocardiogram review. Archived placental slides underwent standardized masked histopathologic review. Logistic regression modeling was performed, taking into account important maternal and infant covariates.Among 283 births, 121 had MVU, of which 67 (55%) developed BPD, and 24 (20%) had PH. Among the common neonatal complications of extreme prematurity, BPD was the only outcome that was increased with MVU (P0.001). After adjustment for birth weight, fetal growth restriction, preeclampsia and other factors, infants with MVU were more likely to develop BPD (adjusted odds ratio = 2.6; 95% confidence interval = 1.4, 4.8). Certain MVU sublesions (fibrinoid necrosis/acute atherosis and distal villous hypoplasia/small terminal villi) were increased with PH (P0.001).Placental MVU may identify BPD infants who were exposed to intrauterine hypoxia-ischemia, which increases their risk for development of PH disease.Our findings have important implications for providing earlier and more effective therapies for BPD.

Objective To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). Study design Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). Results Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. Conclusion Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. Trial registration ClinicalTrials.gov : NCT01022580

To identify the association between birth weight (BW)-for-gestational age (GA) and pulmonary hypertension (PHTN) at 36 weeks in infants with moderate-severe bronchopulmonary dysplasia (BPD).In this retrospective cohort study, we followed 138 premature infants (≤ 28 weeks) with moderate and severe BPD (National Institutes of Health consensus definition) born at Prentice Women's Hospital between 2005 and 2009. BW percentiles were calculated using the Fenton growth curve for premature infants. PHTN was determined using a standardized algorithm of echocardiogram review at 36 weeks. Logistic regression was used to evaluate the associations between BW percentile subgroups and PHTN, taking into account antenatal and neonatal factors that were related to PHTN.PHTN was associated with small BW-for-GA, ranging from thresholds of10th to25th percentile (P0.001). These associations remained significant when comparing BW25th percentile to the reference group (50 to 89 th percentile); after adjustment for GA, gender, multiple gestation, race/ethnicity (odds ratio (OR)=4.2; 95% confidence interval (CI)=1.5, 12.1); and after further adjustment for maternal vascular disease, intrauterine infection, oligohydramnios and relevant postnatal factors (OR=5.7; 95% CI=1.5, 21.2). Longitudinal follow-up of this cohort showed a trend toward higher morbidity and death among PHTN infants with BW25th percentile.BW-for-GA is an important predictor of PHTN in premature infants with moderate-severe BPD. Our findings contribute to the growing evidence supporting fetal mechanisms of later onset pulmonary vascular disease.

To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born32 weeks' gestation with sBPD. The association between center and the primary outcome of D/T was analyzed by multivariable modeling. Hypothesized diagnoses/practices were included to determine if these explained any observed ICV in D/T.D/T occurred in 280 (20%) of 1383 eligible infants from 21 centers. ICV was significant for D/T (range 2-46% by center, P0.001) and tracheostomy placement (n=187, range 2-37%, P0.001), but not death (n=93, range 0-19%, P=0.08). This association persisted in multivariable analysis (adjusted center-specific odds ratios for D/T varied 5.5-fold, P=0.009).ICV in D/T is apparent among infants with sBPD. These results highlight that the indications for tracheostomy (and subsequent chronic ventilation) remain uncertain.

The perinatal transition from fetal to extrauterine life requires a dramatic change in the circulatory pattern as the organ of gas exchange switches from the placenta to the lungs. Pulmonary hypertension can occur during early newborn life, and present as early respiratory failure or as a complication of more chronic diseases, such as bronchopulmonary dysplasia. The most effective pharmacotherapeutic strategies for infants with persistent pulmonary hypertension of the newborn are directed at selective reduction of pulmonary vascular resistance. This article discusses currently available therapies for pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness.

Fetal growth restriction is a risk factor for development of adulthood diseases, but the biological mechanism of this association remains unknown. Limited biomarkers have been studied in settings of preterm birth and maternal inflammation, but the relationship between a wide range of immune biomarkers and fetal growth has not been studied. The hypothesis of this study was that fetal growth restriction is associated with altered immune biomarker levels. We examined the relationship between small for gestational age (SGA) status and 27 umbilical cord blood immune biomarkers. This study was part of a large-scale cohort study of preterm birth and low birth weight conducted at Boston Medical Center, an inner city, predominantly minority patient population. Growth status was determined based on birth weight standardized to an internal reference. There were 74 SGA births and 319 appropriate for age (AGA) births with complete clinical and biomarker data. Adjusting for covariates and using AGA as reference, SGA births had lower levels of log IL-1β (ng/l; β -0.38, 95% CI -0.57, -0.19, P < 0.01), log BDNF (β -0.29, 95% CI -0.55, -0.03, P < 0.05) and log NT-3 (β -0.46, 95% CI -0.77, -0.15, P < 0.01). No associations were found between other biomarkers and SGA. In conclusion, three biomarkers were selectively associated with SGA status. Our results provide information that could be used to guide additional studied aimed at determining mechanisms that contribute to fetal growth.

Objectives To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. Study design This was a multicenter, retrospective cohort study of 1677 infants born Results Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P Conclusions Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

Inhaled nitric oxide is established therapy for term infants with hypoxemic respiratory failure. Laboratory studies demonstrate that inhaled nitric oxide improves lung function and morphology in animal models of bronchopulmonary dysplasia, creating a rationale for clinical studies in premature infants. Four large multicenter randomized trials have now completed enrollment, and one trial has reported neurodevelopmental outcomes at 18-22 months. The purpose of this review is to summarize the results of the most recent preclinical studies and clinical trials.In 2006, short-term outcomes from two large multicenter randomized trials were published. These studies differed in their target population and study design. Early use of inhaled nitric oxide was associated with a decrease in brain injury, and decreased chronic lung disease in infants over 1000 g. Inhaled nitric oxide use in older infants (7-21 days) was associated with decreased chronic lung disease, particularly if started early.Neurodevelopmental outcomes after discharge are still needed from three large multicenter randomized trials. These results will help confirm the long-term implications of the benefits reported in the two most recent trials.

Oligohydramnios (OH) retards fetal lung growth by producing less lung distension than normal. To examine effects of decreased distension on fetal lung development, we produced OH in rats by puncture of uterus and fetal membranes at 16 days of gestation; fetuses were delivered at 21 or 22 days of gestation. Controls were position-matched littermates in the opposite uterine horn. OH lungs had lower weights and less DNA, protein, and water, but no differences in saturated phosphatidylcholine, surfactant proteins (SP)-A and -B, and mRNA for SP-A, -B, -C, and -D. To evaluate effects on epithelial differentiation, we used RTI40and RTII70, proteins specific in lung to luminal surfaces of alveolar type I and II cells, respectively. At 22 days of gestation, OH lungs had less RTI40mRNA ( P < 0.05) and protein ( P < 0.001), but RTII70did not differ from controls. With OH, type I cells (in proportion to type II cells) covered less distal air space perimeter ( P < 0.01). We conclude that OH, which retards lung growth, has little effect on surfactant and impedes formation of type I cells relative to type II cells.

We describe two cases of premature infants who developed clinical and radiologic evidence of gastric lactobezoars within the same month in our neonatal intensive care unit while both were receiving medium-chain triglyceride-rich formula as part of the management of chylothoraces.

We report the use of inhaled prostacyclin (PGI 2 ) in 4 neonates with persistent pulmonary hypertension and hypoxemia refractory to inhaled nitric oxide. Oxygenation rapidly improved after inhalation of PGI 2 in all infants. The condition of one infant subsequently deteriorated, and alveolar capillary dysplasia was found at autopsy. The surviving infants were discharged with normal oxygen saturations in room air. (J Pediatr 2002;141:830-32)

OBJECTIVES. Inflammation has been associated with preterm delivery and adverse neonatal outcomes such as cerebral palsy and chronic lung disease. However, no study to date has simultaneously examined a wide range of inflammatory mediators and their relationship to gestational age. We sought to describe the distribution of immune biomarkers in cord blood across gestational age and to investigate the association between biomarker level patterns and preterm birth. PATIENTS AND METHODS. As part of a large-scale molecular epidemiological study of preterm birth conducted at Boston Medical Center, this study analyzed both clinical and biomarker data from 927 births. Twenty-seven biomarkers were simultaneously quantified by immunoassay. The associations between the quartiles of 27 biomarkers and 3 gestational groups (≤32, 33–36, and ≥37 weeks) were analyzed. Biomarkers found to be significant were further analyzed for dose-response correlation with preterm birth by logistic regression, adjusted for pertinent demographic and clinical factors. RESULTS. The 27 biomarkers could be classified into 1 of 3 groups: (1) biomarkers increased in preterm birth (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, monocyte chemoattractant protein 1, macrophage inflammatory protein [MIP]-1α, MIP-1β, soluble IL-6 receptor α, tumor necrosis factor α, soluble tumor necrosis factor receptor I, and TREM-1 [triggering receptor expressed on myeloid cells 1]); (2) biomarkers decreased in preterm birth (brain-derived neurotrophic factor, IL-1β, IL-18, matrix metalloproteinase 9, and neurotrophin 3); and (3) biomarkers not associated with preterm birth (IL-6, IL-12, IL-17, granulocyte/macrophage colony-stimulating factor, interferon γ, macrophage migration inhibitory factor, neurotrophin 4, RANTES [regulated on activation, normal T-cell expressed and secreted], transforming growth factor β, and tumor necrosis factor β). CONCLUSIONS. Biomarkers have different directions of association with prematurity; for significant biomarkers, the strength of association increases with biomarker concentration. Our results provide important information that could be used to guide additional studies aimed at determining mechanisms that contribute to preterm birth.

OBJECTIVES. The primary objective of this study was to determine whether widespread use of nitric oxide after Food and Drug Administration approval decreased admissions to a neonatal referral center for extracorporeal membrane oxygenation evaluation. We also sought to determine whether antecedent treatment delayed eventual transfer, resulting in sicker patients, increased mortality, increased extracorporeal membrane oxygenation application, and higher direct costs of care.METHODS. This was a retrospective cohort study of all of the patients transferred to a neonatal referral center for extracorporeal membrane oxygenation evaluation before (1995–1999) and after (2000–2005) Food and Drug Administration approval of nitric oxide. Patients were divided into “congenital diaphragmatic hernia” and “persistent pulmonary hypertension” (all other diagnoses) for additional analysis.RESULTS. Admission rates for extracorporeal membrane oxygenation evaluation decreased in the nitric oxide era, and eventual transfer was not delayed. Persistent pulmonary hypertension patients had improved oxygen indexes, a trend toward decreased mortality, decreased extracorporeal membrane oxygenation use, and decreased direct costs. Congenital diaphragmatic hernia patients had unchanged physiologic measurements, mortality, and extracorporeal membrane oxygenation use with increased direct costs of care. As a whole, outcomes for patients transferred for extracorporeal membrane oxygenation evaluation improved, whereas direct costs were unchanged.CONCLUSIONS. Persistent pulmonary hypertension patients had improved outcomes with decreased costs, whereas congenital diaphragmatic hernia patients had unchanged outcomes with increased costs. Overall, patients admitted to this NICU because of the presence of extracorporeal membrane oxygenation services had improved outcomes without increased costs in the nitric oxide era.

Prostacyclin is a pulmonary vasodilator and is produced by prostacyclin synthase and stimulates adenylate cyclase (AC) via the prostacyclin receptor (IP) to produce cAMP. Forskolin is a direct stimulant of AC. Phosphodiesterase 3 hydrolyzes cAMP and is inhibited by milrinone. Objective:To characterize the prostacyclin-AC-cAMP pathway in the ovine ductal ligation model of persistent pulmonary hyper- tension of the newborn (PPHN). Setting:University-based laboratory animal facility. Subjects:Lambs delivered to time-dated pregnant ewes. Interventions:Fifth generation pulmonary arteries (PA) and lung parenchyma were isolated from control fetal lambs (n!8) and fetal lambs with PPHN induced by antenatal ductal ligation (n!9). We studied relaxation responses to various agonists (milrinone, forskolin, prostacyclin, and iloprost, a prostacyclin analog) that increase cAMP in PA after half-maximal constriction with norepinephrine and pretreatment with propranolol"indo- methacin. Lung protein levels of prostacyclin synthase, IP, AC2, and phosphodiesterase 3A were analyzed by Western blot and cAMP by enzyme-linked immunoassay. Main Results:Milrinone relaxed control and PPHN PA and pretreatment with indomethacin significantly impaired this re- sponse. Relaxation to milrinone, prostacyclin, and iloprost were significantly impaired in PA from PPHN lambs. Pretreatment with milrinone markedly enhanced relaxation to prostacyclin and ilo- prost in PPHN PA, similar to relaxation in control PA. Relaxation to forskolin was similar in control and PPHN PAs indicating normal AC activity. Protein levels of prostacyclin synthase and IP were decreased in PPHN lungs compared with control, but AC2, cAMP, and phosphodiesterase 3A remained unchanged. Conclusions:Prostacyclin and iloprost are dilators of PAs from PPHN lambs and their effect is enhanced by milrinone. This combination therapy may be an effective strategy in the manage- ment of patients with PPHN. (Pediatr Crit Care Med 2009; 10: 106-112) K EYWORDS: pulmonary hypertension; nitric oxide; prostacyclin; newborn; phosphodiesterase; cyclic AMP

Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. More than a decade of intensive laboratory and clinical investigation has culminated in the current role for inhaled NO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Not surprisingly, this potent and successful therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment. In addition, there remains intense interest in possible new applications for newborns, as well as strategies that may enhance its efficacy. This review describes several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, and reviews our current knowledge about the role of iNO in other conditions such as congenital diaphragmatic hernia and congenital heart disease. In addition, laboratory and clinical studies addressing a potential role for iNO as a therapeutic modality for the preterm infant are reviewed.

In the twenty-first century, decisions to withhold or withdraw life-supporting measures commonly precede death in the neonatal intensive care unit without major ethical controversy. However, caregivers often feel much greater turmoil with regard to stopping medical hydration and nutrition than they do when considering discontinuation of mechanical ventilation or circulatory support. Nevertheless, forgoing medical fluids and food represents a morally acceptable option as part of a carefully developed palliative care plan considering the infant's prognosis and the burdens of continued treatment. Decisions to stop any form of life support should focus on the clinical circumstances, not the means used to sustain life.

Knowledge about the conversion of the epithelium in the distal air spaces of the lung from secretion to absorption is imperative to the understanding of postnatal lung development; little such information is available in rats. Distal air space fluid clearance was therefore measured in 21- to 22-day gestation rat fetuses and newborn (40 h) rats. Distal air space fluid clearance was measured from the increase in131I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. There was no net fluid movement across the distal air space epithelium in the lungs of 21-day gestation fetuses. Twenty-four hours later, distal air space fluid was cleared at a rapid rate in the 22-day gestation fetuses. Within the first 40 h after birth, the rate rapidly declined to adult levels. The high distal air space fluid clearance at 22 days gestation and at 40 h after birth was mediated by β-adrenergic receptors as demonstrated by elevated plasma epinephrine levels and inhibition by propranolol. Interestingly, the elevated distal air space fluid clearance in the 22-day gestation fetuses was only minimally amiloride sensitive; however, amiloride sensitivity increased over the first 40 h after birth. In conclusion, these studies demonstrate that 1) rapid rates of net alveolar fluid clearance occur late in gestation in the rat and 2) this clearance is driven by elevations of endogenous epinephrine.