Genetic Foundation of Prostaglandin Metabolism Influences Patent Ductus Arteriosus Closure in Extremely Low Birth Weight Infants.

OBJECTIVE: Prostaglandins (PGs) play a major role in maintaining patency of the ductal arteriosus (DA). Pulmonary 15-hydroxyprostaglandin dehydrogenase (PGDH), which is ecoded by the hydroxyprostaglandin dehydrogenase (HPGD) gene, is the primary enzyme responsible for PG breakdown. Animal studies have shown HPGD-knockout mice have significantly higher prostaglandin E2 levels and no ductal remodeling. Functional variants of the HPGD gene that alter PG breakdown have not been studied in preterm infants with patent ductus arteriosus (PDA). STUDY DESIGN: This was an observational cohort study including extreme low birth weight (ELBW) infants classified as having spontaneous, medical, or procedural (transcatheter or surgical ligation) closure of their DA. Urine prostaglandin E metabolite (PGEM) levels were measured in ELBW infants following ibuprofen treatment using competitive ELISA. HPGD genetic variants rs8752, rs2612656, and rs9312555 were analyzed. Kruskal-Wallis, Fisher's exact, chi square, logistic regression, and Wilcoxon signed-rank tests were used; p < 0.05 was considered significant. RESULTS: Infants in the procedural closure group had a younger gestational age (GA). The incidence of spontaneous closure or medical closure was higher compared to procedural closure in the presence of any minor allele of rs8752 (67 and 27%, respectively; p = 0.01), when adjusted for GA and gender. Haplotype analysis of three variants of HPGD revealed differences when comparing the spontaneous and medical closure group to the procedural group (p < 0.05). Urinary PGEM levels dropped significantly in those ELBW infants who responded to ibuprofen (p = 0.003) in contrast to those who did not respond (p = 0.5). CONCLUSION: There was a different genotype distribution for the rs8752 genetic variant of the HPGD gene-as it relates to the mode of treatment for ELBW infants with PDA. We speculate that medical management in the presence of this variant facilitated additional PG breakdown, significantly abrogating the need for procedural closure. Additionally, differences in genotype and haplotype distributions implicate a specific HPGD genetic foundation for DA closure in ELBW infants. KEY POINTS: · PGs and their metabolism play a major role in PDA patency or closure.. · Genetic variants of the HPGD gene influence mode of treatment of PDA in ELBW infants.. · ELBW infants with PDA that responded to medical closure had significantly decreased urine PGEM levels..

Differences in perspective on prognosis and treatment of children with trisomy 18.

Differences in perspective between physicians caring for children with trisomy 18 may be confusing and stressful for parents. The hypothesis of this study was that neonatologists and pediatric pulmonologists differ in their opinions regarding long-term prognosis and recommended interventions. Neonatologists and pediatric pulmonologists in New York State were surveyed. Respondents were asked to report their personal experience caring for affected children, opinions on prognosis, major influences on their opinions, and their likelihood of recommending specific medical or surgical interventions for two clinical vignettes. A total of 393 surveys were mailed, 327 to neonatologists and 66 to pediatric pulmonologists. Sixty-six (20%) neonatologists and 21 (32%) pediatric pulmonologists completed the survey. Neonatologists had cared for more patients with trisomy 18. Twenty-nine percent of pediatric pulmonologists had never cared for a patient with trisomy 18 compared to 2% of neonatologists, P < 0.001. Pediatric pulmonologists were more likely to recommend almost all interventions including antibiotics for pneumonia, mechanical ventilation, cardiac and orthopedic surgery, and "full code resuscitation." Neonatologists were more likely to recommend comfort care only or palliative care. Fifty-four percent of neonatologists and 5% of pediatric pulmonologists thought patients with trisomy 18 without significant congenital heart disease would die before age one despite aggressive medical care, P < 0.001. The major influences impacting these recommendations also varied. Pediatric pulmonologists are more optimistic about the prognosis for children than neonatologists and more likely to recommend medical and surgical interventions. Experience with the condition and perception of survivability may contribute to these differences in approach.

Synergizing Safety: A Customized Approach to Curtailing Unplanned Extubations through Shared Decision-making in the NICU.

Background: Unplanned Extubation (UE) remains an important patient safety issue in the Neonatal Intensive Care Unit. Our SMART AIM was to decrease the rate of UE by 10% from the baseline from January to December 2022 by emphasizing collaboration among healthcare professionals and through the use of shared decision-making. Methods: We established an interdisciplinary Quality Improvement team composed of nurses, respiratory therapists, and physicians (MDs). The definition of UE was standardized. UE was audited using an apparent cause analysis form to discern associated causes and pinpoint areas for improvement. Interventions were implemented in a step-by-step fashion and reviewed monthly using the model for improvement. A shared decision-making approach fostered collaborative problem-solving. Results: Our baseline UE rate was 2.3 per 100 ventilator days. Retaping, general bedside care, and position change accounted for over 50% of the UE events in 2022. The rate of UE was reduced by 48% by the end of December 2022. We achieved special-cause variation by the end of March 2023. Conclusions: The sole education of medical and nursing providers about various approaches to decreasing unnecessary retaping was ineffective in reducing UE rates. Shared decision-making incorporating inputs from nurses, respiratory therapists, and MDs led to a substantial reduction in the UE rate and underscores the potential of systematic evaluation of risk factors combined with collaborative best practices.

Bedside lung mechanics predict survival in hypoplastic lung disease.

Newer bedside pulmonary mechanics using conventional ventilators allow for CONTINUOUS serial determinations of tidal volume (V(T)). We sought to determine whether the degree of pulmonary hypoplasia could be measured using bedside pulmonary graphics and whether survival could be predicted in potential extracorporeal membrane oxygenation (ECMO) candidates. Data on all neonates considered for or treated with ECMO at our center between April 2000 and March 2005 were collected. The "maximal bedside V(T)" was measured daily at the peak pressure where "beaking" began with a peak end expiratory pressure of 4 cm H(2)O. Twenty-two patients were reviewed: eight ECMO plus fourteen similar patients in whom the threshold for ECMO intervention was not achieved. Independent of need for ECMO, any patient with V(T) of < 3 mL/kg or < 0.2 mL/cm length died ( N = 4). All other measures of lung capacity or blood gas assessments were less valuable than V(T) in predicting survival. We conclude that bedside V(T) can be easily measured and that values < 3 mL/kg or < 0.2 mL/cm length demarcate severe lung hypoplasia, which in our patient population was incompatible with survival. We speculate that bedside V(T) may assist in evaluating the utility of ECMO.

Hedgehog signaling pathway gene variant influences bronchopulmonary dysplasia in extremely low birth weight infants.

BACKGROUND: Genome wide association study identified hedgehog interacting protein gene (HHIP) variants with chronic obstructive pulmonary disease and asthma. Loss of HHIP, a key regulator of the hedgehog signaling pathway, leads to impaired lung morphogenesis and lethality in animal models, through unimpeded sonic hedgehog expression blocking mesenchymal-expressed fibroblast growth factor 10 (FGF10). Since bronchopulmonary dysplasia (BPD) is also associated with altered lung development and worsens with stimuli including mechanical ventilation, reactive oxygen species, and inflammation, HHIP and FGF10 may be candidate genes. METHODS: This was an observational, cohort study including extremely low birth weight infants that who developed BPD and those who did not. DNA was isolated from buccal swabs and subjected to allelic discrimination, using specific HHIP and FGF10 probes. Protein levels were measured in tracheal aspirates. Student's t test, Chi-square, Z test and logistic regression were used. RESULTS: Demographic characteristics did not differ except that birth weight (715 ± 153 vs. 835 ± 132 g) and gestational age (25 vs. 26 weeks) were less in babies with BPD. HHIP variant rs13147758 (GG genotype) was found to be independently protective for BPD (odds ratio 0.35, 95% confidence interval 0.15-0.82, P = - 0.02). Early airway HHIP protein levels were increased in infants with BPD compared to those without [median (interquartile range) 130.6 (55.6-297.0) and 41.2 (22.1-145.6) pg/mL, respectively; P = 0.05]. The FGF10 single nucleotide polymorphisms were not associated with BPD. CONCLUSION: HHIP, as a regulator of lung bud formation, affects BPD susceptibility, and may be valuable in understanding the specific mechanisms for this disease as well as for identifying therapeutic targets in the era of personalized medicine.

A single-nucleotide polymorphism (-670) of the maternal Fas gene is associated with intrauterine growth restriction.

OBJECTIVE: We sought to determine whether the Fas (-670) single-nucleotide polymorphism is associated with intrauterine growth restriction. STUDY DESIGN: Twenty-seven pregnant women with intrauterine growth restriction in the absence of preeclampsia and 50 pregnant women with uncomplicated pregnancies were studied. DNA was extracted from maternal and infant buccal smears and allelic discrimination was performed for Fas (-670). Student t test, chi2, and z tests were used. RESULTS: There were no differences in maternal age, race, or parity between the intrauterine growth restriction and control patients. Mothers of intrauterine growth restriction infants had a significantly different genotype distribution for this single nucleotide polymorphism, and for the ratio of GG genotype (GG, AA: 0.41, 0.18 maternal intrauterine growth restriction; 0.14, 0.32 controls; respectively, P=.03). These genotype differences were significantly different in white, but not black mothers with intrauterine growth restriction (P=.03, and .3; respectively). In contrast, no differences were found in infants' Fas (-670) single-nucleotide polymorphism genotypes. CONCLUSION: This study demonstrates an association between the maternal Fas (-670) single-nucleotide polymorphism and the development of intrauterine growth restriction.

Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. A "New" BPD has been characterized in preterm infants that may begin in utero, and then progress post-natally, resulting in arrested lung development and alveolar hypoplasia. Foundations for this "New" BPD may be derived from pro-inflammatory genes including tumor necrosis factor-alpha (TNFalpha). The hypothesis of the current study is that single nucleotide polymorphisms (SNPs) of the pro-inflammatory TNFalpha gene place preterm infants at increased risk for BPD. Preterm infants (105 in number) with birthweights

The genetic basis for bronchopulmonary dysplasia.

While the 'original' bronchopulmonary dysplasia (BPD) was attributed to the iatrogenic effects of oxygen and barotrauma on the preterm lung, analyses of the 'new' BPD suggests that these environmental effects may contribute to arrested pulmonary development, and that there may also be genetic foundations for the susceptibility to BPD. Twinning, family and population studies implicate heritable factors in the evolution of BPD. The candidate genes examined for their potential role in BPD include surfactant apoprotein and inflammatory genes. With the identification and mapping of single nucleotide polymorphisms (SNPs), an explosion of testing for these genetic components that may contribute to a number of complex, multigenic disease conditions-including BPD-have been initiated. Sophisticated multiplex analyses are now available to link candidate SNPs to conditions such as BPD. However, there continues to be wide variation in the expression of BPD throughout neonatal units. Differentiating the effects caused by environmental and environmental-genetic interactions from isolated genetic etiologies is still problematic and will require carefully designed genetic analyses of preterm infant groups and their families.

Are placental Fas and Fas ligand gene polymorphisms associated with preeclampsia?

OBJECTIVE: Increased placental trophoblastic apoptosis has been reported in pregnancies complicated by preeclampsia. Fas-Fas ligand is one of the major signal transduction pathways of apoptosis. The objective of this study was to determine if placental Fas and Fas ligand gene polymorphisms differ between patients with and without preeclampsia. STUDY DESIGN: Forty-five singleton placentas were studied. Twenty-three placentas were from preeclamptic pregnancies and 22 were from normotensive controls. Genotyping was performed for Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174, Fas ligand-2777. Chi-square and Fisher's exact tests were used for statistical analysis. RESULTS: There were no significant differences in maternal age, parity or race between the two groups. There were no significant differences in genotypes or allele frequencies for the Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174 and Fas ligand-2777. CONCLUSION: Immune intolerance of maternal and placental interaction plays an important role in the pathogenesis of preeclampsia. Our findings do not support the role of placental Fas and Fas ligand gene polymorphisms in the pathogenesis of preeclampsia.

Attenuated interleukin-8/leukocyte immunoresponse in preterm infants compared with term infants hospitalized with respiratory syncytial virus bronchiolitis: a pilot study.

Decreased transplacental transfer of antibodies and altered immunoresponsiveness may place preterm (PT) infants at higher risk for serious consequences from respiratory syncytial virus (RSV) bronchiolitis. We hypothesize that among infants hospitalized with RSV bronchiolitis, immune response in PT infants may be different when compared with that of term infants. Nasal-wash samples were collected from 11 PT (<37 weeks of gestation) and 13 term infants (≥37 weeks of gestation) hospitalized with RSV bronchiolitis. Severity of illness (clinical score [CS]), admission peripheral oxygen saturation, and days subjects required supplemental oxygen were compared. Nasal-wash leukocyte count as well as cytokines for interleukin (IL)-8, IL-4, and interferon-γ (IFN-γ) were assayed. No significant differences in CS, admission SaO(2), and O(2) days were seen between PT and term infants. Nasal-wash leukocyte counts and IL-8 levels were higher in term infants compared with PT and correlated with severity (higher CS) in term (p < 0.05) but not in PT (p > 0.05) infants. IL-4 and IFN-γ levels did not differ between the 2 groups (p > 0.05). PT infants hospitalized with RSV bronchiolitis have lower nasal-wash leukocyte counts and a less robust IL-8 response than term infants, and only in term infants did IL-8 levels correlate with clinical disease severity.

Does surfactant type cause a differential proinflammatory response in preterm infants with respiratory distress syndrome?

INTRODUCTION: The objective of this study was to compare the pulmonary inflammatory response of premature infants with respiratory distress following instillation of one of two commonly available surfactant preparations. METHODS: This was a prospective, randomized investigation of preterm infants who were less than 30 weeks of gestational age, weighed less than 1 kg at birth, and who qualified to receive surfactant. Infants with multiple congenital anomalies or whose mothers were taking anti-inflammatory medications were ineligible. Tracheal aspirates (TAs) were collected on days 1, 3, 5, and 7 and airway cytokines from TAs were assayed for interleukin (IL)-8 and IL-6. RESULTS: Infants were evenly matched by gestation (26+/-2 days and 26+/-1 days [mean+/-SD], Surfactant A and B, respectively) and birth weight (730+/-141 g and 732+/-167 g). TA cytokine levels were not different between or within groups. Ventilator requirements and clinical outcomes were similar between the two groups. CONCLUSION: The postnatal airway inflammatory response observed in preterm infants is not altered by the instillation of either surfactant preparation.

Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants.

OBJECTIVES: Inhaled nitric oxide treatment for ventilated premature infants improves survival without bronchopulmonary dysplasia. However, there has been no information regarding possible effects of this therapy on oxidative stress. We hypothesized that inhaled nitric oxide therapy would not influence concentrations of plasma biomarkers of oxidative stress. PATIENTS AND METHODS: As part of the Nitric Oxide Chronic Lung Disease Trial, we collected blood samples at specified intervals from a subpopulation of 100 infants of <1250 g birth weight who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Plasma was assayed for total protein and for 3-nitrotyrosine and carbonylation by using immunoassays. RESULTS: The demographic characteristics and primary outcome for the infants were representative of the entire group of infants who were in the Nitric Oxide Chronic Lung Disease Trial. For all infants at baseline, before receiving study gas, the concentration of total protein was inversely correlated with the respiratory severity score, and plasma carbonyl was positively correlated with severity score, supporting an association between oxidative stress and severity of lung disease. Infants who survived without bronchopulmonary dysplasia had 30% lower protein carbonylation concentrations at study entry than those who had an adverse outcome. At each of 3 time points (1-10 days) during exposure to study gas, there were no significant differences between control and treated infants for concentrations of plasma protein, 3-nitrotyrosine, and carbonylation. CONCLUSIONS: Inhaled nitric oxide treatment for premature infants who are at risk for bronchopulmonary dysplasia does not alter plasma biomarkers of oxidative stress, which supports the safety of this therapy.

Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide.

OBJECTIVE: We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory markers/mediators. METHODS: As part of the Nitric Oxide (to Prevent) Chronic Lung Disease trial, a subset of 99 infants (52 placebo-treated infants and 47 inhaled nitric oxide-treated infants; well matched at baseline) had tracheal aspirate fluid collected at baseline, at 2 to 4 days, and then weekly while still intubated during study gas treatment (minimum of 24 days). Fluid was assessed for interleukin-1beta, interleukin-8, transforming growth factor-beta, N-acetylglucosaminidase, 8-epi-prostaglandin F2alpha, and hyaluronan. Results were normalized to total protein and secretory component of immunoglobulin A. RESULTS: At baseline, there was substantial variability of each measured substance and no correlation between tracheal aspirate fluid levels of any substance and respiratory severity scores. Inhaled nitric oxide administration did not result in any time-matched significant change for any of the analytes, compared with the placebo-treated group. There was no correlation between any of the measured markers/mediators and respiratory severity scores throughout the 24 days of study gas administration. In the posthoc analysis of data for inhaled nitric oxide-treated infants, there was a difference at baseline in 8-epi-prostaglandin F2alpha levels for infants who did (n = 21) and did not (n = 26) develop bronchopulmonary dysplasia at postmenstrual age of 36 weeks. CONCLUSIONS: Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.

Surfactant function and composition in premature infants treated with inhaled nitric oxide.

OBJECTIVES: We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition. METHODS: As part of the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights <1250 g who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Large-aggregate surfactant was analyzed for surface activity with a pulsating bubble surfactometer and for surfactant protein contents with an immunoassay. RESULTS: At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide-treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid. CONCLUSIONS: We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.

Interleukin-1 balance in the lungs of preterm infants who develop bronchopulmonary dysplasia.

BACKGROUND: The local pulmonary balance between the agonist and antagonist of interleukin-1 (IL-1) may influence the development of inflammatory disease and resultant structural damage in a variety of human diseases including adult respiratory distress syndrome and asthma. OBJECTIVES: We tested the hypothesis that IL-1 cytokines are early markers for bronchopulmonary dysplasia (BPD), when measured in tracheal aspirates (TAs) obtained from premature infants being ventilated for respiratory distress syndrome during the first week of life. METHODS: Serial TAs were collected on days 1, 3, 5 and 7 from 35 preterm infants (16 BPD, 19 non-BPD) in the absence of chorioamnionitis, and were assayed for IL-1 cytokines and leukocytes. RESULTS: In spite of comparable maternal demographic and clinical characteristics, premature infants who developed BPD had higher levels of IL-1 receptor antagonist (Ra) in their airways on the first day of life. This antagonist IL-1Ra was an early and persistent marker for BPD during the first week of life. The agonist IL-1beta also increased significantly for BPD patients early, both compared to non-BPD patients, and also within the BPD group. While the early (day 1) IL-1 antagonist/agonist molar balance offered protection, by days 5 and 7, a threshold for IL-1Ra in the presence of increasing IL-1beta expression-favored pro-inflammation in the BPD group. CONCLUSIONS: We conclude that a strong and early expression of airway antagonist (IL-1Ra) proves ultimately to be sub-optimal and non-protective due to the robust expression of airway agonist (IL-1beta) seen by day 5 in premature infants who develop BPD.

Polymorphism of Fas and Fas ligand in preterm premature rupture of membranes in singleton pregnancies.

OBJECTIVE: Fetal inflammatory response has been previously shown to be involved in the pathogenesis of preterm premature rupture of membranes. We investigated the association between polymorphisms at position -670 in the Fas gene and position -124 in the Fas ligand gene demonstrated in neonatal oral mucosa cells and preterm premature rupture of membranes. STUDY DESIGN: Thirty-six singleton pregnancies were studied. Eighteen pregnancies were complicated by preterm premature rupture of membranes, and 18 were delivered at term without preterm premature rupture of membranes. Buccal swabs were obtained from each neonate, and extracted deoxyribonucleic acid was analyzed by polymerase chain reaction-based restriction fragment length polymorphism for an adenine (A) to guanine (G) substitution at position -670 in the Fas promoter gene and at position -124 in the Fas ligand gene. chi2 and Fisher's exact tests were used for statistical analysis. RESULTS: There was no difference with respect to race, maternal age, and parity between the 2 groups. Frequencies of Fas -670 AG, -AA, and -GG genotypes in preterm premature rupture of membranes group were significantly different from those in the control group (P = .004). The frequency of the heterozygous AG genotype was significantly higher in preterm premature rupture of membranes group as compared with controls (83.3% versus 33.3%, P = .003). Fas -670 AA genotype was not observed among patients with preterm premature rupture of membranes. Similarly, the difference of frequencies of the Fas ligand -124 AG, -AA, and -GG genotypes among preterm premature rupture of membranes group and controls was observed but did not reach statistical significance. Neither of the groups demonstrated homozygous GG genotype at position -124 of the Fas ligand gene. CONCLUSION: Our data indicate an association between preterm premature rupture of membranes and increased prevalence of neonatal AG genotype at -670 Fas promoter gene. Genetically predetermined regulation of the Fas/Fas ligand system appears to play an important role in the pathogenesis of the preterm premature rupture of membranes.