Cigarette Smoking Abstinence Among Pregnant Individuals Using E-Cigarettes or Nicotine Replacement Therapy.

Importance: Smoking cigarettes during pregnancy can impair maternal and child health, and pregnant individuals have increasingly used electronic cigarettes (e-cigarettes) for various reasons, including quitting smoking. Objective: To assess smoking abstinence rates among pregnant individuals who used e-cigarettes compared with those who used nicotine replacement therapy (NRT). Design, Setting, and Participants: This cohort study is a secondary data analysis of phase 8 of the US Pregnancy Risk Assessment Monitoring System, conducted between 2016 and 2020. Eligible participants included pregnant individuals who smoked combustible cigarettes within the 3 months before pregnancy and either used e-cigarettes or NRT during pregnancy. Data analysis was conducted from March 2022 to April 2023. Exposures: Combustible cigarette use within 3 months before pregnancy and use of either e-cigarettes or NRT during pregnancy. Main Outcomes and Measures: The primary outcome was the individual's self-reported smoking abstinence status during the last 3 months of pregnancy. Weighted percentages were reported and weighted multivariable logistic regression models were used to examine the association of e-cigarette use vs NRT with smoking abstinence. A propensity score was used to control for confounding by sociodemographics, pregnancy characteristics, prepregnancy smoking intensity, depression, behavioral support, and hookah use. Results: The cohort included 1329 pregnant individuals (759 ≥25 years [60.2%]; 766 non-Hispanic White individuals [79.8%]) of whom 781 had an education level of high school or lower (61.4%), and 952 had an annual household income of $48 000 or less (81.5%). Of the 1329 individuals, 890 (unweighted percentage, 67.0%) were existing e-cigarette users, 67 (unweighted percentage, 5.0%) were new e-cigarette users, and 372 (unweighted percentage, 28.0%) were NRT users. Compared with individuals who used NRT during pregnancy, individuals who used e-cigarettes had a higher rate of smoking abstinence in late pregnancy (456 individuals [50.8%] vs 67 individuals [19.4%]; propensity score adjusted odds ratio [OR], 2.47; 95% CI, 1.17-5.20; P = .02). In the secondary analysis stratified by the timing of e-cigarette use initiation, existing users of e-cigarettes who initiated before pregnancy had a higher smoking abstinence rate than NRT users (446 users [53.1%] vs 67 users [19.4%]; adjusted OR, 2.61; 95% CI, 1.23-5.51; P = .01). However, new e-cigarette users who initiated use during pregnancy had a similar smoking abstinence rate in late pregnancy when compared with NRT users (10 users [20.6%] vs 67 users [19.4%]; adjusted OR, 1.13; 95% CI, 0.22-5.87; P = .88). Conclusions and Relevance: These findings suggest that individuals who used e-cigarettes during pregnancy had a higher smoking abstinence rate in late pregnancy than individuals who used NRT, especially for those who initiated e-cigarette use before pregnancy, indicating that replacement of cigarettes with e-cigarettes during pregnancy may be a viable strategy for harm reduction.

Changes in e-cigarette and cigarette use during pregnancy and their association with small-for-gestational-age birth.

BACKGROUND: Despite increased e-cigarette use, limited research has focused on changes in e-cigarette and combustible cigarette use around pregnancy and the subsequent effects on infant health. OBJECTIVE: This study aimed to characterize changes in e-cigarette and cigarette use from before to during pregnancy and examine their associations with small-for-gestational-age birth. STUDY DESIGN: This was a secondary data analysis of 2016-2018 data of the US Pregnancy Risk Assessment Monitoring System. We analyzed women aged ≥18 years who had a recent live birth (unweighted: n=105,438; weighted: n=5,446,900). Women were grouped on the basis of their self-reported e-cigarette and/or cigarette use 3 months before pregnancy (exclusive e-cigarette users, exclusive cigarette smokers, dual users, and nonusers) and change in e-cigarette and cigarette use during pregnancy (continuing use, quitting, switching, and initiating use). Small-for-gestational-age was defined as a birthweight below the 10th percentile for infants of the same sex and gestational age. We described the distributions of women's sociodemographic and pregnancy characteristics in both weighted and unweighted samples. We used multivariable log-binomial regression models to estimate the relative risks for the associations between changes in e-cigarette and cigarette use during pregnancy and risk of small-for-gestational-age, adjusting for significant covariates. RESULTS: The rates of cessation during pregnancy were the highest among exclusive e-cigarette users (weighted percentage, 80.7% [49,378/61,173]), followed by exclusive cigarette users (54.4% [421,094/773,586]) and dual users (46.4% [69,136/149,152]). Among exclusive e-cigarette users, continued users of e-cigarettes during pregnancy had a higher risk of small-for-gestational-age than nonusers (16.5% [1849/11,206]) vs 8.8% [384,338/4,371,664]; confounder-adjusted relative risk, 1.52 [95% confidence interval, 1.45-1.60]), whereas quitters of e-cigarettes had a similar risk of small-for-gestational-age with nonusers (7.7% [3730/48,587] vs 8.8% [384,338/4,371,664]; relative risk, 0.84 [95% confidence interval, 0.82-0.87]). Among exclusive cigarette users, those who completely switched to e-cigarettes during pregnancy also had a similar risk of small-for-gestational-age with nonusers (7.6% [259/3412] vs 8.8% [384,338/4,371,664]; relative risk, 0.83 [95% confidence interval, 0.73-0.93]). Among dual users before pregnancy, the risk of small-for-gestational-age decreased from 23.2% (7240/31,208) (relative risk, 2.53 [95% confidence interval, 2.47-2.58]) if continuing use to 16.9% (6617/39,142) (relative risk, 1.88 [95% confidence interval, 1.83-1.92]) if only quitting e-cigarettes or 15.1% (1254/8289) (relative risk, 1.61 [95% confidence interval, 1.52-1.70]) if only quitting cigarettes and further to 11.2% (7589/67,880) (relative risk, 1.23 [95% confidence interval, 1.20-1.25]) if both quitting e-cigarettes and cigarettes during pregnancy, compared with nonusers. CONCLUSION: Among exclusive e-cigarette users, quitting e-cigarettes during pregnancy normalized the risk of small-for-gestational-age. Among exclusive cigarette users, quitting smoking or completely switching to e-cigarettes normalized small for gestational age risk. Among dual users, smoking cessation has a greater effect than quitting e-cigarettes only, although discontinuing the use of both may lead to the greatest reduction in the risk of small-for-gestational-age.

Effects of Partially Hydrolyzed Formula on Severity and Outcomes of Neonatal Abstinence Syndrome.

OBJECTIVE: This study compares the effect of partially hydrolyzed formula (PHF) and standard formula (SF) on the severity and short-term outcomes of neonatal abstinence syndrome (NAS). STUDY DESIGN: We performed a retrospective chart review of 124 opioid-dependent mothers and their term or near-term infants. Infants were categorized according to the predominant type of formula consumed during the hospital stay. Finnegan's scale was used to assess symptoms of withdrawal. RESULTS: A total of 110 infants met our inclusion criteria. Thirty-four (31%) infants were fed predominantly PHF, 60 (54%) infants were fed SF, and 16 (15%) infants were fed maternal breast milk. There was no difference between the infants in the PHF and SF groups with respect to requirement of morphine (MSO4) therapy, maximum dose of MSO4 used, duration of MSO4 treatment or length of hospital stay after performing multivariate analyses to control for type of drug used by the mother, maternal smoking, regular prenatal care, inborn status, and maximum Finnegan score prior to MSO4 treatment. CONCLUSION: Use of PHF failed to impact short-term outcomes in infants treated for NAS including maximum MSO4 dose, duration of MSO4 treatment, and length of hospital stay. A prospective randomized controlled trial may be indicated to confirm this finding.

In Vitro Consequences of Electronic-Cigarette Flavoring Exposure on the Immature Lung.

Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.

Bronchopulmonary Dysplasia and Pulmonary Outcomes of Prematurity.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who require mechanical ventilation and oxygen therapy. Despite advances in neonatal care resulting in improved survival and decreased morbidity, limited progress has been made in reducing rates of BPD. Therapeutic options to protect the vulnerable developing lung are limited as are strategies to treat lung injury, resulting in ongoing concerns for long-term pulmonary morbidity after preterm birth. Lung protective strategies and optimal nutrition are recognized to improve pulmonary outcomes. However, characterization of late outcomes is challenged by rapid advances in neonatal care. As a result, current adult survivors reflect outdated medical practices. Although neonatal pulmonary disease tends to improve with growth, compromised respiratory health has been documented in young adult survivors of BPD. With improved survival of premature infants but limited progress in reducing rates of disease, BPD represents a growing burden on health care systems. [Pediatr Ann. 2019;48(4):e148-e153.].

Down Syndrome and Postoperative Complications in Children Undergoing Intestinal Operations.

OBJECTIVE: This paper intends to evaluate the association between Down Syndrome (DS) and postoperative medical and surgical complications and inpatient postoperative mortality in pediatric patients undergoing intestinal operations. METHODS: The 2012 Kids' Inpatient Database was queried to compare short-term postoperative medical and surgical complications and in-patient mortality among patients with DS undergoing intestinal operations to a cohort without DS using inverse probability weighting. Subset analysis was performed for patients undergoing intestinal operations exclusive of gastrostomy placement. Adverse treatment effects were calculated for the outcomes of interest. RESULTS: Of 17,026 pediatric patients undergoing intestinal operations, 444 had DS. In unadjusted analysis, medical complications (urinary tract infection, deep venous thrombosis, sepsis, pneumonia) occurred in 7.9% of patients with DS, compared to 14.1% of those without (p < 0.001). Surgical complications (wound disruption, hemorrhage, superficial or deep wound infection) occurred in 3.5% of patients with DS, compared to 4.6% of those without (p = 0.34), and in-patient mortality occurred in 0.3% of patients with DS, compared to 2.7% of those without (p = 0.009). Adverse treatment effects (ATE) calculated after inverse probability weighting demonstrated no difference for medical or surgical complications but a significantly decreased mortality with DS. CONCLUSIONS: Contrary to common perception and data extrapolated from the adult literature, pediatric patients with DS have neither higher medical nor surgical complication rates after intestinal operations. Similar to patients undergoing congenital heart surgery, pediatric patients with DS have a lower postoperative inpatient mortality after these general operations compared to those without DS. Mechanisms influencing risks in DS patient remain unknown. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Direct hyperbilirubinemia in newborns with gastroschisis.

BACKGROUND: Patients with gastroschisis and prolonged total (or partial) parenteral nutrition (PN) commonly develop direct hyperbilirubinemia (DH). OBJECTIVE: To quantify the prevalence and severity of DH in newborns with gastroschisis and characterize the diagnostic work-up for DH in this patient population. DESIGN/METHODS: Retrospective chart review of patients born with gastroschisis between 2005 and 2015 for the first 6 months of life. RESULTS: 29 patients were identified with gastroschisis. Mean gestational age and birthweight were 36.4 (± 1.8) weeks and 2.5 (± 0.6) kg. 41% were treated with primary reduction versus staged closure. Peak total and direct bilirubin (DB) levels were 10.17 ± 6.21 mg/dL and 5.58 ± 3.94 mg/dL, respectively. 23 patients (79.3%) were diagnosed with DH and 78.2% underwent additional work-up for hyperbilirubinemia consisting of imaging and laboratory studies, none of which revealed a cause for DH other than the presumed PN-associated cholestasis. In all patients, DB began to decline within 1-10 days of initiation of enteral feeds. CONCLUSION(S): DH is common in patients with gastroschisis and is unlikely to be associated with pathology aside from PN. Additional work-up may lead to unnecessary resource utilization. LEVELS OF EVIDENCE: Case series with no comparison group, Level IV.

An update on the diagnosis and management of bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension.

The past decade of neonatal care has been highlighted by increased survival rates in smaller and more premature infants. Despite reduction in mortality associated with extreme prematurity, long term pulmonary morbidities remain a concern, with growing recognition of the clinical burden attributable to infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). Recent publications shed light on the critical contributions of maternal placental pathology and compromised intrauterine growth to fetal pulmonary vascular development. A body of literature has further clarified postnatal risk factors for PH, most notably the severity of BPD but surprisingly the additional presence of non-pulmonary morbidities including necrotizing enterocolitis (NEC). Limitations of current diagnostics persist with growing consideration of novel echocardiographic approaches as well as complementary non-invasive biomarkers to better identify infants at risk. In 2015, a joint report published by the American Heart Association and American Thoracic Society provided the first guidelines for the care of children with PH with limited content to address BPD-associated PH. These guidelines were expanded upon in an expert consensus report produced by the Pediatric Pulmonary Hypertension Network (PPHNet). These recommendations encouraged the use of standardized screening protocols and emphasized the importance of evaluation and treatment of comorbidities when PH is identified. Cardiac catheterization was recommended prior to initiation of therapy for more accurate quantification of pulmonary pressures, clarification of anatomy and guidance in the use of pharmacotherapy. Despite these guidelines, significant practice variation persists and gaps remain with respect to optimal evaluation and management of BPD-associated PH.

Mortality after emergency abdominal operations in premature infants.

CONTEXT/BACKGROUND: To determine risk of 30-day mortality for premature infants undergoing abdominal operations during the first 2 months of life and to identify risk factors for perioperative mortality using available demographic and clinical variables of interest. BASIC PROCEDURES: Retrospective descriptive analysis of premature infants (gestational age less than or equal to 36weeks) undergoing abdominal operations during the first 2 months of life using the American College of Surgeon's National Surgical Quality Improvement Project Pediatric (NSQIP-P, 2012-2015) database. A stepwise logistic regression model incorporating multiple demographic and clinical factors was constructed to identify independent predictors of 30-day mortality. FINDINGS: A total of 1554 premature infants were identified who underwent abdominal operations during the first 2 months of life. Unadjusted 30-day mortality ranged from 31% for infants born <24weeks gestational age to 4.9% for those born at 35-36weeks. Increased gestational age corresponded to decreased risk of mortality but week-by-week was not independently predictive of mortality in multivariate modeling. Female sex (aOR 1.51, 95% C.I. 1.08-2.10, p=0.014), inotrope support (aOR 3.46, 95% C.I. 2.43-4.92, p<0.001), ventilator use (aOR 2.86, 95% C.I. 1.56-5.25, p<0.001) and American Society of Anesthesiologists (ASA) class 3 (aOR 4.14, 95% C.I. 1.58-10.81, p=0.004) at time of operation were all associated with significantly increased risk of 30-day mortality. On stepwise logistic regression incorporating only those variables with statistical significance, female sex, inotrope, and ventilator support retained statistical significance. CONCLUSIONS: Premature infants undergoing abdominal operations during the first 2 months of life have expectedly high risk of 30-day mortality. Female sex, inotrope, and ventilator support are independently associated with increased risk of mortality and can be incorporated into a model where, if present, risk of mortality is greater than 14.2%. LEVEL OF EVIDENCE: Level III.

Aberrant cGMP signaling persists during recovery in mice with oxygen-induced pulmonary hypertension.

Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.

Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy and Long-Term Pulmonary Outcomes.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been made in reducing rates of BPD. Lack of progress may in part be attributed to the limited therapeutic options available for prevention and treatment of BPD. Several lung-protective strategies have been shown to reduce risks, including use of non-invasive support, as well as early extubation and volume ventilation when intubation is required. These approaches, along with optimal nutrition and medical therapy, decrease risk of BPD; however, impacts on long-term outcomes are poorly defined. Characterization of late outcomes remain a challenge as rapid advances in medical management result in current adult BPD survivors representing outdated neonatal care. While pulmonary disease improves with growth, long-term follow-up studies raise concerns for persistent pulmonary dysfunction; asthma-like symptoms and exercise intolerance in young adults after BPD. Abnormal ventilatory responses and pulmonary hypertension can further complicate disease. These pulmonary morbidities, combined with environmental and infectious exposures, may result in significant long-term pulmonary sequalae and represent a growing burden on health systems. Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease.

Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia.

BACKGROUND: Prematurity and fetal growth restriction are risk factors for pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD). Neonatal rats develop PH and vascular remodeling when exposed to hyperoxia. We hypothesize that postnatal growth restriction (PNGR) due to under-nutrition increases the severity of PH induced by hyperoxia in neonatal rats. METHODS: Pups were randomized at birth to litters maintained in room air or 75% oxygen (hyperoxia), together with litters of normal milk intake (10 pups) or PNGR (17 pups). After 14 d, right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricular plus septal weight) and PH by echocardiography. Lungs were analyzed by immunohistochemistry, morphometrics, western blotting, and metabolomics. RESULTS: Hyperoxia and PNGR each significantly increased pulmonary arterial pressure, RVH and pulmonary arterial medial wall thickness, and significantly decreased pulmonary vessel number. These changes were significantly augmented in pups exposed to both insults. Hyperoxia and PNGR both significantly decreased expression of proteins involved in lung development and vasodilation. CONCLUSION: PNGR induces right ventricular and pulmonary vascular remodeling and augments the effects of oxygen in neonatal rats. This may be a powerful tool to investigate the mechanisms that induce PH in low-birth-weight preterm infants with BPD.

Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent.

Animal models demonstrate that exposure to supraphysiological oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in hyperoxia. We hypothesize that consequences of hyperoxia may also be developmentally regulated and mitochondrial reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of hyperoxia, neonatal mice were placed in 75% oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), during early postnatal hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of hyperoxia are developmentally regulated and decrease with age. Attenuated disease in mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted antioxidant therapy in the prevention or treatment of BPD.

Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice.

Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH.

Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension.

Pulmonary hypertension (PH) occurs in 25 to 35% of premature infants with significant bronchopulmonary dysplasia (BPD). Neonatal mice exposed to 14 days of hyperoxia develop BPD-like lung injury and PH. To determinne the impact of hyperoxia on pulmonary artery (PA) cyclic guanosine monophosphate (cGMP) signaling in a murine model of lung injury and PH, neonatal C57BL/6 mice were placed in room air, 75% O2 for 14 days (chronic hyperoxia [CH]) or 75% O2 for 24 hours, followed by 13 days of room air (acute hyperoxia with recovery [AHR]) with or without sildenafil. At 14 days, mean alveolar area, PA medial wall thickness (MWT), right ventricular hypertrophy (RVH), and vessel density were assessed. PA protein was analyzed for cGMP, soluble guanylate cyclase, and PDE5 activity. CH and AHR mice had RVH, but only CH mice had increased alveolar area and MWT and decreased vessel density. In CH and AHR PAs, soluble guanylate cyclase activity was decreased, and PDE5 activity was increased. In CH mice, sildenafil attenuated MWT and RVH but did not improve mean alveolar area or vessel density. In CH and AHR PAs, sildenafil decreased PDE5 activity and increased cGMP. Our results indicate that prolonged hyperoxia leads to lung injury, PH, RVH, and disrupted PA cGMP signaling. Furthermore, 24 hours of hyperoxia causes RVH and disrupted PA cGMP signaling that persists for 13 days. Sildenafil reduced RVH and restored vascular cGMP signaling but did not attenuate lung injury. Thus, hyperoxia can rapidly disrupt PA cGMP signaling in vivo with sustained effects, and concurrent sildenafil therapy can be protective.

Pulmonary hypertension in bronchopulmonary dysplasia.

Pulmonary hypertension (PH) is a common complication of neonatal respiratory diseases, including bronchopulmonary dysplasia (BPD), and recent studies have increased awareness that PH worsens the clinical course, morbidity and mortality of BPD. Recent evidence indicates that up to 18% of all extremely low-birth-weight infants will develop some degree of PH during their hospitalization, and the incidence rises to 25-40% of the infants with established BPD. Risk factors are not yet well understood, but new evidence shows that fetal growth restriction is a significant predictor of PH. Echocardiography remains the primary method for evaluation of BPD-associated PH, and the development of standardized screening timelines and techniques for identification of infants with BPD-associated PH remains an important ongoing topic of investigation. The use of pulmonary vasodilator medications, such as nitric oxide, sildenafil, and others, in the BPD population is steadily growing, but additional studies are needed regarding their long-term safety and efficacy.