Postnatal corticosteroid therapy in bronchopulmonary dysplasia - why animal studies disagree with clinical trials?

The systematic review and meta-analysis of newborn animal models by Irene Lok et al. is the first to extensively summarize the literature regarding postnatal systemic corticosteroid use on lung development of newborn rodent models. The meta-analysis showed that the use of postnatal corticosteroids resulted in a reduction in body weight along with persistent alveolar simplification. The most frequently used corticosteroid was dexamethasone. Corticosteroids have been extensively used in clinical trials in preterm newborns. Trials using early systemic administration of corticosteroids reduced the rate of BPD or mortality with no increase in the rates of cerebral palsy. Use of late systemic corticosteroids (administered >7 days after birth) also reduced the rate of BPD, mortality, and combined outcome of mortality or BPD. Late systemic corticosteroids showed no impact on the rates of neurodevelopmental outcomes in later childhood. It is important to note that later stages of inflammation leading to a more severe form of BPD continues to be a problem with no clear therapy in sight. The authors made a critical point in their paper - the negative effects of steroids were greater in the normal lung control animals than in the injured. This conveys caution in using steroids in a prophylactic manner. IMPACT: Use of systemic corticosteroids in clinical trials have shown good response in preterm neonates evidenced by reduced rate of bronchopulmonary dysplasia. Rodent models have not shown a similar beneficial response. Use of systemic corticosteroids have caused greater arrest of lung development in rodent models with normal lungs compared to those with lung damage.

Patent Ductus Arteriosus Response to Treatment by Course and Associations with Perinatal and Clinical Factors.

OBJECTIVE: The objective of this study is to examine patent ductus arteriosus (PDA) response by treatment course and investigate associations with postmenstrual age (PMA), chronological age (CA), gestational age (GA), antenatal steroid exposure (ANS), birthweight (BW), weight at treatment initiation (WT), and PDA/left pulmonary artery (LPA) ratio. STUDY DESIGN: This is a single-center retrospective cohort study of preterm infants less than 37 weeks' GA born January 1, 2016 to December 31, 2018 who received acetaminophen and/or indomethacin for PDA treatment. Cox proportional hazards regression models were used to determine whether factors of interest were associated with PDA response to medical treatment. RESULTS: In total, 289 treatment courses were administered to 132 infants. Thirty-one (23%) infants experienced treatment-associated PDA closure. Ninety-four (71%) infants had evidence of PDA constriction following any treatment course. Ultimately, 84 (64%) infants experienced definitive PDA closure. For each 7-day increase in CA at the time of treatment initiation, the PDA was 59% less likely to close (p = 0.04) and 42% less likely to respond (i.e., constrict or close) to treatment (p < 0.01). PDA/LPA ratio was associated with treatment-associated PDA closure (p = 0.01). For every 0.1 increase in the PDA/LPA ratio, the PDA was 19% less likely to close in response to treatment. CONCLUSION: In this cohort, PDA closure is independent of PMA, GA, ANS, BW, and WT; however, CA at treatment initiation predicted both treatment-associated PDA closure and PDA response (i.e., constriction or closure), and PDA/LPA ratio was associated with treatment-associated closure. Most infants experienced PDA constriction rather than closure, despite receiving up to four treatment courses. KEY POINTS: · Detailed PDA responses for up to four treatment courses provide a novel perspective.. · Chronological age at the start of treatment predicted treatment-associated PDA closure and response.. · For each 7-day increase in chronological age, the PDA was 59% less likely to close..

Oxygen and steroids affect the regulatory role of natriuretic peptide receptor-C on surfactant secretion by type II cells.

Atrial natriuretic peptide (ANP) and its receptors natriuretic peptide receptor (NPR)-A and NPR-C are all highly expressed in alveolar epithelial type II cells (AEC2s) in the late-gestation ovine fetal lung and are dramatically decreased postnatally. However, of all the components, NPR-C stimulation inhibits ANP-mediated surfactant secretion. Since alveolar oxygen increases dramatically after birth, and steroids are administered to mothers antenatally to enhance surfactant lung maturity, we investigated the effects of O2 concentration and steroids on NPR-C-mediated surfactant secretion in AEC2s. NPR-C expression was highest at 5% O2 while being suppressed by 21% O2, in cultured mouse lung epithelial cells (MLE-15s) and/or human primary AEC2s. Surfactant protein-B (SP-B) was significantly elevated in media from both in vitro and ex vivo culture at 13% O2 versus 21% O2 in the presence of ANP or terbutaline (TER). Both ANP and C-ANP (an NPR-C agonist) attenuated TER-induced SP-B secretion; this effect was reversed by dexamethasone (DEX) pretreatment in AEC2s and by transfection with NPR-C siRNA in MLE-15 cells. DEX markedly reduced AEC2 NPR-C expression, and pregnant ewes treated with betamethasone showed reduced ANP in fetal sheep lung fluid. These data suggest that elevated O2 downregulates AEC2 NPR-C and that steroid-mediated NPR-C downregulation in neonatal lungs may provide a novel mechanism for their effect on perinatal surfactant production.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. METHODS: AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. RESULTS: AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. CONCLUSIONS: These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

Retrospective Analysis of Short-Term Respiratory Outcomes of Three Different Steroids Used in Clinical Practice in Intubated Preterm Infants.

OBJECTIVE: This study aimed to compare short-term respiratory outcomes of three steroids (dexamethasone, hydrocortisone, and methylprednisolone) to facilitate extubation by improving respiratory status in preterm infants. STUDY DESIGN: This is a retrospective, single-center, cohort study of 98 intubated preterm infants ≤346/7 weeks' gestation, admitted to a 64-bed, level III neonatal intensive care unit at the Women & Children's Hospital of Buffalo, Buffalo, NY, between 2006 and 2012, who received a short course of low-dose steroids for lung disease after first week of life. RESULTS: Study infants received dexamethasone (34%), hydrocortisone (44%), or methylprednisolone (22%) based on clinical team preference. By day 7 after initiation of steroids, extubation occurred in 59, 44, and 41%, respectively, in infants on dexamethasone, hydrocortisone, and methylprednisolone (p = 0.3). The mean respiratory severity score (RSS = fraction of inspired oxygen × mean airway pressure), a quantitative measure of respiratory status, decreased by 44% for all infants and by 59% in the dexamethasone group by day 7. CONCLUSION: Steroids improved short-term respiratory outcomes in all infants (RSS and extubation); by day 7, dexamethasone treatment was associated with the greatest decrease in RSS. Additional prospective, randomized trials of short-course low-dose steroids are warranted to substantiate these findings to guide clinical decision making and in evaluating differential steroid effects on long-term neurodevelopmental outcomes.

Respiratory Medications in Infants <29 Weeks during the First Year Postdischarge: The Prematurity and Respiratory Outcomes Program (PROP) Consortium.

OBJECTIVE: To determine patterns of respiratory medications used in neonatal intensive care unit graduates. STUDY DESIGN: The Prematurity Respiratory Outcomes Program enrolled 835 babies <29 weeks of gestation in the first week. Of 751 survivors, 738 (98%) completed at least 1, and 85% completed all 4, postdischarge medication usage in-person/telephone parental questionnaires requested at 3, 6, 9, and 12 months of corrected age. Respiratory drug usage over the first year of life after in neonatal intensive care unit discharge was analyzed. RESULTS: During any given quarter, 66%-75% of the babies received no respiratory medication and 45% of the infants received no respiratory drug over the first year. The most common postdischarge medication was the inhaled bronchodilator albuterol; its use increased significantly from 13% to 31%. Diuretic usage decreased significantly from 11% to 2% over the first year. Systemic steroids (prednisone, most commonly) were used in approximately 5% of subjects in any one quarter. Inhaled steroids significantly increased over the first year from 9% to 14% at 12 months. Drug exposure changed significantly based on gestational age with 72% of babies born at 23-24 weeks receiving at least 1 respiratory medication but only 40% of babies born at 28 weeks. Overall, at some time in the first year, 55% of infants received at least 1 drug including an inhaled bronchodilator (45%), an inhaled steroid (22%), a systemic steroid (15%), or diuretic (12%). CONCLUSION: Many babies born at <29 weeks have no respiratory medication exposure postdischarge during the first year of life. Inhaled medications, including bronchodilators and steroids, increase over the first year.

Black Race Is Associated with a Lower Risk of Bronchopulmonary Dysplasia.

OBJECTIVE: To use a large current prospective cohort of infants <29 weeks to compare bronchopulmonary dysplasia (BPD) rates in black and white infants. STUDY DESIGN: The Prematurity and Respiratory Outcome Program (PROP) enrolled 835 infants born in 2011-2013 at <29 weeks of gestation; 728 black or white infants survived to 36 weeks postmenstrual age (PMA). Logistic regression was used to compare BPD outcomes (defined as supplemental oxygen requirement at 36 weeks PMA) between the races, adjusted for gestational age (GA), antenatal steroid use, intubation at birth, and surfactant use at birth. RESULTS: Of 707 black or white infants with available BPD outcomes, BPD was lower in black infants (38% vs 45%), even though they were of significantly lower GA. At every GA, BPD was more common in white infants. The aOR for BPD was 0.60 (95% CI, 0.42-0.85; P = .004) for black infants compared with white infants after adjusting for GA. Despite the lower rate of BPD, black infants had a higher rate of first-year post-prematurity respiratory disease (black, 79%; white, 63%). CONCLUSIONS: In this large cohort of recently born preterm infants at <29 weeks GA, compared with white infants, black infants had a lower risk of BPD but an increased risk of persistent respiratory morbidity.

Decreasing prevalence of cerebral palsy in birth cohorts in South Carolina using Medicaid, disability service, and hospital discharge data, 1996 to 2009.

AIM: Since cross-sectional trends of 8-year-old cerebral palsy (CP) birth prevalence based on record review were stable from 1985 to 2002 in Metropolitan Atlanta, we examined birth cohort trends using administrative data sets promptly. METHOD: Among 755 433 live births from 1996 to 2009 in South Carolina, 2080 received CP diagnosis by age 4 years from linked Medicaid claims with International Classification of Diseases, Ninth Revision codes 343.X (contributing 1061 [51%] unique cases), hospital discharge data (57 [3%] unique cases), and Department of Disabilities and Special Needs program (64 [3%] unique cases). Trends were assessed using negative binominal regression. RESULTS: Including 3.7 percent of cases who died before age 4 years, CP prevalence per 1000 live births decreased significantly from 3.6 in 1996 to 2.1 in 2006 (-3.0% average annual change; 95% confidence interval -4.4 to -1.6). The overall prevalence was 2.8 per 1000 live births, 46.0 per 1000 very-low-birthweight (VLBW) live births, and 53.0 per 1000 VLBW 1-year survivors. Disparities and downward trends persisted across subgroups with higher rates among non-Hispanic black infants than non-Hispanic white and among males compared to females. INTERPRETATION: Downward CP prevalence rates and persistent disparities remain in South Carolina. Further research should validate this methodology, including early deaths, and develop broad surveillance systems to inform clinical practices and etiology. WHAT THIS PAPER ADDS: Birth cohort cerebral palsy (CP) prevalence decreased in South Carolina from 1996 to 2009. CP prevalence was higher in very-low-birthweight infants, non-Hispanic blacks, and males. Three administrative data sets captured 2080 patients with CP in South Carolina. Medicaid claims contributed 51% of unique cases of CP to the cohort. CP diagnoses included 76 patients who died before age 4 years.

DISMINUCIÓN DE LA PREVALENCIA DE PARÁLISIS CEREBRAL EN COHORTES DE NACIMIENTO EN CAROLINA DEL SUR UTILIZANDO MEDICAID, SERVICIO DE DISCAPACIDAD Y DATOS DE ALTA HOSPITALARIA, 1996-2009: OBJETIVO: Debido a que las tendencias transversales de la prevalencia de nacimientos con parálisis cerebral (PC), a los 8 años de edad, basadas en revisión de los registros, se mantuvieron estables desde 1985 hasta 2002 en el área metropolitana de Atlanta, se examinaron las tendencias de cohorte de nacimientos utilizando conjuntos de datos administrativos. MÉTODO: Entre 755.433 nacidos vivos de 1996 a 2009 en Carolina del Sur, 2080 recibieron el diagnóstico de PC a los 4 años de edad basados en prestaciones vinculados a Medicaid usando códigos de la Clasificación Internacional de Enfermedades, Noveno. Códigos de revisión 343.X (contribuyendo 1061 [51%] casos únicos), datos de alta hospitalaria (57 [3%] casos únicos) y programa del Departamento de Discapacidades y Necesidades Especiales (64 [3%] casos únicos). Las tendencias se evaluaron mediante regresión binominal negativa. RESULTADOS: Incluyendo el 3,7% de los casos que murieron antes de los 4 años, la prevalencia de PC por 1000 nacidos vivos disminuyó significativamente de 3,6 en 1996 a 2,1 en 2006 (-3,0% de variación anual promedio; intervalo de confianza del 95% [-4,4 a -1,6]). La prevalencia general fue de 2,8 por 1000 nacidos vivos, 46,0 por 1000 nacidos vivos con muy bajo peso al nacer (VLBW, por sus siglas en inglés) y 53,0 por 1000 sobrevivientes a 1 año VLBW. Las disparidades y las tendencias decrecientes persistieron en los subgrupos con tasas más altas entre los bebés negros no hispanos que entre los blancos no hispanos y entre los varones en comparación con las mujeres. INTERPRETACIÓN: Las tasas de prevalencia de PC en descenso y las disparidades persistentes permanecen en Carolina del Sur. Las investigaciones adicionales deben validar esta metodología, incluidas las muertes tempranas, y desarrollar sistemas de vigilancia amplios para informar las prácticas clínicas y la etiología.

REDUÇÃO NA PREVALÊNCIA DE PARALISIA CEREBRAL EM COORTES DE NASCIMENTO DA CAROLINA DO SUL USANDO MEDICAID, SERVIÇO DE INCAPACIDADES, E DADOS DE ALTAS HOSPITALARES, 1996-2009: OBJETIVO: Como tendências transversais de prevalência de nascimentos com paralisia cerebral (PC) com base em registros de 8 anos permaneceram estáveis de 1985 a 2002 na região metropolitana de Atlanta, examinamos tendências de coortes de nascimento usando bases de dados administrativos imediatos. MÉTODO: Em 755.433 nascidos vivos de 1996 a 2009 na Carolina do Sul, 2080 receberam diagnóstico de PC até a idade de 4 anos a partir de guias Medicaids com Códigos 343.X Segundo a Classificação Internacional de Doenças, nona revisão (contribuíram 1061 [51%] casos únicos), dados de altas hospitalares (57 [3%] casos únicos), e do programa do Departamento de Incapacidade e Necessidades especiais (64 [3%] casos únicos). As tendências foram avaliadas usando regressão binomial negativa. RESULTADOS: Incluindo 3,7 por cento de casos que foram a óbito antes de 4 anos de vida, a prevalência de PC por 1000 nascidos vivos diminuiu significativamente de 3,6 em 1996 a 2,1 em 2006 3 (-3,0% mudança média anual; intervalo de confiança 95% [-4,4 a -1,6]). A prevalência geral foi 2,8 por 1000 nascidos vivos, 46,0 por 1000 nascidos vivos com peso aos nascimento muito baixo (PNMB), e 53,0 por 1000 PNMB sobreviventes após 1 ano. Disparidades e tendências descendentes persistiram entre subgrupos com maiores taxas entre lactentes negros não-hispânicos e entre meninos em comparação com meninas. INTERPRETAÇÃO: Taxas descendentes de prevalência de PC e disparidades persistentes continuam a ser observadas na Carolina do Sul. Pesquisas devem validar esta metodologia, incluindo mortes precoces, e desenvolver sistemas de vigilância mais amplos para informar práticas clínicas e etiologias.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

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.

Bronchopulmonary dysplasia: new becomes old again!

Despite the many advances in neonatology, bronchopulmonary dysplasia (BPD) continues to be a frustrating disease of prematurity. BPD is a disease which is defined oddly by its treatment rather than its pathophysiology, leading to frequently changing nomenclature which has widespread implications on our ability to both understand and follow the progression of BPD. As various treatment modalities for BPD were developed and a larger number of extremely preterm infants survived, the "old" BPD based on lung injury from oxygen therapy and mechanical ventilation transitioned into a "new" BPD focused more on the interruption of normal development. However, the interruption of normal development does not solely apply to lung development. The effects of prematurity on vascular development cannot be overstated and pulmonary vascular disease has become the new frontier of BPD. As we begin to better understand the complex, multifactorial pathophysiology of BPD, it is necessary to again focus on appropriate, pathology-driven nomenclature that can effectively describe the multiple clinical phenotypes of BPD.

Natriuretic peptide C receptor in the developing sheep lung: role in perinatal transition.

Background: At birth, the release of surfactant from alveolar type II cells (ATIIs) is stimulated by increased activity of the beta-adrenergic/adenylyl cyclase/cyclic 3'-5' adenosine monophosphate-signaling cascade. Atrial natriuretic peptide (ANP) stimulates surfactant secretion through natriuretic peptide receptor A (NPR-A). ANP inhibits adenylyl cyclase activity through its binding to NPR-C. We wished to further understand the role of the NPR-C in perinatal transition. Methods: We studied ATII expression of NPR-C in fetal and newborn sheep using immunohistochemistry, and surfactant secretion in isolated ATIIs by measuring 3[H] choline release into the media. Results: ANP induced surfactant secretion, and, at higher doses, it inhibits the stimulatory effect of the secretagogue terbutaline. ATII NPR-C expression decreased significantly after birth. Premature delivery also markedly decreased ANP and NPR-C in ATIIs. Co-incubation of terbutaline (10-4 M) with ANP (10-6 M) significantly decreased 3[H] choline release from isolated newborn ATII cells when compared with terbutaline alone; this inhibitory effect was mimicked by the specific NPR-C agonist, C-ANP (10-10 M). Conclusion: ANP may act as an important epithelial-derived inhibitor of surfactant release in the fetal lung, and downregulation of ANP and NPR-C following birth may sensitize ATII cells to the effects of circulating catecholamines, thus facilitating surfactant secretion.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Developmentally determined reduction in CD31 during gestation is associated with CD8+ T cell effector differentiation in preterm infants.

Homeostatic T cell proliferation is more robust during human fetal development. In order to understand the relative effect of normal fetal homeostasis and perinatal exposures on CD8+ T cell behavior in PT infants, we characterized umbilical cord blood CD8+ T cells from infants born between 23-42weeks gestation. Subjects were recruited as part of the NHLBI-sponsored Prematurity and Respiratory Outcomes Program. Cord blood from PT infants had fewer naïve CD8+ T cells and lower regulatory CD31 expression on both naïve and effector, independent of prenatal exposures. CD8+ T cell in vitro effector function was greater at younger gestational ages, an effect that was exaggerated in infants with prior inflammatory exposures. These results suggest that CD8+ T cells earlier in gestation have loss of regulatory co-receptor CD31 and greater effector differentiation, which may place PT neonates at unique risk for CD8+ T cell-mediated inflammation and impaired T cell memory formation.

Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome.

OBJECTIVE: Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. STUDY DESIGN: Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. RESULTS: In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. CONCLUSION: Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.

Animal models of bronchopulmonary dysplasia. The preterm and term rabbit models.

Bronchopulmonary dysplasia (BPD) is an important lung developmental pathophysiology that affects many premature infants each year. Newborn animal models employing both premature and term animals have been used over the years to study various components of BPD. This review describes some of the neonatal rabbit studies that have contributed to the understanding of BPD, including those using term newborn hyperoxia exposure models, premature hyperoxia models, and a term newborn hyperoxia model with recovery in moderate hyperoxia, all designed to emulate aspects of BPD in human infants. Some investigators perturbed these models to include exposure to neonatal infection/inflammation or postnatal malnutrition. The similarities to lung injury in human premature infants include an acute inflammatory response with the production of cytokines, chemokines, and growth factors that have been implicated in human disease, abnormal pulmonary function, disordered lung architecture, and alveolar simplification, development of fibrosis, and abnormal vascular growth factor expression. Neonatal rabbit models have the drawback of limited access to reagents as well as the lack of readily available transgenic models but, unlike smaller rodent models, are able to be manipulated easily and are significantly less expensive than larger animal models.

The spectrum of pneumonia among intubated neonates in the neonatal intensive care unit.

We review the pathophysiology, epidemiology, diagnosis, treatment, and prevention of ventilator-associated pneumonia (VAP) in neonates. VAP has been studied primarily in adult ICU patients, although there has been more focus on pediatric and neonatal VAP (neo-VAP) in the last decade. The definition as well as diagnosis of VAP in neonates remains a challenge to date. The neonatal intensivist needs to be familiar with the current diagnostic tools and prevention strategies available to treat and reduce VAP to reduce neonatal morbidity and the emergence of antibiotic resistance. This review also highlights preventive strategies and old and emerging treatments available.

Use of surfactant beyond respiratory distress syndrome, what is the evidence?

Surfactant replacement therapy is currently approved by the United States Food and Drug Administration (FDA) for premature infants with respiratory distress syndrome (RDS) caused by surfactant deficiency due to immaturity. There is strong evidence that surfactant decreases mortality and air leak syndromes in premature infants with RDS. However, surfactant is also used "off-label" for respiratory failure beyond classic RDS. This review discusses current evidence for the use of off-label surfactant therapy for (1) term infants with lung disease such as meconium aspiration syndrome (MAS), pneumonia/sepsis, and congenital diaphragmatic hernia (2) premature infants after 72 h for acute respiratory failure, and (3) the use of surfactant lavage. At last, we briefly describe the use of surfactants for drug delivery and the current evidence on evaluating infants for surfactant deficiency.

Introduction of oral feeding in premature infants on high flow nasal cannula in a level IV neonatal intensive care unit: a quality improvement initiative.

BACKGROUND: Failure to reach full oral feeding remains a significant barrier for premature infants to discharge home. Postmenstrual age (PMA) at first oral feeding is significantly associated with the length of hospital stay (LOS). METHODS: Single-center QI to introduce oral feeding to infants on high-flow nasal cannula (HFNC) by reducing the flow to 2 L during feeds. GLOBAL AIM: To reduce PMA at first oral feeding and reduce the LOS. SMART AIM: To introduce oral feeds in 40% of infants who are on ≤4 L HFNC by the end of 12 months. RESULTS: Over 12 months, SMART aim reached with 100% enrollment. PMA at first oral feeding decreased from a median of 42.4w ((IQR) (40,46.6) to 37.8w (35.8,43.2), PMA at discharge decreased from 47w (44.6,50.7) to 42.6w (41.3,48.8). CONCLUSION: Allowing oral feeding in infants while on HFNC is feasible. This approach can significantly reduce PMA at first and full oral feeding.

Predicting iatrogenic adrenal insufficiency in neonates exposed to prolonged steroid courses: do cortisol levels help?

OBJECTIVE: To determine whether random cortisol levels obtained in neonates to assess for secondary adrenal insufficiency (AI) after prolonged steroid exposure are predictive of central AI. STUDY DESIGN: Data were collected on neonates born 2017-2022 who received ≥10 consecutive days of systemic steroids and had cortisol measured thereafter. Data were then collected on whether those neonates developed signs of AI or had a failed adrenocorticotropic hormone (ACTH) stimulation test. RESULTS: Of the 71 cortisol levels (in 67 neonates) that were analyzed, there was no difference in cortisol levels between neonates who developed AI (median cortisol level of 6.5 mcg/dl) and those who did not (median of 9.2 mcg/dl), or between those who failed their ACTH stimulation test or passed it, using Wilcoxon ranked sum tests. CONCLUSION: These findings demonstrate that cortisol levels may not be helpful in identifying AI in neonates exposed to prolonged steroids.

Efficacy of recombinant erythropoietin for the late treatment of anemia of prematurity in a level IV neonatal intensive care unit: a retrospective single-center cohort study.

OBJECTIVE: To describe the population to which we administered recombinant erythropoietin and to determine the effectiveness of this treatment as quantified by the change in hematocrit. STUDY DESIGN: This retrospective chart review study included infants who received erythropoietin for the treatment of anemia of prematurity. RESULTS: There were 132 infants representing 162 unique treatment courses included in the study. The average duration of therapy was 9 days (±7) and 6 doses (±2). The average change in hematocrit (Hct) was 6.2% (SD 3.9%, p < 0.001). Rise in Hct was associated with a higher number of rEPO doses (p < 0.001) and higher postmenstrual age (p < 0.001). In our small cohort we did not find an association between the number of rEPO doses and retinopathy of prematurity (ROP) requiring treatment. CONCLUSION: Erythropoietin is safe and effective at treating anemia of prematurity as evidenced by a clinically and statistically significant increase in Hct from baseline.