Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures.

Over the past decade, clinicians have increasingly prescribed acetaminophen (APAP) for patients in the neonatal intensive care unit (NICU). Acetaminophen has been shown to reduce postoperative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data.

Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial.

OBJECTIVE: To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk. STUDY DESIGN: We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000 g and receiving respiratory support at 24 hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4 weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36 weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant. RESULTS: As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P = .03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups. CONCLUSIONS: Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01203488.

Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge.

OBJECTIVES: To measure between-center variation in loop diuretic use in infants developing severe bronchopulmonary dysplasia (BPD) in US children's hospitals, and to compare mortality and age at discharge between infants from low-use centers and infants from high-use centers. STUDY DESIGN: We performed a retrospective cohort study of preterm infants at <32 weeks of gestational age with severe BPD. The primary outcome was cumulative loop diuretic use, defined as the proportion of days with exposure between admission and discharge. Infant characteristics associated with loop diuretic use at P < .10 were included in multivariable models to adjust for center differences in case mix. Hospitals were ranked from lowest to highest in adjusted use and dichotomized into low-use centers and high-use centers. We then compared mortality and postmenstrual age at discharge between the groups through multivariable analyses. RESULTS: We identified 3252 subjects from 43 centers. Significant variation between centers remained despite adjustment for infant characteristics, with use present in an adjusted mean range of 7.3% to 49.4% of days (P < .0001). Mortality did not differ significantly between the 2 groups (aOR, 0.98; 95% CI, 0.62-1.53; P = .92), nor did postmenstrual age at discharge (marginal mean, 47.3 weeks [95% CI, 46.8-47.9 weeks] in the low-use group vs 47.4 weeks [95% CI, 46.9-47.9 weeks] in the high-use group; P = .96). CONCLUSIONS: A marked variation in loop diuretic use for infants developing severe BPD exists among US children's hospitals, without an observed difference in mortality or age at discharge. More research is needed to provide evidence-based guidance for this common exposure.

Characterization of Disease Phenotype in Very Preterm Infants with Severe Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia (BPD) is a heterogenous condition with poorly characterized disease subgroups.Objectives: To define the frequency of three disease components: moderate-severe parenchymal disease, pulmonary hypertension (PH), or large airway disease, in a referral cohort of preterm infants with severe BPD. The association between each component and a primary composite outcome of death before hospital discharge, tracheostomy, or home pulmonary vasodilator therapy was assessed.Methods: This was a retrospective, single-center cohort study of infants born at <32 weeks' gestation with severe BPD who underwent both chest computed tomography with angiography (CTA) and echocardiography between 40 and 50 weeks postmenstrual age between 2011 and 2015. Moderate-severe parenchymal lung disease was defined as an Ochiai score ≥8 on CTA. PH was diagnosed by echocardiogram using standard criteria. Large airway disease was defined as tracheomalacia or bronchomalacia on bronchoscopy and/or tracheoscopy or CTA.Measurements and Main Results: Of 76 evaluated infants, 73 (96%) were classifiable into phenotypic subgroups: 57 with moderate-severe parenchymal disease, 48 with PH, and 44 with large airway disease. The presence of all three disease components was most common (n = 23). Individually, PH and large airway disease, but not moderate-severe parenchymal disease, were associated with increased risk for the primary study outcome. Having more disease components was associated with an incremental increase in the risk for the primary outcome (2 vs. 1: odds ratio, 4.9; 95% confidence interval, 1.4-17.2 and 3 vs. 1: odds ratio, 12.8; 95% confidence interval, 2.4-70.0).Conclusions: Infants with severe BPD are variable in their predominant pathophysiology. Disease phenotyping may enable better risk stratification and targeted therapeutic intervention.

Drugs to Prevent Bronchopulmonary Dysplasia: Effect of Baseline Risk on the Number Needed to Treat.

Infants born very preterm have a variable baseline risk of bronchopulmonary dysplasia (BPD). Using the example of evidence-based drug therapies to prevent BPD, we designed a visual aid that displays the "number needed to treat" with CIs for caffeine, vitamin A, and hydrocortisone over a range of baseline risks.

Lifelong pulmonary sequelae of bronchopulmonary dysplasia.

PURPOSE OF REVIEW: To summarize the current literature evaluating long-term pulmonary morbidity among surviving very preterm infants with bronchopulmonary dysplasia (BPD). RECENT FINDINGS: BPD predisposes very preterm infants to adverse respiratory signs and symptoms, greater respiratory medication use, and more frequent need for rehospitalization throughout early childhood. Reassuringly, studies also indicate that older children and adolescents with BPD experience, on average, similar functional status and quality of life when compared to former very preterm infants without BPD. However, measured deficits in pulmonary function may persist in those with BPD and indicate an increased susceptibility to early-onset chronic obstructive pulmonary disease during adulthood. Moreover, subtle differences in exercise tolerance and activity may put survivors with BPD at further risk of future morbidity in later life. SUMMARY: Despite advances in neonatal respiratory care, a diagnosis of BPD continues to be associated with significant pulmonary morbidity over the first two decades of life. Long-term longitudinal studies are needed to determine if recent survivors of BPD will also be at increased risk of debilitating pulmonary disease in adulthood.

The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach.

Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity.Objectives: To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks' postmenstrual age best predicts death or serious respiratory morbidity through 18-26 months' corrected age.Methods: We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Measurements and Main Results: Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks' postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n = 773); grade 1, nasal cannula ≤2 L/min (n = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure (n = 617); and grade 3, invasive mechanical ventilation (n = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33-79%) was observed for death or neurodevelopmental impairment.Conclusions: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks' postmenstrual age, regardless of supplemental oxygen use.

Use of Point-of-Care Gastric pH Testing to Assess the Efficacy of Acid Suppression Therapy in the Neonatal Intensive Care Unit.

OBJECTIVE: The use of acid suppression therapies in newborns lacks efficacy and is associated with adverse effects. Point-of-care (POC) assessment of gastric aspirate pH may provide an objective, noninvasive measure of gastric acidity in tube fed infants. We conducted the present study to characterize the POC gastric pH levels in gastric tube fed infants before and after initiation of enteral omeprazole or ranitidine. STUDY DESIGN: Retrospective cohort study of infants with gastric aspirate pH levels determined by POC pH strips. Gastric pH levels recorded during 7 days before and 14 days after medication initiation were compared using Wilcoxon's sign-rank tests. RESULTS: Among 307 evaluated infants, 284 (92%) had a median gastric pH level ≥4 in 7 days prior to ranitidine or omeprazole. In 14 days after medication initiation, the median gastric pH of infants with pretreatment median gastric pH < 4 increased to 4.5 and 5 (p < 0.01) in the ranitidine and omeprazole groups, respectively. There was no change in infants with pretreatment median gastric pH ≥4. CONCLUSION: Among infants receiving gastric tube feedings and enteral omeprazole or ranitidine, only those with a pretreatment gastric pH level <4 demonstrated a significant increase in gastric pH. Validation of our findings against esophageal pH multichannel intraluminal impedance testing is needed.

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Relationship between pulmonary artery acceleration time and pulmonary artery pressures in infants.

BACKGROUND: Pulmonary artery acceleration time measured by echocardiography inversely correlates with pulmonary artery pressures in adults and children older than 1 year of age. There is a paucity of data investigating this relationship in young children, particularly among preterm infants. OBJECTIVE: To characterize the relationship between pulmonary artery acceleration time (PAAT) and pulmonary artery pressures in infants. DESIGN/METHODS: Patients ≤ 1 year of age at Children's Hospital of Philadelphia between 2011 and 2017 were reviewed. Infants with congenital heart disease were excluded, except those with a patent ductus arteriosus (PDA), atrial septal defect (ASD), or ventricular septal defect (VSD). Linear regression analysis was used to assess the correlation between PAAT measured by echocardiography and systolic pulmonary artery pressure, mean pulmonary artery pressure, and indexed pulmonary vascular resistance from cardiac catheterization. RESULTS: Fifty-seven infants were included, of which 61% were preterm and 49% had a diagnosis of bronchopulmonary dysplasia. The median postmenstrual age and weight at catheterization were 51.1 weeks (IQR 35.8-67.9 weeks) and 4400 g (IQR 3100-6500 g), respectively. Forty-four infants (77%) had a patent ductus arteriosus (PDA). There was a weak inverse correlation between PAAT with mPAP (r = -0.35, P = 0.01), sPAP (r = -0.29, P = 0.03), and PVRi (r = -0.29, P = 0.03). CONCLUSION: There is a weak inverse relationship between PAAT and pulmonary artery pressures. This relationship is less robust in our population of infants with a high incidence of PDAs compared to previous studies in older children. Thus, PAAT may be less clinically meaningful for diagnosing pulmonary arterial hypertension in infants, particularly those with PDAs.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

Association between Off-Peak Hour Birth and Neonatal Morbidity and Mortality among Very Low Birth Weight Infants.

OBJECTIVE: To assess the independent association between overnight or "off-peak" hour delivery and 3 neonatal morbidities strongly associated with childhood neurocognitive impairment. STUDY DESIGN: Retrospective population based cohort study of all infants with birth weights of 500-1499 g born without severe congenital anomalies in California or Pennsylvania between 2002 and 2009. Off-peak hour delivery was defined as birth between 12:00 a.m. and 6:59 a.m. The study outcomes were death; bronchopulmonary dysplasia, retinopathy of prematurity, and severe (grade 3 or 4) intraventricular hemorrhage among survivors; the composite of each morbidity or mortality; and the composite of death or 1 or more of the evaluated morbidities. RESULTS: Of 47 617 evaluated infants, 9317 (19.6%) were born during off-peak hours. The frequencies of all study outcomes were higher among infants born during off-peak compared with peak hours. After adjusting for maternal, infant, and hospital characteristics, off-peak hour delivery was associated with increased odds of severe intraventricular hemorrhage among survivors (OR 1.39, 95% CI 1.23-1.57) and the composite outcomes of death or severe intraventricular hemorrhage (OR 1.16, 95% CI 1.07-1.25) and death or major morbidity (OR 1.08, 95% CI 1.02-1.15). There was no evidence of subgroup effects based on delivery mode, birth hospital neonatal intensive care level or annual very low birth weight infant delivery volume, or weekday vs weekend off-peak hour delivery for any study outcome. CONCLUSIONS: Very low birth weight infants born between midnight and 7:00 a.m. are at increased risk for severe intraventricular hemorrhage and death or major neonatal morbidity.

Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. STUDY DESIGN: Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed. RESULTS: Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P < .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life. CONCLUSIONS: Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

The Association between Positive Tracheal Aspirate Cultures and Adverse Pulmonary Outcomes in Preterm Infants with Severe Bronchopulmonary Dysplasia.

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use.

Interobserver Reliability of the Respiratory Physical Examination in Premature Infants: A Multicenter Study.

OBJECTIVE: To measure the inter-rater reliability of 7 visual and 3 auscultatory respiratory physical examination findings at 36-40 weeks' postmenstrual age in infants born less than 29 weeks' gestation. Physicians also estimated the probability that each infant would remain hospitalized for 3 months after the examination or be readmitted for a respiratory illness during that time. STUDY DESIGN: Prospective, multicenter, inter-rater reliability study using standardized audio-video recordings of respiratory physical examinations. RESULTS: We recorded the respiratory physical examination of 30 infants at 2 centers and invited 32 physicians from 9 centers to review the examinations. The intraclass correlation values for physician agreement ranged from 0.73 (95% CI 0.57-0.85) for subcostal retractions to 0.22 (95% CI 0.11-0.41) for expiratory abdominal muscle use. Eight (27%) infants remained hospitalized or were readmitted within 3 months after the examination. The area under the receiver operating characteristic curve for prediction of this outcome was 0.82 (95% CI 0.78-0.86). Physician predictive accuracy was greater for infants receiving supplemental oxygen (0.90, 95% CI 0.86-0.95) compared with those breathing in room air (0.71, 95% CI 0.66-0.75). CONCLUSIONS: Physicians often do not agree on respiratory physical examination findings in premature infants. Physician prediction of short-term respiratory morbidity was more accurate for infants receiving supplemental oxygen compared with those breathing in room air.