Bronchopulmonary dysplasia and diuretic use in an outpatient setting.

INTRODUCTION: During Neonatal Intensive Care Unit hospitalization, children born preterm with bronchopulmonary dysplasia (BPD) are frequently prescribed diuretics for chronic respiratory symptoms. However, less is known about diuretic use and weaning in an outpatient setting. The study sought to characterize clinical features associated with outpatient diuretic use and timing of diuretic weaning in children with BPD. METHODS: Data was obtained by chart review from 1224 registry participants born <32 weeks gestation, discharged between 2008 and 2023 and recruited from outpatient BPD clinics at Johns Hopkins Children's Center and the Children's Hospital of Philadelphia (97.4% diagnosed with BPD). Data was analyzed using Chi-square tests, t-tests, and ANOVA tests. RESULTS: Children on diuretics at their first pulmonary visit (n = 737) were more likely to have lower birth weights, earlier gestational age, and severe BPD compared to those not on diuretics (n = 487). Of those prescribed diuretics, most children were on a thiazide alone (46.4%) or a thiazide and a potassium sparing agent (44.8%) with a minority prescribed loop diuretics alone (3.3%) or loop diuretic combinations (4.7%). Most children weaned off diuretics by 2 years of age. Public insurance, early gestational age, technology dependence, home supplemental oxygen use and loop diuretics were associated with slower diuretic weaning. CONCLUSION: Outpatient diuretic use is common in children with BPD, however variations in diuretic use and diuretic combinations exist across centers. Time to wean off home supplemental oxygen is similar between children on one diuretic compared to none. Timing of outpatient diuretic weaning is influenced by diuretic class, respiratory support, and co-morbidities.

Surfactant treatment at birth in a contemporary cohort of preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: Initial surfactant studies demonstrated improvements in survival and need for respiratory support. However, as the use of non-invasive respiratory support has increased the use of surfactant has decreased. We examined in a contemporary cohort of BPD patients if surfactant use was associated with BPD severity. STUDY DESIGN: An observational study using data from the BPD Collaborative Registry. RESULTS: 971 infants with BPD met entry criteria, 864 (89%) had received surfactant in the first 72 h of life (SURF) and the remainder had not (no surfactant). There was an association between SURF and BPD grade, with a greater likelihood of grade 3 BPD in infants who received surfactant in the DR or who had 2 or more doses. CONCLUSIONS: We speculate that the use of surfactant in the DR and use of multiple doses reflect the impact of perinatal factors beyond immaturity alone that increase the risk for grade 3 BPD.

Associations of PM2.5 exposure with emergency department visits and readmissions among preterm infants with bronchopulmonary dysplasia.

OBJECTIVES: To quantify the association of ambient air pollution (particulate matter, PM2.5) exposure with medically attended acute respiratory illness among infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Single center, retrospective cohort study of preterm infants with BPD in Metropolitan Philadelphia. Multivariable logistic regression quantified associations of annual mean PM2.5 exposure (per µg/m3) at the census block group level with medically attended acute respiratory illness, defined as emergency department (ED) visits or hospital readmissions within a year after first hospital discharge adjusting for age at neonatal intensive care unit (NICU) discharge, year, sex, race, insurance, BPD severity, and census tract deprivation. As a secondary analysis, we examined whether BPD severity modified the associations. RESULTS: Of the 378 infants included in the analysis, 189 were non-Hispanic Black and 235 were publicly insured. Census block PM2.5 level was not significantly associated with medically attended acute respiratory illnesses, ED visits, or hospital readmissions in the full study cohort. We observed significant effect modification by BPD grade; each 1 µg/m3 higher annual PM2.5 exposure was medically attended acute respiratory illness (adjusted odds ratio [aOR] 1.65, 95% CI: 1.06-2.63) among infants with Grade 1 BPD but not among infants with grade 3 BPD (aOR 0.83, 95% CI: 0.47-1.48) (interaction p = .024). CONCLUSIONS: Cumulative PM2.5 exposure in the year after NICU discharge was not significantly associated with medically attended acute respiratory illness among infants with BPD. However, infants with Grade 1 BPD had significantly higher odds with higher exposures. If replicated, these findings could inform anticipatory guidance for families of these infants to avoid outdoor activities during high pollution days after NICU discharge.

Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration. STUDY DESIGN: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time. RESULTS: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001). CONCLUSIONS: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed.

Associations of neighborhood social vulnerability with emergency department visits and readmissions among infants with bronchopulmonary dysplasia.

OBJECTIVES: To characterize associations of the CDC Social Vulnerability Index (SVI) with medically attended acute respiratory illness among infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Retrospective cohort of 378 preterm infants with BPD from a single center. Multivariable logistic regression quantified associations of SVI with medically attended acute respiratory illness, defined as emergency department (ED) visits or hospital readmissions within a year after first hospital discharge. Mediation analysis quantified the extent to which differences in SVI may explain known Black-White disparities in medically attended acute respiratory illness. RESULTS: SVI was associated with medically attended respiratory illness (per SVI standard deviation increment, aOR 1.44, 95% CI: 1.17-1.78). Adjustment for race and ethnicity attenuated the association (aOR 1.27, 95% CI: 0.97-1.64). SVI significantly mediated 31% of the Black-White disparity in ED visits (p = 0.04). CONCLUSIONS: SVI was associated with, and may partially explain racial disparities in, medically attended acute respiratory illness among infants with BPD.

Ranking Future Outcomes Most Important to Parents of Children with Bronchopulmonary Dysplasia.

OBJECTIVE: To assess which potential future outcomes are most important to parents of children with bronchopulmonary dysplasia, a disease that affects future respiratory, medical, and developmental outcomes for children born preterm. STUDY DESIGN: We recruited parents from 2 children's hospitals' neonatal follow-up clinics and elicited their importance rating for 20 different potential future outcomes associated with bronchopulmonary dysplasia. These outcomes were identified and selected through a literature review and discussions with panels of parents and clinician stakeholders, via a discrete choice experiment. RESULTS: One hundred and 5 parents participated. Overall, parents ranked "Will my child be more vulnerable to other problems because of having lung disease?" as the most important outcome, with other respiratory health related outcomes also highly ranked. Outcomes related to child development and effects on the family were among the lowest ranked. Individually, parents rated outcomes differently, resulting in a broad distribution of importance scores for many of the outcomes. CONCLUSIONS: The overall rankings suggest that parents prioritize future outcomes related to physical health and safety. Notably, for guiding research, some top-rated outcomes are not traditionally measured in outcome studies. For guiding individual counseling, the broad distribution of importance scores for many outcomes highlights the extent to which parents differ in their prioritization of outcomes.

Can we balance early exogenous surfactant therapy and non-invasive respiratory support to optimise outcomes in extremely preterm infants? A nuanced review of the current literature.

Therapeutic advances have significantly improved the survival of premature infants. However, a high burden of bronchopulmonary dysplasia (BPD) persists. Aiming at prevention of neonatal lung injury, continuous positive airway pressure (CPAP) and non-invasive ventilation (NIV) strategies have replaced mechanical ventilation for early respiratory support and treatment of respiratory distress syndrome. Multiple randomised controlled trials have demonstrated that broad application of CPAP/NIV decreases exposure to mechanical ventilation and reduces rates of BPD. Here, we explore why this treatment effect is not larger. We discuss that today's neonatal intensive care unit population evolving from the premature to the extremely premature infant demands better targeted therapy, and indicate how early and accurate identification of preterm infants likely to fail CPAP/NIV could increase the treatment effect and minimise the potential harm of delaying exogenous surfactant therapy in these infants. Finally, we argue that less invasive modes of surfactant administration may represent both a pragmatic and beneficial approach in combining CPAP/NIV and early surfactant. Beneficial treatment effects might be higher than reported in the literature when targeting this approach to preterm infants suffering from respiratory failure primarily due to surfactant deficiency. Considering ongoing limitations of current approaches and focusing both on prospects and potential harm of modified strategies, this commentary ultimately addresses the need and the challenge to prove that pushing early CPAP/NIV and strategies of early and less invasive surfactant application prevents lung injury in the long term.

Pulmonary Hypertension in Preterm Infants Treated With Laser vs Anti-Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity.

Importance: Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified. Objective: To determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment. Design, Setting, and Participants: This multicenter retrospective cohort study took place at neonatal intensive care units of 48 children's hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation. Exposures: Anti-VEGF therapy vs laser photocoagulation. Main Outcomes and Measures: New receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening. Results: Among 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks' postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10). Conclusions and Relevance: Anti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

Nasal continuous positive airway pressure levels for the prevention of morbidity and mortality in preterm infants.

BACKGROUND: Preterm infants are at risk of lung atelectasis due to various anatomical and physiological immaturities, placing them at high risk of respiratory failure and associated harms. Nasal continuous positive airway pressure (CPAP) is a positive pressure applied to the airways via the nares. It helps prevent atelectasis and supports adequate gas exchange in spontaneously breathing infants. Nasal CPAP is used in the care of preterm infants around the world. Despite its common use, the appropriate pressure levels to apply during nasal CPAP use remain uncertain. OBJECTIVES: To assess the effects of 'low' (≤ 5 cm H2O) versus 'moderate-high' (> 5 cm H2O) initial nasal CPAP pressure levels in preterm infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation. SEARCH METHODS: We ran a comprehensive search on 6 November 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-randomized trials. SELECTION CRITERIA: We included RCTs, quasi-RCTs, cluster-RCTs and cross-over RCTs randomizing preterm infants of gestational age < 37 weeks or birth weight < 2500 grams within the first 28 days of life to different nasal CPAP levels. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal to collect and analyze data. We used the GRADE approach to assess the certainty of the evidence for the prespecified primary outcomes. MAIN RESULTS: Eleven trials met inclusion criteria of the review. Four trials were parallel-group RCTs reporting our prespecified primary or secondary outcomes. Two trials randomized 316 infants to low versus moderate-high nasal CPAP for initial respiratory support, and two trials randomized 117 infants to low versus moderate-high nasal CPAP following endotracheal extubation. The remaining seven studies were cross-over trials reporting short-term physiological outcomes. The most common potential sources of bias were absent or unclear blinding of personnel and assessors and uncertain selective reporting. Nasal CPAP for initial respiratory support after birth and neonatal resuscitation None of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months. The remaining five outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.56 to 1.85; 1 trial, 271 participants); mortality by hospital discharge (RR 1.04, 95% CI 0.51 to 2.12; 1 trial, 271 participants); BPD at 28 days of age (RR 1.10, 95% CI 0.56 to 2.17; 1 trial, 271 participants); BPD at 36 weeks' PMA (RR 0.80, 95% CI 0.25 to 2.57; 1 trial, 271 participants), and treatment failure or need for mechanical ventilation (RR 1.00, 95% CI 0.63 to 1.57; 1 trial, 271 participants). We assessed the certainty of the evidence as very low for all five outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. Nasal CPAP following mechanical ventilation and endotracheal extubation One of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. On the basis of these data, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcome of treatment failure or need for mechanical ventilation (RR 1.52, 95% CI 0.92 to 2.50; 2 trials, 117 participants; I2 = 17%; risk difference 0.15, 95% CI -0.02 to 0.32; number needed to treat for an additional beneficial outcome 7, 95% CI -50 to 3). We assessed the certainty of the evidence as very low due to risk of bias, inconsistency across the studies, and imprecise effect estimates. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months or BPD at 28 days of age. The remaining three outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants); mortality by hospital discharge (RR 2.94, 95% CI 0.12 to 70.30; 1 trial, 93 participants), and BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants). We assessed the certainty of the evidence as very low for all three outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates.  AUTHORS' CONCLUSIONS: There are insufficient data from randomized trials to guide nasal CPAP level selection in preterm infants, whether provided as initial respiratory support or following extubation from invasive mechanical ventilation. We are uncertain as to whether low or moderate-high nasal CPAP levels improve morbidity and mortality in preterm infants. Well-designed trials evaluating this important aspect of a commonly used neonatal therapy are needed.

The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children's hospitals.

OBJECTIVE: To evaluate the association between chronic diuretic exposures and enteral electrolyte use in infants developing severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: Retrospective longitudinal cohort study in infants admitted to United States children's hospitals. We identified diuretic exposures and measured enteral NaCl and KCl use during pre-defined exposure risk-interval days. We used mixed-effects logistic regression to model the association between diuretic exposures and electrolyte use. RESULTS: We identified 442,341 subject-days in 3252 infants. All common diuretic classes and class combinations were associated with increased NaCl and KCl use. Thiazide monotherapy was associated with greater electrolyte use than loop monotherapy. The addition of potassium-sparing diuretics was associated with a limited reduction in KCl use compared to thiazide monotherapy. CONCLUSIONS: Chronic diuretic exposures are associated with increased NaCl and KCl use. Presumptions about the relative impact of different diuretic classes on electrolyte derangements may be inaccurate and require further study.

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.

The Clinical Evaluation of Severe Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia is a common disease of prematurity that presents along a wide spectrum of disease severity. Infants with high severity require prolonged hospitalizations and benefit from multidisciplinary care. We describe our approach to the evaluation of infants with severe bronchopulmonary dysplasia. Important considerations include the phenotypic heterogeneity in clinical presentation that necessitates individualized care, the common presence of comorbidities and importance of a comprehensive multisystem evaluation, and the value of applying a chronic care model that prioritizes long-term respiratory and neurodevelopmental goals. Key features of the history, physical examination, and diagnostic studies are discussed with these considerations in mind.

Pharmacologic Management of Severe Bronchopulmonary Dysplasia.

Few medications are available and well tested to treat infants who already have developed or inevitably will develop severe bronchopulmonary dysplasia (sBPD). Infants who develop sBPD clearly have not benefited from decades of research efforts to identify clinically meaningful preventive therapies for very preterm infants in the first days and weeks of their postnatal lives. This review addresses challenges to individualized approaches to medication use for sBPD. Specific challenges include understanding the combination of an individual infant's postmenstrual and postnatal age and the developmental status of drug-metabolizing enzymes and receptor expression. This review will also explore the reasons for the variable responsiveness of infants to specific therapies, based on current understanding of developmental pharmacology and pharmacogenetics. Data demonstrating the remarkable variability in the use of commonly prescribed drugs for sBPD are presented, and a discussion about the current use of some of these medications is provided. Finally, the potential use of antifibrotic medications in late-stage sBPD, which is characterized by a profibrotic state, is addressed.

Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants.

Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.

Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children's hospitals.

OBJECTIVE: To identify the number of cumulative medication exposures and most frequently used medications in infants with severe BPD. STUDY DESIGN: We performed a retrospective cohort study in infants with severe BPD admitted to United States children's hospitals. We measured cumulative medication exposures in individual subjects and between-center variation after adjustment for infant characteristics. We then identified the specific medications and therapeutic classes with the highest rates of use. RESULTS: In 3252 subjects across 43 hospitals, we identified a median (interquartile range) of 30 (17-45) cumulative medication exposures per infant. The adjusted mean number of medication exposures varied between centers (p < 0.0001), with a range of 22-50. Diuretics and furosemide were the most frequently prescribed therapeutic class and specific medication for the management of severe BPD. CONCLUSIONS: Infants with severe BPD are exposed to alarming number of medications of unclear efficacy and safety, with marked variation between center.

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.

Positive end-expiratory pressure for preterm infants requiring conventional mechanical ventilation for respiratory distress syndrome or bronchopulmonary dysplasia.

BACKGROUND: Conventional mechanical ventilation (CMV) is a common therapy for neonatal respiratory failure. While CMV facilitates gas exchange, it may simultaneously injure the lungs. Positive end-expiratory pressure (PEEP) has received less attention than other ventilation parameters when considering this benefit-risk balance. While an appropriate PEEP level may result in clinical benefits, both inappropriately low or high levels may cause harm. An appropriate PEEP level may also be best achieved by an individualized approach. OBJECTIVES: 1. To compare the effects of PEEP levels in preterm infants requiring CMV for respiratory distress syndrome (RDS). We compare both: zero end-expiratory pressure (ZEEP) (0 cm H2O) versus any PEEP and low (< 5 cm H2O) vs high (≥ 5 cm H2O) PEEP.2. To compare the effects of PEEP levels in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD). We compare both: ZEEP (0 cm H2O) vs any PEEP and low (< 5 cm H2O) versus high (≥ 5 cm H2O) PEEP.3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials, MEDLINE via PubMed, Embase, and CINAHL to 14 February 2018. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: We included all randomized or quasi-randomized controlled trials studying preterm infants born at less than 37 weeks' gestational age, requiring CMV and undergoing randomization to either different PEEP levels (RDS or BPD); or, two or more alternative methods for individualizing PEEP levels (RDS only). We included cross-over trials but limited outcomes to those from the first cross-over period. DATA COLLECTION AND ANALYSIS: We performed data collection and analysis according to the recommendations of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for prespecified key clinically relevant outcomes. MAIN RESULTS: Four trials met the inclusion criteria. Two cross-over trials with 28 participants compared different PEEP levels in infants with RDS. Meta-analysis was limited to short-term measures of pulmonary gas exchange and showed no differences between low and high PEEP.We identified no trials comparing PEEP levels in infants with BPD.Two trials enrolling 44 participants compared different methods for individualizing PEEP in infants with RDS. Both trials compared an oxygenation-guided lung-recruitment maneuver (LRM) with gradual PEEP level titrations for individualizing PEEP to routine care (control). Meta-analysis showed no difference between LRM and control on mortality by hospital discharge (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.17 to 5.77); there was no statistically significant difference on BPD, with an effect estimate favoring LRM (RR 0.25, 95% CI 0.03 to 2.07); and a statistically significant difference favoring LRM for the outcome of duration of ventilatory support (mean difference -1.06 days, 95% CI -1.85 to -0.26; moderate heterogeneity, I2 = 67%). Short-term oxygenation measures also favored LRM. We graded the quality of the evidence as low for all key outcomes due to risk of bias and imprecision of the effect estimates. AUTHORS' CONCLUSIONS: There continues to be insufficient evidence to guide PEEP level selection for preterm infants on CMV for RDS or BPD. Low-quality data suggests that selecting PEEP levels through the application of an oxygenation-guided LRM may result in clinical benefit. Well-conducted randomized trials, particularly to further evaluate the potential benefits of oxygenation-guided LRMs, are needed.