<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>OBJECTIVES: </strong>To assess the effects of 'low' (≤ 5 cm HO) versus 'moderate-high' (&gt; 5 cm HO) initial nasal CPAP pressure levels in preterm&nbsp;infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation.</p>

<p><strong>SEARCH METHODS: </strong>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.</p>

<p><strong>SELECTION CRITERIA: </strong>We included RCTs, quasi-RCTs, cluster-RCTs and cross-over RCTs randomizing preterm infants of gestational age &lt; 37 weeks or birth weight &lt; 2500 grams within the first 28 days of life to different nasal CPAP levels.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>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.</p>

<p><strong>MAIN RESULTS: </strong>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; I = 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.&nbsp; 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.</p>

<p>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.</p>

<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>OBJECTIVES: </strong>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 HO) versus any PEEP and low (&lt; 5 cm HO) vs high (≥ 5 cm HO) PEEP.2. To compare the effects of PEEP levels in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD). We compare both: ZEEP (0 cm HO) vs any PEEP and low (&lt; 5 cm HO) versus high (≥ 5 cm HO) PEEP.3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS.</p>

<p><strong>SEARCH METHODS: </strong>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.</p>

<p><strong>SELECTION CRITERIA: </strong>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.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>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.</p>

<p><strong>MAIN RESULTS: </strong>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, I = 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.</p>

<p><strong>AUTHORS' CONCLUSIONS: </strong>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.</p>

<p><strong>OBJECTIVE: </strong>To test the hypothesis that significant positive end-expiratory pressure (PEEP) level variation exists between neonatal centers.</p>

<p><strong>STUDY DESIGN: </strong>We performed a secondary analysis cohort study of the Nasal Intermittent Positive-Pressure Ventilation trial. Our study population was extremely low birth weight infants requiring mechanical ventilation within 28 days of life. The exposure was neonatal center; 34 international centers participated in the trial. Subjects from centers with fewer than 5 eligible cases were excluded. The main outcome was the maximal PEEP level used during the first course of mechanical ventilation. Infant characteristics judged a priori to directly influence clinical PEEP level selection and all characteristics associated with PEEP at P &lt;.05 in bivariable analyses were included with and without center in multivariable linear regression models. Variation in PEEP level use between centers following adjustment for infant characteristics was assessed.</p>

<p><strong>RESULTS: </strong>A total of 278 extremely low birth weight infants from 17 centers were included. Maximal PEEP ranged from 3 to 9 cm H2O, mean = 5.7 (SD = 0.9). Significant variation between centers remained despite adjustment for infant characteristics (P &lt; .0001). Further, center alone explained a greater proportion of the PEEP level variation than all infant characteristics combined.</p>

<p><strong>CONCLUSIONS: </strong>Marked variation in PEEP levels for extremely low birth weight infants exists between neonatal centers. Research providing evidence-based guidance for this important aspect of respiratory care in preterm infants at high risk of lung injury is needed.</p>

<p><strong>TRIAL REGISTRATION: </strong>ClinicalTrials.govNCT00433212.</p>

<p><strong>BACKGROUND: </strong>Conventional mechanical ventilation (CMV) of neonates has been used as a treatment of respiratory failure for over 30 years. While CMV facilitates gas exchange, it may simultaneously damage the lung. Positive end expiratory pressure (PEEP) has received less attention than other ventilation parameters when considering this balance of benefit and possible harm. While an appropriate level of PEEP may exert substantial benefits in ventilation, both inappropriately low or high levels may lead to harm. An appropriate level of PEEP for neonates may also be best achieved by an individualized approach.</p>

<p><strong>OBJECTIVES: </strong>1. To compare the effects of different levels of PEEP in preterm newborn infants requiring CMV for respiratory distress syndrome (RDS).2. To compare the effects of different levels of PEEP in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD).3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS.</p>

<p><strong>SEARCH METHODS: </strong>The search was performed in accordance with the standard search strategy for the Cochrane Neonatal Review Group. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, EMBASE, study references and experts were utilized for study identification.</p>

<p><strong>SELECTION CRITERIA: </strong>All randomized and quasi-randomized controlled trials studying preterm infants (less than 37 weeks gestational age) requiring CMV with endotracheal intubation and undergoing randomization to either different PEEP levels (RDS or BPD) or two or more alternative methods for individualizing PEEP levels (RDS only) were included. Cross-over trials were included but we limited the findings to those in the first cross-over period.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>Data collection and analysis were performed in accordance with the recommendations of the Cochrane Neonatal Review Group.</p>

<p><strong>MAIN RESULTS: </strong>An initial evaluation identified 10 eligible articles. Ultimately, a single study met our inclusion criteria. The study addressed the effects of different levels of PEEP in preterm newborn infants requiring CMV for RDS. Only short term physiologic measures were reported. All results were limited to a small sample size without statistically significant results. No trials addressing the effect of PEEP in infants with BPD or strategies to individualize the management of PEEP were identified.</p>

<p><strong>AUTHORS' CONCLUSIONS: </strong>There is insufficient evidence to guide selection of appropriate PEEP levels for RDS or CMV. There is a need for well designed clinical trials evaluating the optimal application of this important and frequently applied intervention.</p>