Does the use of higher versus lower oxygen concentration improve neurodevelopmental outcomes at 18-24 months in very low birthweight infants?

BACKGROUND: Immediately after birth, the oxygen saturation is between 30 and 50%, which then increases to 85-95% within the first 10 min. Over the last 10 years, recommendations regarding the ideal level of the initial fraction of inspired oxygen (FiO2) for resuscitation in preterm infants have changed from 1.0, to room air to low levels of oxygen (< 0.3), up to moderate concentrations (0.3-0.65). This leaves clinicians in a challenging position, and a large multi-center international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidence to guide clinical practice with confidence. METHODS: An international cluster, cross-over randomized trial of initial FiO2 of 0.3 or 0.6 during neonatal resuscitation in preterm infants at birth to increase survival free of major neurodevelopmental outcomes at 18 and 24 months corrected age will be conducted. Preterm infants born between 230/7 and 286/7 weeks' gestation will be eligible. Each participating hospital will be randomized to either an initial FiO2 concentration of either 0.3 or 0.6 to recruit for up to 12 months' and then crossed over to the other concentration for up to 12 months. The intervention will be initial FiO2 of 0.6, and the comparator will be initial FiO2 of 0.3 during respiratory support in the delivery room. The sample size will be 1200 preterm infants. This will yield 80% power, assuming a type 1 error of 5% to detect a 25% reduction in relative risk of the primary outcome from 35 to 26.5%. The primary outcome will be a composite of all-cause mortality or the presence of a major neurodevelopmental outcome between 18 and 24 months corrected age. Secondary outcomes will include the components of the primary outcome (death, cerebral palsy, major developmental delay involving cognition, speech, visual, or hearing impairment) in addition to neonatal morbidities (severe brain injury, bronchopulmonary dysplasia; and severe retinopathy of prematurity). DISCUSSION: The use of supplementary oxygen may be crucial but also potentially detrimental to preterm infants at birth. The HiLo trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants. Should 60% initial oxygen concertation increase survival free of major neurodevelopmental outcomes at 18-24 months corrected age, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice. TRIAL REGISTRATION: The trial was registered on January 31, 2019, at ClinicalTrials.gov with the Identifier: NCT03825835.

CPAP Versus NIPPV Postextubation in Preterm Neonates: A Comparative-Effectiveness Study.

BACKGROUND AND OBJECTIVES: Nasal intermittent positive pressure ventilation (NIPPV) has been shown to be superior to nasal continuous positive airway pressure (CPAP) postextubation in preterm neonates. However, studies have not permitted high CPAP pressures or rescue with other modes. We hypothesized that if CPAP pressures >8 cmH2O and rescue with other modes were permitted, CPAP would be noninferior to NIPPV. METHODS: We conducted a pragmatic, comparative-effectiveness, noninferiority study utilizing network-based real-world data from 22 Canadian NICUs. Centers self-selected CPAP or NIPPV as their standard postextubation mode for preterm neonates <29 weeks' gestation. The primary outcome was failure of the initial mode ≤72 hours. Secondary outcomes included failure ≤7 days, and reintubation ≤72 hours and ≤7 days. Groups were compared using a noninferiority adjusted risk-difference (aRD) margin of 0.05, and margin of no difference. RESULTS: A total of 843 infants extubated to CPAP and 974 extubated to NIPPV were included. CPAP was not noninferior (and inferior) to NIPPV for failure of the initial mode ≤72 hours (33.0% vs 26.3%; aRD 0.07 [0.03 to 0.12], Pnoninferiority(NI) = .86), and ≤7 days (40.7% vs 35.8%; aRD 0.09 [0.05 to 0.13], PNI = 0.97). However, CPAP was noninferior (and equivalent) to NIPPV for reintubation ≤72 hours (13.2% vs 16.1%; aRD 0.01 [-0.05 to 0.02], PNI < .01), and noninferior (and superior) for reintubation ≤7 days (16.4% vs 22.8%; aRD -0.04 [-0.07 to -0.001], PNI < .01). CONCLUSIONS: CPAP was not noninferior to NIPPV for failure ≤72 hours postextubation; however, it was noninferior to NIPPV for reintubation ≤72 hours and ≤7 days. This suggests CPAP may be a reasonable initial postextubation mode if alternate rescue strategies are available.

Continuous Positive Airway Pressure versus Nasal Intermittent Positive Pressure Ventilation in Preterm Neonates: What if Mean Airway Pressures were Equivalent?

Respiratory support for preterm neonates in modern neonatal intensive care units is predominantly with the use of noninvasive interfaces. Continuous positive airway pressure (CPAP) and nasal intermittent positive pressure ventilation (NIPPV) are the prototypical and most commonly utilized forms of noninvasive respiratory support, and each has unique gas flow characteristics. In meta-analyses of clinical trials till date, NIPPV has been shown to likely reduce respiratory failure and need for intubation compared to CPAP. However, a significant limitation of the included studies has been the higher mean airway pressures used during NIPPV. Thus, it is unclear to what extent any benefits seen with NIPPV are due to the cyclic pressure application versus the higher mean airway pressures. In this review, we elaborate on these limitations and summarize the available evidence comparing NIPPV and CPAP at equivalent mean airway pressures. Finally, we call for further studies comparing noninvasive respiratory support modes at equal mean airway pressures. KEY POINTS: · Most current literature on CPAP vs. NIPPV in preterm neonates is confounded by use of higher mean airway pressures during NIPPV.. · In this review, we summarize existing evidence on CPAP vs. NIPPV at equivalent mean airway pressures.. · We call for future research on noninvasive support modes to account for mean airway pressures..

Peri-extubation settings in preterm neonates: a systematic review and meta-analysis.

OBJECTIVE: To systematically review: 1) peri-extubation settings; and 2) association between peri-extubation settings and outcomes in preterm neonates. STUDY DESIGN: In this systematic review, studies were eligible if they reported patient-data on peri-extubation settings (objective 1) and/or evaluated peri-extubation levels in relation to clinical outcomes (objective 2). Data were meta-analyzed when appropriate using random-effects model. RESULTS: Of 9681 titles, 376 full-texts were reviewed and 101 included. The pooled means of peri-extubation settings were summarized. For objective 2, three experimental studies were identified comparing post-extubation CPAP levels. Meta-analyses revealed lower odds for treatment failure [pooled OR 0.46 (95% CI 0.27-0.76); 3 studies, 255 participants] but not for re-intubation [pooled OR 0.66 (0.22-1.97); 3 studies, 255 participants] with higher vs. lower CPAP. CONCLUSIONS: Summary of peri-extubation settings may guide clinicians in their own practices. Higher CPAP levels may reduce extubation failure, but more data on peri-extubation settings that optimize outcomes are needed.

Variations in Site-Specific Costs for Infants Born Extremely Preterm in Canadian Neonatal Intensive Care Units.

OBJECTIVE: To quantify site-specific costs and their association with survival without major morbidity (SWMM) in Canada for neonates <28 weeks of gestation admitted to large tertiary neonatal intensive care units. METHODS: We conducted a retrospective analysis of infants born at <28 weeks of gestation and admitted to Canadian Neonatal Network sites from 2010 through 2021. Sites that cared for at least 50 eligible infants by gestational age in weeks over the study period were included. Using a validated costing algorithm that assessed physician, nursing, respiratory therapy, diagnostic imaging, transfusions, procedural, medication, and certain indirect costs, we calculated site and resource-specific costs in 2017 Canadian dollars (CAD) and evaluated their relationship with SWMM. RESULTS: Seven sites with 8180 (range 841-1605) eligible neonates with a mean (SD) gestation of 25.4 [1.3] weeks were included. Survival to discharge or transfer was 85.3% with a mean (SD) length of stay of 75 (46) days. The mean (SD) total and daily costs per neonate varied between $94 992 ($60 283) and $174 438 ($130 501) CAD and $1833 ($916) to $2307 ($1281) CAD, respectively. Between sites, there was no relationship between costs and SWMM. CONCLUSIONS: There was marked variation in costs and SWMM between sites in Canada with universal health care. The lack of concordance between both outcomes and costs among sites may provide possibilities for outcomes improvement and cost containment.

The Impact of Infant Sex on Multiple Courses versus a Single Course of Antenatal Corticosteroids: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: Animal literature has suggested that the impact of antenatal corticosteroids (ACS) may vary by infant sex. Our objective was to assess the impact of infant sex on the use of multiple courses versus a single course of ACS and perinatal outcomes. STUDY DESIGN: We conducted a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth trial, which randomly allocated pregnant people to multiple courses versus a single course of ACS. Our primary outcome was a composite of perinatal mortality or clinically significant neonatal morbidity (including neonatal death, stillbirth, severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], cystic periventricular leukomalacia, and necrotizing enterocolitis [stage II or III]). Secondary outcomes included individual components of the primary outcome as well as anthropometric measures. Baseline characteristics were compared between participants who received multiple courses versus a single course of ACS. An interaction between exposure to ACS and infant sex was assessed for significance and multivariable regression analyses were conducted with adjustment for predefined covariates, when feasible. RESULTS: Data on 2,300 infants were analyzed. The interaction term between treatment status (multiple courses vs. a single course of ACS) and infant sex was not significant for the primary outcome (p = 0.86), nor for any of the secondary outcomes (p > 0.05). CONCLUSION: Infant sex did not modify the association between exposure to ACS and perinatal outcomes including perinatal mortality or neonatal morbidity or anthropometric outcomes. However, animal literature indicates that sex-specific differences after exposure to ACS may emerge over time and thus investigating long-term sex-specific outcomes warrants further attention. KEY POINTS: · We explored the impact of infant sex on perinatal outcomes after multiple versus a single course of ACS.. · Infant sex was not a significant effect modifier of ACS exposure and perinatal outcomes.. · Animal literature indicates that sex-specific differences after ACS exposure may emerge over time.. · Further investigation of long-term sex-specific outcomes is warranted..

High continuous positive airway pressures versus non-invasive positive pressure ventilation in preterm neonates: protocol for a multicentre pilot randomised controlled trial.

INTRODUCTION: Low pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5-8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown. METHODS AND ANALYSIS: In this multicentre pilot randomised controlled trial, infants <29 weeks' gestational age (GA) who either: (A) fail treatment with traditional nCPAP or (B) being extubated from invasive mechanical ventilation with mean airway pressure ≥10 cmH2O, will be randomised to receive either high nCPAP (positive end-expiratory pressure 9-15 cmH2O) or NIPPV (target mean Paw 9-15 cmH2O). Primary outcome is feasibility of the conduct of a larger, definitive trial as assessed by rates of recruitment and protocol violations. The main secondary outcome is failure of assigned treatment within 7 days postrandomisation. Multiple other clinical outcomes including bronchopulmonary dysplasia will be ascertained. All randomised participants will be analysed using intention to treat. Baseline and demographic variables as well as outcomes will be summarised and compared using univariate analyses, and a p<0.05 will be considered significant. ETHICS AND DISSEMINATION: The trial has been approved by the respective research ethics boards at each institution (McMaster Children's Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness. TRIAL REGISTRATION NUMBER: NCT03512158.

Grading of Intraventricular Hemorrhage and Neurodevelopment in Preterm <29 Weeks' GA in Canada

Objective: The aim of this study was to evaluate the neurodevelopmental outcome at 18−24 months in surviving preterm infants with grades I−IV intraventricular hemorrhages (IVHs) compared to those with no IVH. Study Design: We included preterm survivors <29 weeks' GA admitted to the Canadian Neonatal Network's NICUs from April 2009 to September 2011 with follow-up data at 18−24 months in a retrospective cohort study. The neonates were grouped based on the severity of the IVH detected on a cranial ultrasound scan and recorded in the database: no IVH; subependymal hemorrhage or IVH without ventricular dilation (grades I−II); IVH with ventricular dilation (grade III); and persistent parenchymal echogenicity/lucency (grade IV). The primary outcomes of neurodevelopmental impairment (NDI), significant neurodevelopmental impairment (sNDI), and the effect modification by other short-term neonatal morbidities were assessed. Using multivariable regression analysis, the adjusted ORs (AOR) and 95% of the CIs were calculated. Results: 2327 infants were included. The odds of NDI were higher in infants with grades III and IV IVHs (AOR 2.58, 95% CI 1.56, 4.28 and AOR 2.61, 95% CI 1.80, 3.80, respectively) compared to those without IVH. Infants with an IVH grade ≤II had similar outcomes for NDI (AOR 1.08, 95% CI 0.86, 1.35) compared to those without an IVH, but the odds of sNDI were higher (AOR 1.58, 95% CI 1.16, 2.17). Conclusions: There were increased odds of sNDI in infants with grades I−II IVHs, and an increased risk of adverse NDI in infants with grades ≥III IVHs is corroborated with the current literature.

Timing of Systemic Steroids and Neurodevelopmental Outcomes in Infants < 29 Weeks Gestation

Objective: To determine the association between postnatal age (PNA) at first administration of systemic postnatal steroids (sPNS) for bronchopulmonary dysplasia (BPD) and mortality or significant neurodevelopmental impairment (sNDI) at 18−24 months corrected age (CA) in infants < 29 weeks' gestation. Methods: Data from the Canadian Neonatal Network and Canadian Neonatal Follow-up Network databases were used to conduct this retrospective cohort study. Infants exposed to sPNS for BPD after the 1st week of age were included and categorized into 8 groups based on the postnatal week of the exposure. The primary outcome was a composite of mortality or sNDI. A multivariable logistic regression model adjusting for potential confounders was used to determine the association between the sPNS and ND outcomes. Results: Of the 10,448 eligible infants, follow-up data were available for 6200 (59.3%) infants. The proportion of infants at first sPNS administration was: 8%, 17.5%, 23.1%, 18.7%, 12.6%, 8.3%, 5.8%, and 6% in the 2nd, 3rd, 4th, 5th, 6th, 7th, 8−9th, and ≥10th week of PNA respectively. No significant association between the timing of sPNS administration and the composite outcome of mortality or sNDI was observed. The odds of sNDI and Bayley-III motor composite < 70 increased by 1.5% (95% CI 0.4, 2.9%) and 2.6% (95% CI 0.9, 4.4%), respectively, with each one-week delay in the age of initiation of sPNS. Conclusions: No significant association was observed between the composite outcome of mortality or sNDI and PNA of sPNS. Among survivors, each week's delay in initiation of sPNS may increase the odds of sNDI and motor delay.

Toward Optimal High Continuous Positive Airway Pressure as Postextubation Support in Preterm Neonates: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to evaluate whether the initial pressure level on high continuous positive airway pressure (CPAP; ≥9 cm H2O), in relation to preextubation mean airway pressure (Paw), influences short-term clinical outcomes in preterm neonates. STUDY DESIGN: In this retrospective cohort study, preterm neonates <29 weeks' gestational age (GA) extubated from mean Paw ≥9 cm H2O and to high CPAP (≥9 cm H2O) were classified into "higher level CPAP" (2-3 cm H2O higher than preextubation Paw) and "equivalent CPAP" (-1 to +1 cm H2O in relation to preextubation Paw). Only the first eligible extubation per infant was analyzed. The primary outcome was failure within ≤7 days of extubation, defined as any one or more of (1) need for reintubation, (2) escalation to an alternate noninvasive respiratory support mode, or (3) use of CPAP >preextubation Paw + 3 cm H2O. Secondary outcomes included individual components of the primary outcome, along with other clinical and safety outcomes. RESULTS: Over a 10-year period (Jan 2011-Dec 2020), 175 infants were extubated from mean Paw >9 cm H2O to high CPAP pressures. Twenty-seven patients (median GA = 24.7, [interquartile range (IQR)]: (24.0-26.4) weeks and chronological age = 31, IQR: [21-40] days) were classified into the "higher level CPAP" group while 148 infants (median GA = 25.4, IQR: [24.6-26.6] weeks and chronological age = 26, IQR: [10-39] days) comprised the "equivalent CPAP" group. There was no difference in the primary outcome (44 vs. 51%; p = 0.51), including postadjustment for confounders (adjusted OR [aOR] = 0.47 [95% confidence interval (CI): 0.17-1.29; p = 0.14]). However, reintubation risk within 7 days was lower with higher level CPAP (7 vs. 37%; p < 0.01), including postadjustment (aOR = 0.07; 95% CI: 0.02-0.35; p < 0.01). CONCLUSION: In this cohort, use of initial distending CPAP pressures 2 to 3 cm H2O higher than preextubation Paw did not alter the primary outcome of failure but did lower the risk of reintubation. The latter is an interesting hypothesis-generating finding that requires further confirmation. KEY POINTS: · Use of high CPAP pressures (≥9 cm H2O) is gradually increasing in the care of preterm neonates.. · This study compares higher level versus equivalent CPAP in relation to preextubation Paw.. · The findings demonstrate no difference in failure as defined with use of higher level CPAP pressures..

Clinical burden associated with therapies for cardio-pulmonary critical decompensation in preterm neonates across Canadian neonatal intensive care units.

The aim of this retrospective cohort study was to study the clinical burden associated with cardio-pulmonary critical decompensations (CPCDs) in preterm neonates and factors associated with mortality. Through the Canadian Neonatal Network (30 tertiary NICUs, 2010-2017), we identified infants < 32-week gestational age with CPCDs, defined by "significant exposure" to cardiotropes and/or inhaled nitric oxide (iNO): (1) either therapy for ≥ 3 consecutive days, (2) both for ≥ 2 consecutive days, or (3) any exposure within 2 days of death. Early CPCDs (≤ 3 days of age) and late CPCDs (> 3 days) were examined separately. Outcomes included CPCD-incidence, mortality, and inter-site variability using standardized ratios (observed/adjusted expected rate) and network funnel plots. Mixed-effects analysis was used to quantify unit-level variability in mortality. Overall, 10% of admissions experienced CPCDs (n = 2915). Late CPCDs decreased by ~ 5%/year, while early CPCDs were unchanged during the study period. Incidence and CPCD-associated mortality varied between sites, for both early (0.6-7.5% and 0-100%, respectively) and late CPCDs (2.5-15% and 14-83%, respectively), all p < 0.01. Units' late-CPCD incidence and mortality demonstrated an inverse relationship (slope = -2.5, p < 0.01). Mixed-effects analysis demonstrated clustering effect, with 6.4% and 8.6% of variability in mortality after early and late CPCDs respectively being site-related, unexplained by available patient-level characteristics or unit volume. Mortality was higher with combined exposure than with only-cardiotropes or only-iNO (41.3%, 24.8%, 21.5%, respectively; p < 0.01). CONCLUSIONS: Clustering effects exist in CPCD-associated mortality among Canadian NICUs, with higher incidence units showing lower mortality. These data may aid network-level benchmarking, patient-level risk stratification, parental counseling, and further research and quality improvement work. WHAT IS KNOWN: • Preterm neonates remain at high risk of acute and chronic complications; the most critically unwell require therapies such as cardiotropic drugs and inhaled nitric oxide. • Infants requiring these therapies are known to be at high risk for adverse neonatal outcomes and for mortality. WHAT IS NEW: • This study helps illuminate the national burden of acute cardio-pulmonary critical decompensation (CPCD), defined as the need for cardiotropic drugs or inhaled nitric oxide, and highlights the high risk of morbidity and mortality associated with this disease state. • Significant nationwide variability exists in both CPCD incidence and associated mortality; a clustering effect was observed with higher incidence sites showing lower CPCD-associated mortality.

Poractant alfa versus bovine lipid extract surfactant: prospective comparative effectiveness study.

OBJECTIVE: To compare short term respiratory outcomes in preterm infants treated with bovine lipid extract surfactant or poractant alfa. STUDY DESIGN: Prospective comparative effectiveness cohort study of infants <32 weeks' gestational age requiring surfactant in thirteen centers. Each center provided bovine lipid extract surfactant for a set period of time in the year 2019 and then changed to poractant alfa for the remainder of the year. The primary outcome was total duration of respiratory support. RESULT: 968 infants were included. 494 received bovine lipid extract surfactant and 474 received poractant alfa. No difference was observed in the total duration of respiratory support (mechanical ventilation or non-invasive) (median 38 vs 40.5 days), need to re-dose surfactant, bronchopulmonary dysplasia, survival to discharge, or length of admission. CONCLUSION: In this pragmatic study, we did not identify any difference in short term outcomes between the groups based on the type of surfactant received.

Comparison of High CPAP versus NIPPV in Preterm Neonates: A Retrospective Cohort Study.

OBJECTIVE: The aim of this study was to compare outcomes following receipt of high continuous positive airway pressure (CPAP) versus nasal intermittent positive pressure ventilation (NIPPV) in extremely preterm neonates. STUDY DESIGN: We retrospectively compared outcomes of preterm neonates (22-28 weeks' gestation) following their first episode of either high CPAP (≥ 9 cm H2O) or NIPPV. Primary outcome was failure of high CPAP or NIPPV within 7 days, as determined by either need for intubation or use of an alternate noninvasive mode. RESULTS: During the 3-year study period, 53 infants received high CPAP, while 119 patients received NIPPV. There were no differences in the primary outcome (adjusted odds ratio 1.21; 95% confidence interval 0.49-3.01). The use of alternate mode of noninvasive support was higher with the use of high CPAP but no other outcome differences were noted. CONCLUSION: Based on this cohort, there was no difference in incidence of failure between high CPAP and NIPPV, although infants receiving high CPAP were more likely to require an alternate mode of noninvasive support. KEY POINTS: · Use of high CPAP pressures (defined as ≥9 cm H2O) is gradually increasing during care of preterm neonates.. · Limited data exists regarding its efficacy and safety.. · This study compares high CPAP with NIPPV, and demonstrates comparable short-term clinical outcomes..

Nasal Intermittent Positive Pressure Ventilation versus Continuous Positive Airway Pressure and Apnea of Prematurity: A Systematic Review and Meta-Analysis.

OBJECTIVE: The study aimed to systematically review and analyze the impact of nasal intermittent positive pressure ventilation (NIPPV) versus continuous positive airway pressure (CPAP) on apnea of prematurity (AOP) in preterm neonates. STUDY DESIGN: In this systematic review and meta-analysis, experimental studies enrolling preterm infants comparing NIPPV (synchronized, nonsynchronized, and bi-level) and CPAP (all types) were searched in multiple databases and screened for the assessment of AOP. Primary outcome was AOP frequency per hour (as defined by authors of included studies). RESULTS: Out of 4,980 articles identified, 18 studies were included with eight studies contributing to the primary outcome. All studies had a high risk of bias, with significant heterogeneity in definition and measurement of AOP. There was no difference in AOPs per hour between NIPPV versus CPAP (weighted mean difference = -0.19; 95% confidence interval [CI]: -0.76 to 0.37; eight studies, 456 patients). However, in a post hoc analysis evaluating the presence of any AOP (over varying time periods), the pooled odds ratio (OR) was lower with NIPPV (OR: 0.46; 95% CI: 0.32-0.67; 10 studies, 872 patients). CONCLUSION: NIPPV was not associated with decrease in AOP frequency, although demonstrated lower odds of developing any AOP. However, definite recommendations cannot be made based on the quality of the published evidence. KEY POINTS: · AOP is a common clinical complication related to preterm birth.. · NIPPV is often used to mitigate AOP and complications.. · Relative impact of NIPPV and CPAP on AOP remains unclear..

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.

Necrotizing enterocolitis and mortality after transfusion of ABO non-identical blood.

BACKGROUND: The relationship between ABO non-identical transfusion and the outcomes of necrotizing enterocolitis (NEC), and all-cause mortality in very-low birth weight (VLBW) neonates receiving red blood cell transfusion is unknown. STUDY DESIGN AND METHODS: A retrospective multicenter cohort study was conducted in VLBW neonates in neonatal intensive care units between 2004 and 2016. VLBW (≤1500 grams) neonates were followed until discharge or in-hospital death. The primary exposure was ABO group. Secondary exposures included platelet count, plasma transfusions, and maternal ABO group. Outcome measures were NEC (defined as Bell stage ≥ 2) and all-cause mortality. Time-dependent Cox regression models with competing risks were used to investigate factors associated with NEC and mortality. RESULTS: Thousand and sixteen neonates were included with 10.8% developing NEC (n = 110) and 14.1% mortality (n = 143). Platelet count (hazard ratio [HR] = 0.995; 95% confidence interval [CI]: 0.922-0.998) and number of plasma transfusions (HR = 2.908; 95% CI:1.265-6.682) were associated with NEC, while ABO group (non-O vs. O) was not (HR = 0.761; 95% CI: 0.393-1.471). Higher all-cause mortality occurred in neonates without NEC who were non-O compared with O (HR = 17.5; 95% CI: 1.784-171.692), but not in neonates with NEC (HR = 1.112; 95% CI: 0.142-8.841). Plasma transfusion was associated with increased mortality in both groups. DISCUSSION: ABO non-identical transfusion was not associated with NEC or mortality in neonates with NEC. It was associated with increased mortality in neonates without NEC. As many neonatal intensive care units transfuse only O group blood as routine practice, future trials are needed to investigate the association between this practice and neonatal mortality.

High CPAP vs. NIPPV in preterm neonates - A physiological cross-over study.

OBJECTIVE: To evaluate the physiological impact of high CPAP (≥9 cmH2O) vs. NIPPV at equivalent mean airway pressures. STUDY DESIGN: In this cross-over study, preterm neonates on high CPAP or NIPPV were placed on the alternate mode. After 30 min, left and right ventricular cardiac output and work of breathing indices were assessed, following which patients were placed back on the original mode and a similar procedure ensued. RESULTS: Fifteen infants with mean (SD) postmenstrual age 32.7 (3.0) weeks, and weight 1569 (564) grams were included. No differences in LVO [320 (63) vs. 331 (86) mL/kg/min, P = 0.46] or RVO [420 (135) vs. 437 (141) mL/kg/min, P = 0.19] were noted during high CPAP vs. NIPPV, along with no differences in work of breathing indices. CONCLUSION: High CPAP pressures did not adversely impact cardiac output or work of breathing compared to NIPPV at equivalent mean airway pressure.

Characteristics and outcomes of preterm neonates according to number of doses of surfactant received.

OBJECTIVES: To identify characteristics and outcomes of infants who received multiple doses of surfactant vs those who received one dose or none. STUDY DESIGN: In this retrospective study, we included neonates of 22-28 weeks' gestation admitted to NICUs in the Canadian Neonatal Network. Patients were divided into three groups: no surfactant, single dose, and multiple doses. The primary outcome was a composite of mortality or any of the major morbidities, including severe neurological injury, bronchopulmonary dysplasia, or ≥stage 3 retinopathy of prematurity. RESULTS: Of 8024 eligible neonates, 2461 (31%) did not receive surfactant, 3545 (44%) received one dose, and 2018 (25%) received >1 dose. Receiving one or more doses of surfactant was associated with significantly higher adjusted odds of mortality or major morbidities in a dose-dependent manner. CONCLUSIONS: Receiving one or more doses of surfactant was associated with adverse neonatal outcomes. Receipt of more than one dose may reflect underlying severe lung immaturity.