Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Impact of neonatal noninvasive resuscitation strategies on lung mechanics, tracheal pressure, and tidal volume in preterm lambs.

This study investigated the relationship between three respiratory support approaches on lung volume recruitment during the first 2 h of postnatal life in preterm lambs. We estimated changes in lung aeration, measuring respiratory resistance and reactance by oscillometry at 5 Hz. We also measured intratracheal pressure in subsets of lambs. The first main finding is that sustained inflation (SI) applied noninvasively (Mask SI; n = 7) or invasively [endotracheal tube (ETT) SI; n = 6] led to similar rapid lung volume recruitment (∼6 min). In contrast, Mask continuous positive airway pressure (CPAP) without SI (n = 6) resuscitation took longer (∼30-45 min) to reach similar lung volume recruitment. The second main finding is that, in the first 15 min of postnatal life, the Mask CPAP without SI group closed their larynx during custom ventilator-driven expiration, leading to intratracheal positive end-expiratory pressure of ∼17 cmH2O (instead of 8 cmH2O provided by the ventilator). In contrast, the Mask SI group used the larynx to limit inspiratory pressure to ∼26 cmH2O (instead of 30 cmH2O provided by the ventilator). These different responses affected tidal volume, being larger in the Mask CPAP without SI group [8.4 mL/kg; 6.7-9.3 interquartile range (IQR)] compared to the Mask SI (5.0 mL/kg; 4.4-5.2 IQR) and ETT SI groups (3.3 mL/kg; 2.6-3.7 IQR). Distinct physiological responses suggest that spontaneous respiratory activity of the larynx of preterm lambs at birth can uncouple pressure applied by the ventilator to that applied to the lung, leading to unpredictable lung pressure and tidal volume delivery independently from the ventilator settings.NEW & NOTEWORTHY We compared invasive and noninvasive resuscitation on lambs at birth, including or not sustained inflation (SI). Lung volume recruitment was faster in those receiving SI. During noninvasive resuscitation, larynx modulation reduced tracheal pressure from that applied to the mask in lambs receiving SI, while it led to increased auto-positive end-expiratory pressure and very large tidal volumes in lambs not receiving SI. Our results highlight the need for individualizing pressures and monitoring tidal volumes during resuscitation at birth.

Can Red Blood Cell and Platelet Transfusions Have a Pathogenic Role in Bronchopulmonary Dysplasia?

OBJECTIVE: To evaluate whether transfusions in infants born preterm contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We conducted a multihospital, retrospective study seeking associations between red blood cell or platelet transfusions and BPD. We tabulated all transfusions administered from January 2018 through December 2022 to infants born ≤29 weeks or <1000 g until 36 weeks postmenstrual age and compared those with BPD grade. We performed a sensitivity analysis to assess the possibility of a causal relationship. We then determined whether each transfusion was compliant with restrictive guidelines, and we estimated effects fewer transfusions might have on future BPD incidence. RESULTS: Eighty-four infants did not develop BPD and 595 did; 352 developed grade 1 (mild), 193 grade 2 (moderate), and 50 grade 3 (severe). Transfusions were given at <36 weeks to 7% of those who did not develop BPD, 46% who did, and 98% who developed severe BPD. For every transfusion the odds of developing BPD increased by a factor of 2.27 (95% CI, 1.59-3.68; P < .001). Sensitivity analyses suggested that transfusions might contribute to BPD. Fifty-seven percent of red blood cell transfusions and 68% of platelet transfusions were noncompliant with new restrictive guidelines. Modeling predicted that complying with restrictive guidelines could reduce the transfusion rate by 20%-30% and the moderate to severe BPD rate by ∼4%-6%. CONCLUSIONS: Transfusions were associated with BPD incidence and severity. Lowering transfusion rates to comply with current restrictive guidelines might result in a small but meaningful reduction in BPD rates.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Mortality in Congenital Diaphragmatic Hernia: A Multicenter Registry Study of Over 5000 Patients Over 25 Years.

OBJECTIVE: To determine if risk-adjusted survival of patients with CDH has improved over the last 25 years within centers that are long-term, consistent participants in the CDH Study Group (CDHSG). SUMMARY BACKGROUND DATA: The CDHSG is a multicenter collaboration focused on evaluation of infants with CDH. Despite advances in pediatric surgical and intensive care, CDH mortality has appeared to plateau. Herein, we studied CDH mortality rates amongst long-term contributors to the CDHSG. METHODS: We divided registry data into 5-year intervals, with Era 1 (E1) beginning in 1995, and analyzed multiple variables (operative strategy, defect size, and mortality) to assess evolution of disease characteristics and severity over time. For mortality analyses, patients were risk stratified using a validated prediction score based on 5-minute Apgar (Apgar5) and birth weight. A risk-adjusted, observed to expected (O:E) mortality model was created using E1 as a reference. RESULTS: 5203 patients from 23 centers with >22years of participation were included. Birth weight, Apgar5, diaphragmatic agenesis, and repair rate were unchanged over time (all P > 0.05). In E5 compared to E1, minimally invasive and patch repair were more prevalent, and timing of diaphragmatic repair was later (all P < 0.01). Overall mortality decreased over time: E1 (30.7%), E2 (30.3%), E3 (28.7%), E4 (26.0%), E5 (25.8%) ( P = 0.03). Risk-adjusted mortality showed a significant improvement in E5 compared to E1 (OR 0.78, 95% CI 0.62-0.98; P = 0.03). O:E mortality improved over time, with the greatest improvement in E5. CONCLUSIONS: Risk-adjusted and observed-to-expected CDH mortality have improved over time.

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.

BACKGROUND: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. METHODS: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. RESULTS: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. CONCLUSIONS: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Variability for Age at Successful Extubation in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: The objective of this study was to characterize clinical factors associated with successful extubation in infants with congenital diaphragmatic hernia. STUDY DESIGN: Using the Children's Hospitals Neonatal Database, we identified infants with congenital diaphragmatic hernia from 2017 to 2020 at 32 centers. The main outcome was age in days at the time of successful extubation, defined as the patient remaining extubated for 7 consecutive days. Unadjusted Kaplan-Meier and multivariable Cox proportional hazards ratio equations were used to estimate associations between clinical factors and the main outcome. Observations occurred through 180 days after birth. RESULTS: There were 840 eligible neonates with a median gestational age of 38 weeks and birth weight of 3.0 kg. Among survivors (n = 693), the median age at successful extubation was 15 days (interquartile range [IQR]: 8-29 days, 95th percentile: 71 days). For nonsurvivors (n = 147), the median age at death was 21 days (IQR: 11-39 days, 95th percentile: 110 days). Center (adjusted hazards ratio: 0.22-15, P < .01), low birth weight, intrathoracic liver position, congenital heart disease, lower 5-minute Apgar score, lower pH upon admission to Children's Hospitals Neonatal Database center, and use of extracorporeal support were independently associated with older age at successful extubation. Tracheostomy was associated with multiple failed extubations. CONCLUSION: Our findings suggest that infants who have not successfully extubated by about 3 months of age may be candidates for tracheostomy with chronic mechanical ventilation or palliation. The variability of timing of successful extubation among our centers supports the development of practice guidelines after validating clinical criteria.

Early brain and abdominal oxygenation in extremely low birth weight infants.

BACKGROUND: Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined. METHODS: A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables. RESULTS: In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001). CONCLUSION: Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population. IMPACT: Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

Early extubation to noninvasive respiratory support of former preterm lambs improves long-term respiratory outcomes.

Invasive mechanical ventilation (IMV) and exposure to oxygen-rich gas during early postnatal life are contributing factors for long-term pulmonary morbidities faced by survivors of preterm birth and bronchopulmonary dysplasia. The duration of IMV that leads to long-term pulmonary morbidities is unknown. We compared two durations of IMV (3 h vs. 6 days) during the first 6-7 days of postnatal life in preterm lambs to test the hypothesis that minimizing the duration of IMV will improve long-term respiratory system mechanics and structural outcomes later in life. Moderately preterm (∼85% gestation) lambs were supported by IMV for either 3 h or 6 days before weaning from all respiratory support to become former preterm lambs. Respiratory system mechanics and airway reactivity were assessed monthly from 1 to 6 mo of chronological postnatal age by the forced oscillation technique. Quantitative morphological measurements were made for smooth muscle accumulation around terminal bronchioles and indices of alveolar formation. Minimizing IMV to 3 h led to significantly better (P < 0.05) baseline respiratory system mechanics and less reactivity to methacholine in the first 3 mo of chronological age (2 mo corrected age), significantly less (P < 0.05) accumulation of smooth muscle around peripheral resistance airways (terminal bronchioles), and significantly better (P < 0.05) alveolarization at the end of 5 mo corrected age compared with continuous IMV for 6 days. We conclude that limiting the duration of IMV following preterm birth of fetal lambs leads to better respiratory system mechanics and structural outcomes later in life.

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Association of Intrapartum Drugs with Spontaneous Intestinal Perforation: A Single-Center Retrospective Review.

OBJECTIVE: Spontaneous intestinal perforation (SIP) occurs commonly in extremely low gestational age newborns (ELGANs; <30 weeks' GA). Early, concurrent neonatal use of indomethacin (Neo_IN) and hydrocortisone (Neo_HC) is a known risk for SIP. Mothers in premature labor often receive indomethacin (Mat_IN) for tocolysis and steroids (Mat_S) for fetal maturation. Coincidentally, ELGANs may receive Neo_IN or Neo_HC within the first week of life. There are limited data on the effect of combined exposures to maternal and neonatal medications. We hypothesized that proximity exposure to these medications may increase the risk of SIP. STUDY DESIGN: We reviewed the medical records of ELGANs from June 2014 to December 2019 at a single level III neonatal intensive care unit. We compared antenatal and postnatal indomethacin and steroid use between neonates with and without SIP. For analysis, chi-square, Student's t-test, Fisher's exact test, and Mann-Whitney U tests were used. RESULTS: Among 417 ELGANs, SIP was diagnosed in 23, predominantly in neonates < 26 weeks' GA (n = 21/126, 16.7%). Risk factors analysis focused on this GA cohort in which SIP was most prevalent. Mat_IN administration within 2 days of delivery increased SIP risk (odds ratio: 3; 95% confidence interval: 1.25-7.94; p = 0.036). Neo_HC was not independently associated with SIP (p = 0.38). A higher proportion of SIP group had close temporal exposure of Mat_IN and Neo_HC compared with the non-SIP group, though not statistically significant (14 vs. 7%, p = 0.24). CONCLUSION: Peripartum Mat_IN was associated with increased risk for SIP in this small study sample. Larger studies are needed to further delineate SIP risk from the interaction of peripartum maternal medication with early postnatal therapies and disease pathophysiology. KEY POINTS: · Perinatal indomethacin is associated with SIP in preterm infants born at less than 26 weeks.. · Temporal proximity of prenatal/postnatal medication exposure matters.. · Indomethacin and Hydrocortisone the risks, benefits, and timing related to SIP..

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.

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

OBJECTIVE: Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. STUDY DESIGN: We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. RESULTS: The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9-38) and the median duration was 127 hours (IQR: 95-194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16-74]; vs. no milrinone: 65% [50-71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. CONCLUSION: In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

Neonatal Outcomes Associated with Umbilical Cord Milking in Preterm Multiple Gestations.

OBJECTIVE: Our aim was to evaluate the effect of umbilical cord milking on outcomes for preterm multiples. STUDY DESIGN: We implemented a policy of cord milking in neonates born at less than 30 weeks' gestation in September 2011. We compared cord milking in multiples with a historical cohort. Multivariable logistic regression models estimated the effect of cord milking on a composite neonatal adverse outcome. Secondary outcomes were hematocrit at birth, need for blood transfusion, and inotrope use. RESULTS: We identified 149 neonates (120 twins, 29 triplets), 51 historical controls, and 98 neonates with cord milking. Cord milking was associated with a lower rate of adverse composite neonatal outcome in univariable analysis (odds ratio [OR]: 0.36; 95% confidence interval [CI]: 0.15-0.84). However, in multivariable modeling, the effect was not significant (adjusted OR [aOR]: 0.54, 95% CI: 0.23-1.28). Hematocrit was 4.6 unit % (95% CI: 2-7.3) higher in the cord milking group, and cord milking was associated with a lower rate of blood transfusion (aOR: 0.28; 95% CI: 0.1-0.74; p = 0.01). There was no difference in inotrope administration. CONCLUSION: Umbilical cord milking was not associated with a decrease in composite neonatal adverse outcome. However, we observed an increase in hematocrit and decreased need for blood transfusion in neonates with cord milking.

Efficacy and Safety of Nasal High-Flow Therapy for Neonatal Transport.

OBJECTIVE: Noninvasive ventilation, including nasal high-flow therapy (nHFT), provides effective neonatal respiratory support. There are limited data on nHFT use during neonatal transport. Our objective was to assess the efficacy and safety of nHFT during neonatal transport. METHODS: One hundred ninety-five neonates transported on nHFT via a Neo-Pod "T" system (Westmed Inc, Tucson, AZ) were identified from Life Flight transport data. Data included demographics, transport location, distance, indication, and mode as well as pretransport and intratransport respiratory support data. We compared neonates who successfully tolerated nHFT transport with those who required support escalation (defined as increase in flow ≥2 L/min or fraction of inspired oxygen [FiO2] ≥20%). RESULTS: Eighty-seven percent of neonates (170/195) were effectively transported on nHFT. Infants requiring escalation of nHFT support had a significantly higher pretransport FiO2 (median = 0.60 [interquartile range, 0.36-1.00] vs. 0.36 [0.23-0.56]; P < .05) and a longer ground time for stabilization (56 ± 25 vs. 39 ± 18 minutes, P < .05) and were more frequently transported by air. CONCLUSION: Nasal HFT can be an effective mode of respiratory support in the transport of selected neonates. FiO2 at the time of transport may be a key parameter to aid in determining neonates who can be safely transported on nHFT.

Former-preterm lambs have persistent alveolar simplification at 2 and 5 months corrected postnatal age.

Preterm birth and mechanical ventilation (MV) frequently lead to bronchopulmonary dysplasia, the histopathological hallmark of which is alveolar simplification. How developmental immaturity and ongoing injury, repair, and remodeling impact completion of alveolar formation later in life is not known, in part because of lack of suitable animal models. We report a new model, using former-preterm lambs, to test the hypothesis that they will have persistent alveolar simplification later in life. Moderately preterm lambs (~85% gestation) were supported by MV for ~6 days before being transitioned from all respiratory support to become former-preterm lambs. Results are compared with term control lambs that were not ventilated, and between males (M) and females (F). Alveolar simplification was quantified morphometrically and stereologically at 2 mo (4 M, 4 F) or 5 mo (4 M, 6 F) corrected postnatal age (cPNA) compared with unventilated, age-matched term control lambs (4 M, 4 F per control group). These postnatal ages in sheep are equivalent to human postnatal ages of 1-2 yr and ~6 yr, respectively. Multivariable linear regression results showed that former-preterm lambs at 2 or 5 mo cPNA had significantly thicker distal airspace walls ( P < 0.001 and P < 0.009, respectively), lower volume density of secondary septa ( P < 0.007 and P < 0.001, respectively), and lower radial alveolar count ( P < 0.003 and P < 0.020, respectively) compared with term control lambs. Sex-specific differences were not detected. We conclude that moderate preterm birth and MV for ~6 days impedes completion of alveolarization in former-preterm lambs. This new model provides the opportunity to identify underlying pathogenic mechanisms that may reveal treatment approaches.

Variation in Positive End-Expiratory Pressure Levels for Mechanically Ventilated Extremely Low Birth Weight Infants.

OBJECTIVE: To test the hypothesis that significant positive end-expiratory pressure (PEEP) level variation exists between neonatal centers. STUDY DESIGN: 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 <.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. RESULTS: 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 < .0001). Further, center alone explained a greater proportion of the PEEP level variation than all infant characteristics combined. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00433212.

Impact of umbilical cord milking and pasteurized donor human milk on necrotizing enterocolitis: a retrospective review.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious complication of prematurity. Our objective was to evaluate the impact of an umbilical cord milking protocol (UCM) and pasteurized donor human milk (PDHM) on NEC rates in infants less than 30 weeks gestational age from January 1, 2010 to September 30, 2016. We hypothesized an incremental decrease in NEC after each intervention. METHODS: We performed a retrospective review of 638 infants born less than 30 weeks gestational age. Infants were grouped into three epochs: pre-UCM/pre-PDHM (Epoch 1, n = 159), post-UCM/pre-PDHM (Epoch 2, n = 133), and post-UCM/post-PDHM (Epoch 3, n = 252). The incidence of NEC, surgical NEC, and NEC/death were compared. Logistic regression was used to determine independent significance of time epoch, gestational age, birth weight, and patent ductus arteriosus for NEC, surgical NEC, and death/NEC. RESULTS: At birth, infants in Epoch 1 were younger than Epoch 2 and 3 (26.8 weeks versus 27.3 and 27.2, respectively, P = 0.036) and smaller (910 g versus 1012 and 983, respectively, P = 0.012). Across epochs, there was a significant correlation between patent ductus arteriosus treatment and NEC rate (P < 0.001, Cochran-Mantel-Haenszel). There was a significant decrease in rates of NEC, surgical NEC, and NEC/death between groups. Logistic regression showed this as significant for rates of NEC and surgical NEC between Epoch 1 and 3. Patent ductus arteriosus was a significant variable affecting the incidence of NEC, but not surgical NEC or death/NEC. CONCLUSIONS: An umbilical cord milking protocol and pasteurized donor human milk availability was associated with decreased rates of NEC and surgical NEC. This suggests an additive effect of these interventions in preventing NEC.

Preterm birth and ventilation decrease surface density of glomerular capillaries in lambs, regardless of postnatal respiratory support mode.

BACKGROUND: Prematurity is often complicated by respiratory support, including invasive mechanical ventilation (IMV) and noninvasive support (NIS). Compared with IMV, NIS reduces injury to the lung and brain. Prematurity may also disrupt glomerular architecture. Whether NIS differentially affects glomerular architecture is incompletely understood. We hypothesized that IMV would lead to greater disruption of glomerular architecture than NIS. METHODS: This is a secondary analysis of kidneys from moderately preterm lambs delivered at ~131 d gestation (term ~150 d) that had antenatal steroid exposure and surfactant treatment before resuscitation by IMV. At ~3 h of age, half of the lambs were switched to NIS. Support was for 3 d or 21 d. Structural indices of glomerular architecture were quantified. RESULTS: The number of glomerular generations was unaffected by moderate preterm birth and respiratory support, either IMV or NIS. At 3 d and 21 d of IMV or NIS, glomerular capillary surface density was not different. Glomerular capillary surface density was significantly lower in the inner and outer cortex compared with unventilated gestation age-matched or postnatal age-matched reference lambs. CONCLUSION: Moderate preterm birth and invasive or noninvasive respiratory support decreases glomerular capillarization in the lamb kidney. This adverse effect on glomerular development may contribute to increased risk for adult-onset hypertension and renal dysfunction.

A trial comparing noninvasive ventilation strategies in preterm infants.

BACKGROUND: To reduce the risk of bronchopulmonary dysplasia in extremely-low-birth-weight infants, clinicians attempt to minimize the use of endotracheal intubation by the early introduction of less invasive forms of positive airway pressure. METHODS: We randomly assigned 1009 infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks to one of two forms of noninvasive respiratory support--nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP)--at the time of the first use of noninvasive respiratory support during the first 28 days of life. The primary outcome was death before 36 weeks of postmenstrual age or survival with bronchopulmonary dysplasia. RESULTS: Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4%), as compared with 180 of 490 infants assigned to nasal CPAP (36.7%) (adjusted odds ratio, 1.09; 95% confidence interval, 0.83 to 1.43; P=0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. CONCLUSIONS: Among extremely-low-birth-weight infants, the rate of survival to 36 weeks of postmenstrual age without bronchopulmonary dysplasia did not differ significantly after noninvasive respiratory support with nasal IPPV as compared with nasal CPAP. (Funded by the Canadian Institutes of Health Research; NIPPV ClinicalTrials.gov number, NCT00433212; Controlled-Trials.com number, ISRCTN15233270.).