Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

Cerebrospinal fluid cytokines in the diagnosis of bacterial meningitis in infants.

BACKGROUND: Bacterial meningitis poses diagnostic challenges in infants. Antibiotic pretreatment and low bacterial density diminish cerebrospinal fluid (CSF) culture yield, while laboratory parameters do not reliably identify bacterial meningitis. Pro and anti-inflammatory cytokines are elevated in bacterial meningitis and may be useful diagnostic adjuncts when CSF cultures are negative. METHODS: In a prospective cohort study of infants, we used cytometric bead arrays to measure tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), IL-6, IL-8, IL-10, and IL-12 in CSF. Receiver operating characteristic (ROC) analyses and Principal component analysis (PCA) were used to determine cytokine combinations that identified bacterial meningitis. RESULTS: Six hundred and eighty four infants < 6 mo were included; 11 had culture-proven bacterial meningitis. IL-6 and IL-10 were the individual cytokines possessing greatest accuracy in diagnosis of culture proven bacterial meningitis (ROC analyses; area under the concentration-time curve (AUC) 0.91; 0.9103 respectively), and performed as well as, or better than combinations identified using ROC and PCA. CSF cytokines were highly correlated with each other and with CSF white blood cell count (WBC) counts in infants with meningitis. A subset of antibiotic pretreated culture-negative subjects demonstrated cytokine patterns similar to culture positive subjects. CONCLUSION: CSF cytokine levels may aid diagnosis of bacterial meningitis, and facilitate decision-making regarding treatment for culture negative meningitis.

Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates.

BACKGROUND AND OBJECTIVE: Heated, humidified high-flow nasal cannula (HHHFNC) is commonly used as a noninvasive mode of respiratory support in the NICU. The safety and efficacy of HHHFNC have not been compared with other modes of noninvasive support in large randomized trials. The objective was to assess the efficacy and safety of HHHFNC compared with nasal continuous positive airway pressure (nCPAP) for noninvasive respiratory support in the NICU. METHODS: Randomized, controlled, unblinded noncrossover trial in 432 infants ranging from 28 to 42 weeks' gestational age with planned nCPAP support, as either primary therapy or postextubation. The primary outcome was defined as a need for intubation within 72 hours of applied noninvasive therapy. RESULTS: There was no difference in early failure for HHHFNC (23/212 [10.8%]) versus nCPAP (18/220 [8.2%]; P = .344), subsequent need for any intubation (32/212 [15.1%] vs 25/220 [11.4%]; P = .252), or in any of several adverse outcomes analyzed, including air leak. HHHFNC infants remained on the study mode significantly longer than nCPAP infants (median: 4 vs 2 days, respectively; P < .01), but there were no differences between study groups for days on supplemental oxygen (median: 10 vs 8 days), bronchopulmonary dysplasia (20% vs 16%), or discharge from the hospital on oxygen (19% vs 18%). CONCLUSIONS: Among infants ≥28 weeks' gestational age, HHHFNC appears to have similar efficacy and safety to nCPAP when applied immediately postextubation or early as initial noninvasive support for respiratory dysfunction.

Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants.

BACKGROUND: Low cortisol concentrations in premature infants have been correlated with increased severity of illness, hypotension, mortality, and development of bronchopulmonary dysplasia. A total of 360 mechanically ventilated infants with a birth weight of 500 to 999 g were enrolled in a randomized, multicenter trial of prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia. Mortality and bronchopulmonary dysplasia were decreased in the hydrocortisone-treated patients exposed to chorioamnionitis. We now report outcomes at 18 to 22 months' corrected age. PATIENTS AND METHODS: Surviving infants were evaluated with standardized neurologic examination and Bayley Scales of Infant Development-II. Neurodevelopmental impairment was defined as a Mental Developmental Index or Psychomotor Developmental Index of <70, cerebral palsy, blindness or deafness. RESULTS: A total of 252 (87%) of 291 survivors were evaluated. Cerebral palsy was diagnosed in 13% of hydrocortisone-treated versus 14% of placebo-treated infants. Fewer hydrocortisone-treated infants had a Mental Development Index <70, and more of the hydrocortisone-treated infants showed evidence of awareness of object permanence. Incidence of neurodevelopmental impairment was not different (39% [hydrocortisone] vs 44% [placebo]). There were no differences in physical growth measures. Chorioamnionitis-exposed infants treated with hydrocortisone were shorter and weighed less than controls but had no evidence of neurodevelopmental impairment. Among infants not exposed to chorioamnionitis, hydrocortisone-treated patients were less likely to have a Mental Development Index of <70 or to be receiving glucocorticoids at follow-up. CONCLUSIONS: Early, low-dose hydrocortisone treatment was not associated with increased cerebral palsy. Treated infants had indicators of improved developmental outcome. Together with the short-term benefit previously reported, these data support additional studies of hydrocortisone treatment of adrenal insufficiency in extremely premature infants.

The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants.

OBJECTIVE: The purpose of this study was to determine whether the interval between antenatal steroid exposure and delivery influences neonatal outcome in very low birth weight infants. STUDY DESIGN: A retrospective review was performed of all live-born singleton infants who weighed between 500 and 1500 g and who were exposed to a partial course (1 dose) or a complete course (2 12-mg doses of betamethasone given 24 hours apart) of antenatal corticosteroids. Infants were divided into 4 groups, depending on the interval between the first dose of antenatal corticosteroids and delivery (<24 hours, between 24 and 48 hours, between 48 hours and 7 days, and >7 days). Logistic regression was used to control for differences between the 4 groups. RESULTS: Three hundred twenty-five singleton deliveries were reviewed. Gestational age at delivery and birth weight were similar for all 4 groups. The babies in the last group were treated with antenatal corticosteroids at a slightly earlier gestational age. There was no statistical difference between the groups with respect to respiratory distress syndrome treated with surfactant, intraventricular hemorrhage, necrotizing enterocolitis, and deaths. CONCLUSION: In infants who weighed 500 to 1500 g, the time interval between exposure to antenatal corticosteroids and delivery does not appear to affect neonatal outcome. Further studies should evaluate the effects of antenatal corticosteroids and the effects of the interval from exposure to delivery in very low birth weight infants.