Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial.

OBJECTIVE: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs). STUDY DESIGN: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined. RESULTS: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72). CONCLUSIONS: A small increased risk of major thrombotic events was identified in the Epo treatment group. TRIAL REGISTRATION: NCT02811263.

Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis.

OBJECTIVE: To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants. STUDY DESIGN: An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of >5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay. RESULTS: Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. CONCLUSION: iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants.

Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome.

OBJECTIVES: To test the hypothesis that inhaled nitric oxide (iNO) would lead to improved oxygenation and a decrease in duration of mechanical ventilation in pediatric patients with acute respiratory distress syndrome. STUDY DESIGN: A total of 55 children with acute respiratory distress syndrome were enrolled from 9 centers. Patients were randomized to iNO or placebo and remained on the study drug until death, they were free of ventilator support, or day 28 after the initiation of therapy. RESULTS: Mean baseline oxygenation indexes (OIs) were 22.0 ± 18.4 and 25.6 ± 14.9 (iNO and placebo groups, respectively, P = .27). There was a trend toward an improved OI in the iNO group compared with the placebo group at 4 hours that became significant at 12 hours. There was no difference in the OI between groups at 24 hours. Days alive and ventilator free at 28 days was greater in the iNO group, 14.2 ± 8.1 and 9.1 ± 9.5 days (iNO and placebo groups, respectively, P = .05). Although overall survival at 28 days failed to reach statistical significance, 92% (22 of 24) in the iNO group and 72% (21 of 29) in the placebo group (P = .07), the rate of extracorporeal membrane oxygenation-free survival was significantly greater in those randomized to iNO 92% (22 of 24) vs 52% (15 of 29) for those receiving placebo (P < .01). CONCLUSION: The use of iNO was associated with a significantly reduced duration of mechanical ventilation and significantly greater rate of extracorporeal membrane oxygenation-free survival.

Early neonatal intensive care unit therapy improves predictive power for the outcomes of ventilated extremely low birth weight infants.

OBJECTIVE: To assess the predictive value of early therapy for ventilated extremely low birth weight (ELBW) infants beyond information available at delivery. STUDY DESIGN: Prospective, single-center cohort analysis of 177 ventilated ELBW infants. We collected information known at delivery (gestational age, birth weight, singleton, sex, antenatal steroids) and additional information while infants were mechanically ventilated (head ultrasound scanning, clinician intuitions of death before discharge). An adverse outcome was defined as mortality or Bayley Mental Developmental Index or Psychomotor Developmental Index <70 at 2 years. We compared the predictive ability of clinical variables separately, in combination, and in addition to information available at delivery. RESULTS: A total of 77% of infants survived to follow-up; 56% of survivors had Bayley Mental Developmental Index and Psychomotor Developmental Index ≥ 70. A total of 95% of infants with both abnormal head ultrasound scanning results and predicted death before discharge had an adverse outcome, independent of gestational age. Conversely, 40% of infants with normal head ultrasound scanning results and no predicted death before discharge had an adverse outcome, independent of gestational age. After adjusting for variables known at birth, predicted death before discharge and abnormal head ultrasound scanning results added significantly to the ability to predict outcomes. CONCLUSION: Information gained early in the neonatal intensive care unit improves prediction of mortality or neurodevelopmental impairment in ventilated ELBW infants beyond information available in the delivery room.

Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multicenter, randomized, controlled trial.

OBJECTIVE: We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure. STUDY DESIGN: Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug. RESULTS: Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01). CONCLUSION: Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.

Cardiopulmonary effects of nebulized sodium nitroprusside in term infants with hypoxic respiratory failure.

OBJECTIVE: To study whether nebulized nitroprusside (neb-NP) improves oxygenation in term infants with hypoxic respiratory failure (HRF). STUDY DESIGN: We studied 22 newborn term infants (gestational age, 39.7+/-0.4 weeks [mean+/-SEM]; birth weight, 3.6+/-0.1 kg) with hypoxia (Pao2<100 mm Hg) during mechanical ventilation (Fio2=1.0). Sodium nitroprusside (5 mg followed by 25 mg) was nebulized into the inspiratory arm of the ventilator circuit. Vital signs and arterial blood gas values were recorded after 20 minutes at each dose and before and after initiation of inhaled nitric oxide (iNO). RESULTS: Pao2 increased significantly with 5 mg neb-NP (from 64.6+/-5.6 to 90.1+/-15.3 mm Hg, P=.04) and with 25 mg neb-NP (113.2+/-20.4 mm Hg, P=.009). Differences between mean Pao2 at 5 mg versus 25 mg neb-NP were also statistically significant (P=.03). When comparing the effect of neb-NP to iNO, the treatment-induced increases in Pao2 were similar (52.1+/-18.7 vs 62.2+/-18.2 mm Hg, respectively, P=not significant). CONCLUSIONS: Neb-NP causes a dose-dependent increase in oxygenation in term infants with HRF, similar in magnitude to iNO* Neb-NP may be beneficial in infants with HRF when iNO is not readily available.