A Randomized Clinical Trial of Inhaled Nitric Oxide Treatment in Premature Infants Reveals the Effect of Maternal Racial Identity on Efficacy.

Respiratory distress syndrome increases the risk of death and bronchopulmonary dysplasia (BPD) in premature infants. Inhaled nitric oxide (iNO) may reduce these risks. Recent meta-analyses have suggested that iNO is effective only at doses higher than 5 ppm and in infants born to Black mothers. In a randomized, double-blinded, controlled trial, infants born before 32 0/7 weeks gestation, weighing <1500 g, and requiring respiratory support were assigned to receive iNO for either seven days (short iNO), or until 33 0/7 weeks PMA (long iNO). The primary outcome was death or BPD. A total of 273 patients were enrolled, of whom 83 receiving long iNO (61.5%) experienced the primary outcome, compared with 65 (47.1%) receiving short iNO (relative risk (RR) 1.37; 95% confidence interval (CI), 1.06-1.79; p = 0.017). This increase was due solely to increased BPD in infants weighing 750-999 g (RR 1.33, 95% CI 1.07-1.66, p = 0.009). However, there was no difference in the numbers of infants requiring supplemental oxygen at 40 weeks PMA. Among infants < 750 g, long-iNO-treated infants had a lower cumulative probability of death (χ2 5.12, p = 0.02). Long iNO increased the primary outcome in non-Black infants (RR 1.93, 95% CI 1.20-3.24) but not in Black infants. Understanding how maternal racial identity determines responses of premature infants to iNO may help narrow the gap in health outcomes between Black and non-Black infants.

Neurodevelopmental Outcomes Comparing Bevacizumab to Laser for Type 1 ROP.

BACKGROUND AND OBJECTIVE: To evaluate neurodevelopmental outcomes among infants treated for retinopathy of prematurity (ROP) at the authors' institution. PATIENTS AND METHODS: Before-and-after retrospective chart reviews identified 40 infants treated with laser and 46 treated with primary intravitreal bevacizumab (IVB). Primary outcomes were death, hearing loss, bilateral visual impairment (BVI), and cerebral palsy (CP); odds ratios (ORs) were calculated to determine factors associated with CP. Secondary outcomes were mean Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores. RESULTS: Overall, there were no significant differences in primary outcome measures by treatment group. However, adjusted odds of BVI were significantly higher with laser compared to IVB (OR = 13.1; P = .038). Although IVB was not associated with CP, both hydrocephalus and BVI were strongly correlated with CP. Mean Bayley-III scores were similar when comparing nine laser-treated infants to 13 IVB-treated infants. CONCLUSIONS: Visual outcomes are an important aspect of neurodevelopment. IVB was not associated with severe developmental disabilities and may protect against vision loss in this analysis. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:337-343.].

Cognitive Development and Quality of Life Associated With BPD in 10-Year-Olds Born Preterm.

OBJECTIVES: To compare neurocognitive, language, executive function, academic achievement, neurologic and behavioral outcomes, and quality of life at age 10 years in children born extremely preterm who developed bronchopulmonary dysplasia (BPD) to children who did not develop BPD. METHODS: The Extremely Low Gestational Age Newborns study population included 863 children born extremely preterm whose BPD status before discharge was known had an IQ (Differential Ability Scales II [DAS II]) assessment at 10 years. We evaluated the association of BPD with any cognitive (DAS II), executive function (NEuroPSYchological Assessment II), academic achievement (Wechsler Individual Achievement Test-III and Oral and Written Language Scales [OWLS]) as well as social dysfunctions (Social Responsiveness Scale). We used logistic regression models, adjusting for potential confounding factors, to assess the strength of association between the severity of BPD and each outcomes. RESULTS: Three hundred and seventy-two (43%) children were oxygen-dependent at 36 weeks postconception age, whereas an additional 78 (9%) were also oxygen- and ventilator-dependent. IQ scores 2 or more SDs below the expected mean (ie, z scores ≤-2) occurred twice as commonly among children who had BPD as among those who did not. Children with severe BPD consistently had the lowest scores on DAS II, OWLS, Wechsler Individual Achievement Test-III, NEuroPSYchological Assessment II, and Social Responsiveness Scale assessments. CONCLUSIONS: Among 10-year-old children born extremely preterm, those who had BPD were at increased risk of cognitive, language, and executive dysfunctions; academic achievement limitations; social skill deficits; and low scores on assessments of health-related quality of life.

Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience.

OBJECTIVE: To analyze data from a registry of Japanese neonates with hypoxic respiratory failure associated with pulmonary hypertension (PH) to compare the effectiveness of inhaled nitric oxide (iNO) in neonates born <34 weeks vs. ≥34 weeks gestational age (GA). MATERIALS AND METHODS: iNO was administered according to approved Japanese product labeling. Study data were collected before iNO administration and at predefined intervals until discontinuation. RESULTS: A total of 1,114 neonates were included (n=431, <34 weeks GA; n=675, ≥34 weeks GA; n=8, missing age data). Mean decrease from baseline oxygenation index (OI) was similar in both age groups. OI reduction was more pronounced in the <34 weeks subgroups with baseline OI ≥25. Survival rates were similar in the <34 weeks GA and ≥34 weeks GA groups stratified by baseline OI (OI<15, 89% vs. 93%; 15≤OI<25, 85% vs. 91%; 25≤OI≤40, 73% vs. 79%; OI>40, 64% vs. 66%). CONCLUSION: iNO improved oxygenation in preterm neonates as effectively as in late preterm and term neonates, without negative impact on survival. If clinically significant PH is present, as measured by pulse oximetry or echocardiography, a therapeutic trial of iNO might be indicated for preterm neonates.

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.

Early blood gas predictors of bronchopulmonary dysplasia in extremely low gestational age newborns.

Aim. To determine among infants born before the 28th week of gestation to what extent blood gas abnormalities during the first three postnatal days provide information about the risk of bronchopulmonary dysplasia (BPD). Methods. We studied the association of extreme quartiles of blood gas measurements (hypoxemia, hyperoxemia, hypocapnea, and hypercapnea) in the first three postnatal days, with bronchopulmonary dysplasia, among 906 newborns, using multivariable models adjusting for potential confounders. We approximated NIH criteria by classifying severity of BPD on the basis of the receipt of any O2 on postnatal day 28 and at 36 weeks PMA and assisted ventilation. Results. In models that did not adjust for ventilation, hypoxemia was associated with increased risk of severe BPD and very severe BPD, while infants who had hypercapnea were at increased risk of very severe BPD only. In contrast, infants who had hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated the associations with hypoxemia and with hypercapnea and made the decreased risk of very severe BPD statistically significant. Conclusions. Among ELGANs, recurrent/persistent blood gas abnormalities in the first three postnatal days convey information about the risk of severe and very severe BPD.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD. METHODS: We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities. RESULTS: We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration. CONCLUSIONS: External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

Systemic inflammation, intraventricular hemorrhage, and white matter injury.

To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage without white matter injury differed from that of 68 peers who had both lesions, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had both hemorrhage and white matter injury were more likely than others to have elevated concentrations of C-reactive protein and interleukin 8 on days 1, 7, and 14, and elevated concentrations of serum amyloid A and tumor necrosis factor-α on 2 of these days. Intraventricular hemorrhage should probably be viewed as 2 entities: hemorrhage alone and hemorrhage with white matter injury. Each entity is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone.

Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials.

BACKGROUND: Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory. DESIGN/METHODS: Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings. RESULTS: Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92-1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98-1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤ 5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74-0.98]) was found. CONCLUSIONS: Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.

Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation?

OBJECTIVE: To evaluate the relationships among cerebral palsy (CP) phenotypes and bronchopulmonary dysplasia (BPD) severity and, in the process, to generate hypotheses regarding causal pathways linking BPD to CP. STUDY DESIGN: We studied 1047 infants born before the 28th week of gestation. Receipt of supplemental oxygen at 36 weeks postmenstrual age (PMA), with or without the need for mechanical ventilation (MV) at 36 weeks PMA, defined two levels of BPD. At 24 months, the children underwent neurologic examinations and CP diagnoses were made using an algorithm based on topographic localisation. RESULTS: The 536 infants with BPD were at increased risk of all three CP phenotypes. In time-oriented multivariable analyses that adjusted for potential confounders, receipt of supplemental oxygen without MV at 36 weeks PMA (BPD) was not associated with increased risk of any CP phenotype. In contrast, BPD accompanied by MV at 36 weeks PMA (BPD/MV) was associated with a nearly sixfold increased risk of quadriparesis and a fourfold increased risk of diparesis. CONCLUSIONS: Combined treatment with both MV and supplemental oxygen at 36 weeks PMA strongly predicts the more common bilateral CP phenotypes. BPD without MV at 36 weeks PMA was not significantly associated with any form of CP.

Early blood gas abnormalities and the preterm brain.

The authors explored associations between blood gas abnormalities in more than 1,000 preterm infants during the first postnatal days and indicators of neonatal brain damage. During 2002-2004, women delivering infants before 28 weeks' gestation at one of 14 participating institutions in 5 US states were asked to enroll in the study. The authors compared infants with blood gas values in the highest or lowest quintile for gestational age and postnatal day (extreme value) on at least 1 of the first 3 postnatal days with the remainder of the subjects, with separate analyses for blood gas abnormalities on multiple days and for partial pressure of oxygen in the alveolar gas of <35. Outcomes analyzed were ventriculomegaly and an echolucent lesion on an ultrasound scan in the neonatal intensive care unit, and cerebral palsy, microcephaly, and a low score on a Bayley Scale of Infant Development at 24 months. Every blood gas derangement (hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis) was associated with multiple indicators of brain damage. However, for some, the associations were seen with only 1 day of exposure; others were evident with 2 or more days' exposure. Findings suggest that individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might be indicators of immaturity/vulnerability and illness severity.

Elective high-frequency oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis of individual patients' data.

BACKGROUND: Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group. METHODS: We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes. FINDINGS: For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.95 (95% CI 0.88-1.03), of death or severe adverse neurological event 1.00 (0.88-1.13), or any of these outcomes 0.98 (0.91-1.05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect. INTERPRETATION: HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids. FUNDING: Nestlé Belgium, Belgian Red Cross, and Dräger International.

Risk factors affecting school readiness in premature infants with respiratory distress syndrome.

OBJECTIVE: With advances in neonatal care, more children born prematurely are successfully reaching school age. It is unknown how many will be ready for school and what factors affect school readiness. Our objective was to assess readiness of children born prematurely for entry into public school, and determine risk factors associated with lack of school readiness in this population. METHODS: This was a single-center prospective cohort study. Follow- up data were collected for 135 of 167 (81%) surviving premature infants with RDS requiring surfactant-replacement therapy. The children were seen between July 2005 and September 2006 (average age: 5.7 +/- 1.0 years) and underwent standardized neurodevelopmental and health assessments and socioeconomic status classification. A 4-level school-readiness score was constructed by using each child's standardized scores on assessments of basic concepts (Bracken School-Readiness Assessment), perceptual skills (Visual-Motor Integration Test), receptive vocabulary (Peabody Picture Vocabulary Test, Third Edition), daily living functional skills (Pediatric Functional Independence Measure), and presence of sensory impairments or autism. Proportional odds models were used to identify risk factors predicting lower school-readiness levels. RESULTS: Mean birth weight was 1016 +/- 391 g, and mean gestational age was 27.5 +/- 2.6 weeks. Ninety-one (67%) children were school-ready. Using multivariate analysis, male gender, chronic lung disease, and severe intraventricular hemorrhage or periventricular leukomalacia were associated with lower school-readiness levels. However, the most powerful factor determining school-readiness level was low socioeconomic status. CONCLUSION: Interventions targeting neonatal morbidities may be much less effective at improving overall performance at school age compared with the effect of the impoverished social environment.

Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide.

BACKGROUND: Chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia in premature infants are associated with abnormal neurodevelopmental outcomes. In a previous randomized, controlled, single-center trial of premature infants with the respiratory distress syndrome, inhaled nitric oxide decreased the risk of death or chronic lung disease as well as severe intraventricular hemorrhage and periventricular leukomalacia. We hypothesized that infants treated with inhaled nitric oxide would also have improved neurodevelopmental outcomes. METHODS: We conducted a prospective, longitudinal follow-up study of premature infants who had received inhaled nitric oxide or placebo to investigate neurodevelopmental outcomes at two years of corrected age. Neurologic examination, neurodevelopmental assessment, and anthropometric measurements were made by examiners who were unaware of the children's original treatment assignment. RESULTS: A total of 138 children (82 percent of survivors) were evaluated. In the group given inhaled nitric oxide, 17 of 70 children (24 percent) had abnormal neurodevelopmental outcomes, defined as either disability (cerebral palsy, bilateral blindness, or bilateral hearing loss) or delay (no disability, but one score of less than 70 on the Bayley Scales of Infant Development II), as compared with 31 of 68 children (46 percent) in the placebo group (relative risk, 0.53; 95 percent confidence interval, 0.33 to 0.87; P=0.01). This effect persisted after adjustment for birth weight and sex, as well as for the presence or absence of chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia. The improvement in neurodevelopmental outcome in the group given inhaled nitric oxide was primarily due to a 47 percent decrease in the risk of cognitive impairment (defined by a score of less than 70 on the Bayley Mental Developmental Index) (P=0.03). CONCLUSIONS: Premature infants treated with inhaled nitric oxide have improved neurodevelopmental outcomes at two years of age.

Interleukin (IL)-1 beta in tracheal aspirates from premature infants induces airway epithelial cell IL-8 expression via an NF-kappa B dependent pathway.

Tracheal aspirate IL-8 concentration and airway epithelial cell IL-8 expression are each increased in premature infants undergoing mechanical ventilation. We sought to determine the cytokines responsible for IL-8 expression in this context. Tracheal aspirates were collected from 18 mechanically ventilated premature infants. IL-8 protein abundance was high in tracheal aspirates from ventilated premature infants (mean, 5806 +/- 4923 pg/mL). IL-1 alpha (mean, 20 +/- 6 pg/mL), IL-1 beta (mean 67 +/- 46 pg/mL), and tumor necrosis factor (TNF)-alpha (mean, 8 +/- 2 pg/mL) were also found. Incubation of tracheal aspirates with 16HBE14o- human bronchial epithelial cells increased IL-8 protein in both cell lysates and supernatants, as well as transcription from the IL-8 promoter. Aspirates also induced nuclear factor (NF)-kappa B activation. Mutation of the IL-8 promoter NF-kappa B site abolished aspirate-induced IL-8 transcription. Endotoxin concentrations in the tracheal aspirates were negligible and incapable of inducing IL-8 promoter activity. Finally, incubation of tracheal aspirates with a neutralizing antibody against IL-1 beta reduced epithelial cell IL-8 production, whereas neutralizing antibodies against IL-1 alpha and TNF-alpha had no effect. We conclude that airway fluid from mechanically ventilated premature infants contains soluble factors capable of inducing airway epithelial cell IL-8 expression via a NF-kappa B-dependent pathway, and that IL-1 beta plays a specific role in this process.

Inhaled nitric oxide in premature infants with the respiratory distress syndrome.

BACKGROUND: Inhaled nitric oxide improves gas exchange, decreases pulmonary vascular lability, and reduces pulmonary inflammation. We hypothesized that the use of inhaled nitric oxide would decrease the incidence of chronic lung disease and death in premature infants with the respiratory distress syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled study of the effect of inhaled nitric oxide during the first week of life on the incidence of chronic lung disease and death in premature infants (less than 34 weeks' gestation) who were undergoing mechanical ventilation for the respiratory distress syndrome. Infants were randomly assigned to receive inhaled nitric oxide (10 ppm on day 1, followed by 5 ppm for six days) or inhaled oxygen placebo for seven days. We further randomly assigned the infants in each group to receive intermittent mandatory or high-frequency oscillatory ventilation. RESULTS: A total of 207 premature infants were enrolled. In the group given inhaled nitric oxide, 51 infants (48.6 percent) died or had chronic lung disease, as compared with 65 infants (63.7 percent) in the placebo group (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97; P=0.03). There was no significant difference between the nitric oxide and placebo groups in the overall incidence of intraventricular hemorrhage and periventricular leukomalacia (33.3 percent and 38.2 percent, respectively), but the group given inhaled nitric oxide had a lower incidence of severe intraventricular hemorrhage and periventricular leukomalacia (12.4 percent vs. 23.5 percent; relative risk, 0.53; 95 percent confidence interval, 0.28 to 0.98; P=0.04). The type of ventilation had no significant effect on the outcome. CONCLUSIONS: The use of inhaled nitric oxide in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.

Predictive power of initial severity of pulmonary disease for subsequent development of bronchopulmonary dysplasia.

Using retrospectively acquired data from 138 mechanically ventilated premature infants, logistic regression was used to determine the relationships between the risk of bronchopulmonary dysplasia (BPD) and indices of initial respiratory disease severity [oxygen index (OI) and alveolar-arterial pO(2) difference (A-a DO(2))]. Indices were calculated from the first arterial blood gas analysis after initial surfactant administration. Infants were also classified as having mild [OI <4 cm H(2)O x mm Hg(-1), A-a DO(2) <150 mm Hg (20 kPa)] or severe [OI >or=10 cm H(2)O x mm Hg(-1), A-a DO(2) >or=300 mm Hg (40 kPa)] respiratory disease, and the ability of this classification to predict subsequent BPD risk was calculated. OI and A-a DO(2) were significantly higher in the BPD group. Logistic regression analysis showed that BPD risk increased linearly with both OI (9%/cm H(2)O x mm Hg(-1)) and A-a DO(2) [16%/50 mm Hg (16%/6.7 kPa)]. However, the predictive power (receiver-operator characteristic) of these models was modest. Unexpectedly, 29% of infants with mild initial disease developed BPD. These data suggest that, while BPD prediction in infants with severe disease is straightforward, the identification of those few infants with mild to moderate disease destined to develop BPD remains problematic.