Drugs to Prevent Bronchopulmonary Dysplasia: Effect of Baseline Risk on the Number Needed to Treat.

Infants born very preterm have a variable baseline risk of bronchopulmonary dysplasia (BPD). Using the example of evidence-based drug therapies to prevent BPD, we designed a visual aid that displays the "number needed to treat" with CIs for caffeine, vitamin A, and hydrocortisone over a range of baseline risks.

Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants.

Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.

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.

Benefits of Oxygen Saturation Targeting Trials: Oximeter Calibration Software Revision and Infant Saturations.

It has been reported in the 3 Benefits of Oxygen Saturation Targeting (BOOST-II) trials that changes in oximeter calibration software resulted in clearer separation between the oxygen saturations in the two trial target groups. A revised analysis of the published BOOST-II data does not support this conclusion.

Effects of Targeting Higher or Lower Oxygen Saturations in Centers with More Versus Less Separation between Median Saturations.

Subgroup analysis of the Canadian Oxygen Trial to compare outcomes of extremely preterm infants in centers with more versus less separation between median arterial oxygen saturations in the two target ranges. Centers with more separation observed lower rates of death or disability in the 85%-89% range than in the 91%-95% target range.

Prediction of Late Death or Disability at Age 5 Years Using a Count of 3 Neonatal Morbidities in Very Low Birth Weight Infants.

OBJECTIVE: To evaluate bronchopulmonary dysplasia (BPD), serious brain injury, and severe retinopathy of prematurity (ROP) as predictors of poor long-term outcome in very low birth weight infants. STUDY DESIGN: We examined the associations between counts of the 3 morbidities and long-term outcomes in 1514 of 1791 (85%) infants with birth weights of 500-1250 g who were enrolled in the Caffeine for Apnea of Prematurity trial from October 1999, to October 2004, had complete morbidity data, and were alive at 36 weeks postmenstrual age (PMA). BPD was defined as use of supplemental oxygen at 36 weeks PMA. Serious brain injury on cranial ultrasound included grade 3 and 4 hemorrhage, cystic periventricular leucomalacia, porencephalic cysts, or ventriculomegaly of any cause. Poor long-term outcome was death after 36 weeks PMA or survival to 5 years with 1 or more of the following disabilities: motor impairment, cognitive impairment, behavior problems, poor general health, deafness, and blindness. RESULTS: BPD, serious brain injury, and severe ROP occurred in 43%, 13%, and 6% of the infants, respectively. Each of the 3 morbidities was similarly and independently correlated with poor 5-year outcome. Rates of death or disability (95% CI) in children with none, any 1, any 2, and all 3 morbidities were 11.2% (9.0%-13.7%), 22.9% (19.6%-26.5%), 43.9% (35.5%-52.6%), and 61.5% (40.6%-79.8%), respectively. CONCLUSIONS: In very low birth weight infants who survive to 36 weeks PMA, a count of BPD, serious brain injury, and severe ROP predicts the risk of a late death or survival with disability at 5 years.

Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams.

OBJECTIVE: To determine the extent that social variables influence cognitive development of very low birth weight (VLBW) infants across the preschool years. STUDY DESIGN: Participants were VLBW (500-1250 g) children enrolled in the Caffeine for Apnea of Prematurity randomized trial between 1999 and 2004. We investigated the relationships between 4 potential social advantages: higher maternal education, higher paternal education, caregiver employment, and 2 biologic parents in the same home--and gain in cognitive scores. Cognitive assessments were performed at the corrected ages of 18 months (Mental Development Index score on the Bayley Scales of Infant Development II) and 5 years (Full Scale IQ on the Wechsler Preschool and Primary Scale of Intelligence III). Cognitive gain was computed by subtracting each individual 18-month Mental Development Index score from the corresponding Full Scale IQ at 5 years. RESULTS: Data were available for 1347 children. Mean (SD) cognitive scores were 90.8 (15.7) at 18 months and 98.9 (14.5) at 5 years. Multivariable regression showed that higher maternal education, higher paternal education, and caregiver employment had independent and additive effects of similar size on cognitive gain (P < .001); the mean cognitive gain between 18 months and 5 years increased by 3.6 points in the presence of each of these advantages. When all 3 were present, cognitive scores improved on average by 10.9 points compared with children without any of these advantages. CONCLUSION: In VLBW children, a count of 3 social advantages strongly predicts gains in cognitive scores across the preschool years.

Impact of study oximeter masking algorithm on titration of oxygen therapy in the Canadian oxygen trial.

OBJECTIVE: To compare oxygen saturations as displayed to caregivers on offset pulse oximeters in the 2 groups of the Canadian Oxygen Trial. STUDY DESIGN: In 5 double-blind randomized trials of oxygen saturation targeting, displayed saturations between 88% and 92% were offset by 3% above or below the true values but returned to true values below 84% and above 96%. During the transition, displayed values remained static at 96% in the lower and at 84% in the higher target group during a 3% change in true saturations. In contrast, displayed values changed rapidly from 88% to 84% in the lower and from 92% to 96% in the higher target group during a 1% change in true saturations. We plotted the distributions of median displayed saturations on days with >12 hours of supplemental oxygen in 1075 Canadian Oxygen Trial participants to reconstruct what caregivers observed at the bedside. RESULTS: The oximeter masking algorithm was associated with an increase in both stability and instability of displayed saturations that occurred during the transition between offset and true displayed values at opposite ends of the 2 target ranges. Caregivers maintained saturations at lower displayed values in the higher than in the lower target group. This differential management reduced the separation between the median true saturations in the 2 groups by approximately 3.5%. CONCLUSIONS: The design of the oximeter masking algorithm may have contributed to the smaller-than-expected separation between true saturations in the 2 study groups of recent saturation targeting trials in extremely preterm infants.

Impact of delivery room resuscitation on outcomes up to 18 months in very low birth weight infants.

OBJECTIVE: To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. STUDY DESIGN: The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. RESULTS: The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. CONCLUSIONS: In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation.

Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups.

OBJECTIVE: To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial. STUDY DESIGN: Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (< or =3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions. RESULTS: There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (-0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03). CONCLUSIONS: There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms.

OBJECTIVES: To determine whether surgical closure of a patent ductus arteriosus (PDA) is a risk factor for bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP), and neurosensory impairment in extremely low birth weight (ELBW) infants. STUDY DESIGN: We studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants participated in the multicenter Trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months. RESULTS: Of the 95 infants who survived after PDA ligation, 50 (53%) had neurosensory impairment, compared with 84 of the 245 infants (34%) who survived after receiving only medical therapy (adjusted odds ratio, 1.98; 95% CI, 1.18-3.30; P = .0093). BPD (adjusted odds ratio, 1.81; 95% CI, 1.09-3.03; P = .023) and severe ROP (adjusted odds ratio, 2.20; 95% CI, 1.19-4.07; P = .012) were also more common after surgical PDA closure. CONCLUSIONS: PDA ligation may be associated with increased risks of BPD, severe ROP, and neurosensory impairment in ELBW infants.

The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants.

OBJECTIVE: To determine whether extremely low birth weight infants (ELBW) transfused at lower hemoglobin thresholds versus higher thresholds have different rates of survival or morbidity at discharge. STUDY DESIGN: Infants weighing <1000 g birth weight were randomly assigned within 48 hours of birth to a transfusion algorithm of either low or high hemoglobin transfusion thresholds. The composite primary outcome was death before home discharge or survival with any of either severe retinopathy, bronchopulmonary dysplasia, or brain injury on cranial ultrasound. Morbidity outcomes were assessed, blinded to allocation. RESULTS: Four hundred fifty-one infants were randomly assigned to low (n = 223) or high (n = 228) hemoglobin thresholds. Groups were similar, with mean birth weight of 770 g and gestational age of 26 weeks. Fewer infants received one or more transfusions in the low threshold group (89% low versus 95% high, P = .037). Rates of the primary outcome were 74.0% in the low threshold group and 69.7% in the high (P = .25; risk difference, 2.7%; 95% CI -3.7% to 9.2%). There were no statistically significant differences between groups in any secondary outcome. CONCLUSIONS: In extremely low birth weight infants, maintaining a higher hemoglobin level results in more infants receiving transfusions but confers little evidence of benefit.

Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP).

OBJECTIVES: To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD. STUDY DESIGN: We studied 999 extremely low birth weight infants who participated in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) and who survived to a postmenstrual age of 36 weeks. RESULTS: The incidence of BPD in the 2 subgroups of infants with PDA was 52% (55/105) after indomethacin prophylaxis and 56% (137/246) after placebo. In contrast, rates of BPD in the 2 subgroups without a PDA were 43% (170/391) after indomethacin prophylaxis and 30% (78/257) after placebo (P [interaction] = .015). Logistic regression analysis with adjustment for prognostic baseline factors showed that adverse and independent effects of indomethacin prophylaxis on the need for supplemental oxygen and on weight loss by the end of the first week of life may increase the risk of BPD in infants without PDA. CONCLUSIONS: Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Male/female differences in indomethacin effects in preterm infants.

To test whether indomethacin prophylaxis has sex-mediated effects on severe intraventricular hemorrhage (grade III and IV) and on long-term outcomes in extremely-low-birth-weight infants. A secondary analysis was performed in the entire "Trial of Indomethacin Prophylaxis in Preterms study" cohort. The results suggest a weak differential treatment effect of indomethacin by sex.

Heat Loss Prevention (HeLP) in the delivery room: A randomized controlled trial of polyethylene occlusive skin wrapping in very preterm infants.

OBJECTIVES: To determine if polyethylene occlusive skin wrapping of very preterm infants prevents heat loss after delivery better than conventional drying and to evaluate if any benefit is sustained after wrap removal. STUDY DESIGN: This was a randomized controlled trial of infants <28 weeks' gestation. The experimental group was wrapped from the neck down. Only the head was dried. Control infants were dried completely. Rectal temperatures were compared on admission to the neonatal intensive care unit immediately after wrap removal and 1 hour later. RESULTS: Of 55 infants randomly assigned (28 wrap, 27 control), 2 died in the delivery room and 53 completed the study. Wrapped infants had a higher mean rectal admission temperature, 36.5 degrees C (SD, 0.8 degrees C), compared with 35.6 degrees C (SD, 1.3 degrees C) in control infants ( P = .002). One hour later, mean rectal temperatures were similar in both groups (36.6 degrees C, SD, 0.7 degrees C vs 36.4 degrees C, SD, 0.9 degrees C, P = .4). Size at birth was an important determinant of heat loss: Mean rectal admission temperature increased by 0.21 degrees C (95% CI, 0.04 to 0.4) with each 100-g increase in birth weight. CONCLUSIONS: Polyethylene occlusive skin wrapping prevents rather than delays heat loss at delivery in very preterm infants.