Roger F. Soll

Mortality and Neonatal Morbidity Among Infants 501 to 1500 Grams From 2000 to 2009

OBJECTIVE: To identify changes in mortality and neonatal morbidities for infants with birth weight 501 to 1500 g born from 2000 to 2009. METHODS: There were 355 806 infants weighing 501 to 1500 g who were born in 2000–2009. Mortality during initial hospitalization and major neonatal morbidity in survivors (early and late infection, chronic lung disease, necrotizing enterocolitis, severe retinopathy of prematurity, severe intraventricular hemorrhage, and periventricular leukomalacia) were assessed by using data from 669 North American hospitals in the Vermont Oxford Network. RESULTS: From 2000 to 2009, mortality for infants weighing 501 to 1500 g decreased from 14.3% to 12.4% (difference, −1.9%; 95% confidence interval, −2.3% to −1.5%). Major morbidity in survivors decreased from 46.4% to 41.4% (difference, −4.9%; 95% confidence interval, −5.6% to −4.2%). In 2009, mortality ranged from 36.6% for infants 501 to 750 g to 3.5% for infants 1251 to 1500 g, whereas major morbidity in survivors ranged from 82.7% to 18.7%. In 2009, 49.2% of all very low birth weight infants and 89.2% of infants 501 to 750 g either died or survived with a major neonatal morbidity. CONCLUSIONS: Mortality and major neonatal morbidity in survivors decreased for infants with birth weight 501 to 1500 g between 2000 and 2009. However, at the end of the decade, a high proportion of these infants still either died or survived after experiencing ≥1 major neonatal morbidity known to be associated with both short- and long-term adverse consequences.

Resuscitation of Newborn Infants with 21% or 100% Oxygen: An Updated Systematic Review and Meta-Analysis

Background: The issue of whether 21% O2 is more effective than 100% O2 for resuscitation of newborn infants remains controversial. Objectives: We have updated the systematic review and meta-analysis including all studies reporting resuscitation of newborn infants with 21 or 100% O2. Methods: Randomized or quasi-randomized studies of depressed newborn infants resuscitated with 21 or 100% O2 with or without masking of treatment were considered for inclusion. The outcomes of interest included neonatal mortality and hypoxic ischemic encephalopathy. Results: Ten studies fulfilled the inclusion criteria. Of these, 6 studies were identified as being strictly randomized. In total, 1,082 infants were allocated to resuscitation with 21% O2 and 1,051 infants with 100% O2. The risk of neonatal mortality was reduced in the 21% O2 group compared to the 100% O2 group both in the analysis of all studies (typical RR 0.69, 95% CI 0.54, 0.88) and in the analysis of strictly randomized studies (typical RR 0.32, 95% CI 0.12, 0.84). A trend toward a decrease in the risk of hypoxic ischemic encephalopathy stage 2 and 3 was noted with resuscitation in 21% O2 in the analysis of all studies (typical RR 0.88, 95% CI 0.72, 1.08). Conclusions: There is a significant reduction in the risk of neonatal mortality and a trend towards a reduction in the risk of severe hypoxic ischemic encephalopathy in newborns resuscitated with 21% O2.

A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome

OBJECTIVE To compare the efficacy of two surfactants, Exosurf Neonatal (Burroughs Wellcome Co.) and Survanta (Ross Laboratories), for the treatment of neonatal respiratory distress syndrome. DESIGN Multicenter randomized trial. SETTING Eleven tertiary care university neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network. PATIENTS Newborn infants (n = 617) weighing 501 to 1500 gm with respiratory distress syndrome who were receiving assisted ventilation with 30% oxygen or more within 6 hours of birth were enrolled between January 1991 and January 1992. INTERVENTIONS Infants were randomly assigned to receive up to four intratracheal doses of either Exosurf Neonatal (n = 309) or Survanta (n = 308). MAIN OUTCOME MEASURES The occurrence of death or bronchopulmonary dysplasia 28 days after birth and the average fraction of inspired oxygen (FIO2) and mean airway pressure (MAP) during the first 72 hours after treatment. RESULTS Death or bronchopulmonary dysplasia occurred in 67% of the infants in the Exosurf group and 62% of those in the Survanta group (adjusted relative risk, 1.07; 95% confidence interval, 0.96 to 1.20). During the 72 hours after the first surfactant dose, the average FIO2 (+/- SEM) was 0.50 +/- 0.01 for Exosurf and 0.42 +/- 0.01 for Survanta (difference, 0.08; 95% confidence interval, 0.05 to 0.11); the average MAP (+/- SEM) was 7.64 +/- 0.21 cm H2O for Exosurf and 6.93 +/- 0.21 cm H2O for Survanta (difference, 0.71 cm H2O; 95% confidence interval, 0.13 to 1.29 cm H2O). There was no difference between the groups in the incidence of other neonatal morbidities or in the duration of hospitalization, assisted ventilation, or supplemental oxygen administration. CONCLUSION We found no difference between treatment groups in the incidence of death or bronchopulmonary dysplasia, although we did observe a difference in the initial response to treatment as measured by FIO2 and MAP.

Synthetic surfactant for respiratory distress syndrome in preterm infants.

BACKGROUND This section is under preparation and will be included in the next issue. OBJECTIVES To assess the effect of intratracheal administration of synthetic surfactant in premature newborns with established respiratory distress syndrome (RDS). SEARCH STRATEGY Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactants; limits: age groups, newborn infant; publication types, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language. SELECTION CRITERIA Randomized controlled trials which compared the effect of synthetic surfactant treatment to routine management in the treatment of preterm infants with respiratory distress syndrome. DATA COLLECTION AND ANALYSIS Data regarding clinical outcome including the incidence of pneumothorax, pulmonary interstitial emphysema, pulmonary hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, apnea of prematurity, intraventricular hemorrhage (any grade, and severe intraventricular hemorrhage), bronchopulmonary dysplasia, neonatal mortality, bronchopulmonary dysplasia or death, retinopathy of prematurity (any retinopathy, and retinopathy greater than Stage 3), mortality at hospital discharge, mortality to one year of age, and cerebral palsy (any, and moderate/severe cerebral palsy) was excerpted from the report of the clinical trials by the reviewer. Data were analyzed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS Six randomized controlled trials of synthetic surfactant treatment of established respiratory distress syndrome were identified. Five of the studies used Exosurf Neonatal (a synthetic surfactant composed of dipalmitoylphosphatidylcholine, hexadecanol and tyloxapol); one small study utilized a mixture of dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG). Treatment with intratracheal Exosurf Neonatal in premature infants with established respiratory distress syndrome improves pulmonary gas exchange and decreases the requirement for ventilatory support. In individual trials, the use of Exosurf Neonatal resulted in a statistically significant reduction in pneumothorax, patent ductus arteriosus, bronchopulmonary dysplasia (BPD), BPD or death at 28 days, and mortality. Similar results are seen when these large trials of Exosurf Neonatal are analyzed in conjunction with the smaller trial of dry powdered DPPC and phosphatidylglycerol (PG). The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.64, 95% CI 0.55, 0.76, typical risk difference -0.09, 95% CI -0.12,-0.06), a decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.62, 95% CI 0.54, 0.71, typical risk difference -0.12, 95% CI -0.16, -0.09), a decrease in the risk of patent ductus arteriosus (typical relative risk 0.90, 95% CI 0.84, 0.97; typical risk difference -0.06 95% CI -0.10, -0.02), a decrease in the risk of intraventricular hemorrhage (typical relative risk 0.88, 95% CI 0.77, 0.99; typical risk difference -0.04, 95% CI -0.08, -0.00), a decrease in the risk of bronchopulmonary dysplasia (typical relative risk 0.75, 95% CI 0.61, 0.92; typical risk difference -0.04, 95% CI -0.06, -0.01), a decrease in the risk of neonatal mortality (typical relative risk 0. 73, 95% CI 0.61, 0.88; typical risk difference -0.05, 95% CI -0.07, -0.02), a decrease in the risk of bronchopulmonary dysplasia or death at 28 days (typical relative risk 0.73, 95% CI 0.65, 0.83; typical risk difference -0.06, 95% CI -0.11, -0.05), a decrease in the risk of mortality prior to hospital discharge (typical relative risk 0.79, 95% CI 0.68, 0.92; typical risk difference -0.05, 95% CI -0.07, -0.02) and a decrease in the risk of mortality during the first year of life (typical relative risk 0.80, 95% CI 0.69, 0.94; typical risk difference -0.04, 95% CI -0.07, -0.01). (ABS

Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop.

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Hypothermia and other treatment options for neonatal encephalopathy

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Neurodevelopmental Outcome of Extremely Low Birth Weight Infants from the Vermont Oxford Network: 1998–2003

Background: Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. Objective: To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability. Methods: Predefined measures of living situation, health and developmental outcome were collected at 18–24 months’ corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401–1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability. Results: 6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate. Conclusion: ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.

The Vermont Oxford Network: a community of practice.

The Vermont Oxford Network is a not-for-profit organization established in the late 1980s with the goals of improving the quality and safety of medical care for newborn infants and their families through a coordinated program of research, education, and quality improvement. In this paper the authors discuss the activities and programs sponsored by the Network to achieve those goals.

Early Postnatal Dexamethasone Therapy for the Prevention of Chronic Lung Disease

OBJECTIVE To test the hypothesis that early postnatal dexamethasone will reduce the incidence of death or chronic lung disease (CLD) in ventilated extremely low birth weight premature infants. DESIGN Multicenter randomized double-blinded controlled clinical trial. SETTING A total of 42 neonatal intensive care units in the Vermont Oxford Network. PARTICIPANTS Infants weighing 501 to 1000 g were eligible for enrollment at 12 hours of age if they needed assisted ventilation, had received surfactant replacement therapy, were physiologically stable, had no obvious life-threatening congenital anomaly, and had blood cultures obtained and antibiotic therapy initiated. INTERVENTION Infants were randomly assigned to dexamethasone or saline placebo. Intravenous dexamethasone was administered for 12 days according to the following dosing schedule: 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.10 mg/kg/d for 3 days, 0.05 mg/kg/d for 3 days. Infants in either group could receive treatment with selective late postnatal steroids beginning on day 14 of life if they were on assisted ventilation with supplemental oxygen greater than 30%. OUTCOME MEASUREMENTS The primary outcome measure was CLD or death at 36 weeks postmenstrual age. RESULTS The study was stopped before completion of sample size goals because of concern about serious side effects in the early steroid treatment group. A total of 542 infants were enrolled (early treatment N = 273, control N = 269). The 2 groups had similar demographic characteristics. No differences were noted in the primary outcome of CLD or death at 36 weeks postmenstrual age (early treatment 50% vs control: 53%, relative risk: 0.93; 95% confidence interval [CI]: 0.79-1.09). Fewer infants who received early steroid treatment had a patent ductus arteriosus (relative risk: 0.78; 95% CI: 0.63-0.96), and fewer infants in the early steroid group received indomethacin therapy (relative risk: 0.74; 95% CI: 0.64-0.86) or late steroid treatment (relative risk: 0.69; 95% CI: 0.58-0.81). However, more infants who received early steroid treatment had complications associated with therapy including an increase in hyperglycemia (relative risk: 1.29; 95% CI: 1.13-1.46) and an increase in the use of insulin therapy (relative risk: 1.62; 95% CI: 1.36-1.94). A trend toward increased gastrointestinal hemorrhage (relative risk: 1.55; 95% CI: 0.92-2.61), gastrointestinal perforation (relative risk: 1.53; 95% CI: 0.89-2.61), and an increased systolic blood pressure (relative risk: 1.34; 95% CI: 0.97-1.85) was noted. In infants receiving cranial ultrasound examinations, a marginal increase in periventricular leukomalacia was noted in the early steroid treatment group (relative risk: 2.23; 95% CI: 0.99-5.04). Infants who received early steroid therapy had fewer days in supplemental oxygen but experienced poor weight gain. CONCLUSIONS A 12-day course of early postnatal steroid therapy given to extremely low birth weight infants did not decrease the risk of CLD or death at 36 weeks postmenstrual age and was associated with an increased risk of complications and poor weight gain.

Overview of Surfactant Replacement Trials

Clinical trials have evaluated the overall efficacy of surfactant therapy, as well as the relative efficacy of different surfactant preparations, the optimal timing of administration and the optimal dosage. Surfactant therapy leads to significant clinical improvement in infants at risk for, or having, respiratory distress syndrome (RDS). Clinical trials that compared the effects of synthetic or animal-derived surfactant preparations to placebo or no therapy demonstrate that surfactant therapy lead to rapid improvement in oxygenation, decreased ventilator support, decreased risk of pneumothorax, and mortality. Earlier treatment, prophylactic treatment of infants at high risk of developing RDS, and selective re-treatment leads to improved clinical outcome as well. Currently available animal-derived surfactants are superior to non-protein-containing synthetic surfactants. Ongoing evaluation will determine if important differences in animal-derived products are noted. Future trials will evaluate third-generation surfactant products and further refine what constitutes optimal use of surfactant.