Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants.

OBJECTIVE: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. STUDY DESIGN: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. RESULTS: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). CONCLUSION: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01029353.

Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. METHODS: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. DISCUSSION: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. TRIAL REGISTRATION: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022).

Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy.

OBJECTIVE: This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes. STUDY DESIGN: This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate-severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate-severe impairment defined by any of the following: intelligence quotient <70, moderate-severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy. RESULTS: Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13-0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42-9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment. CONCLUSION: RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy. KEY POINTS: · Elevation of specific cytokines and chemokines in neonates with encephalopathy has been noted along with increased risk of neurodevelopmental impairment in infancy.. · Cytokine/chemokines at <7 days were assessed among neonates in a trial of hypothermia for HIE.. · Neonates who died or were impaired at 6 to 7 years following hypoxic-ischemic encephalopathy had lower RANTES and higher MCP-1 levels than those who survived without impairment..

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial.

OBJECTIVE: To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk. STUDY DESIGN: We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000 g and receiving respiratory support at 24 hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4 weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36 weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant. RESULTS: As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P = .03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups. CONCLUSIONS: Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01203488.

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

OBJECTIVE: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. STUDY DESIGN: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. RESULTS: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. CONCLUSIONS: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00614744.

Unexpected results of a randomized quality improvement program for children with severe asthma.

Objective: To assess whether an asthma intervention program reduces treatment days outside the home among children with severe asthma receiving comprehensive care (CC) in our center.Methods: Between October 21, 2014 and September 28, 2016, children with severe asthma were randomized to receive CC alone (n = 29) or CC plus the asthma intervention program (n = 34) which involved collaboration with pharmacists and school nurses, motivational interviewing, and tracking the one-second forced expiratory volume at home. All patients were followed through March 31, 2017. Frequentist and Bayesian intent-to-treat analyses were performed.Results: The asthma intervention program doubled the telephone calls between the staff and families (753 vs 356 per 100 child years for the intervention group vs. control group; Rate Ratio [RR], 2.11 [95% confidence interval, 1.29-3.45]). Yet, we found no evidence that it reduced the composite number of days of healthcare outside home which includes: clinic visits, ED visits, and hospital admissions (1179 vs 958 per 100 child-years in the intervention group vs. control group; [RR], 1.23 [95% CI, 0.82-1.84]) or secondary outcomes which are individual components (clinic visits, ED visits, hospitalizations, PICU admissions and school absences; RR 1.15 - 2.30; p > 0.05). Bayesian analysis indicated a 67% probability that the intervention program increases total treatment days outside the home and only a 14% probability of a true decrease of >20% as originally hypothesized.Conclusion: A multi-component intervention program provided to children with severe asthma failed to reduce and may have increased days of healthcare outside home and school absenteeism.

Gallstone Pancreatitis: Admission Versus Normal Cholecystectomy-a Randomized Trial (Gallstone PANC Trial).

INTRODUCTION: Early cholecystectomy shortly after admission for mild gallstone pancreatitis has been proposed based on observational data. We hypothesized that cholecystectomy within 24 hours of admission versus after clinical resolution of gallstone pancreatitis that is predicted to be mild results in decreased length-of-stay (LOS) without an increase in complications. METHODS: Adults with predicted mild gallstone pancreatitis were randomized to cholecystectomy with cholangiogram within 24 hours of presentation (early group) versus after clinical resolution (control) based on abdominal exam and normalized laboratory values. Primary outcome was 30-day LOS including readmissions. Secondary outcomes were time to surgery, endoscopic retrograde cholangiopancreatography (ERCP) rates, and postoperative complications. Frequentist and Bayesian intention-to-treat analyses were performed. RESULTS: Baseline characteristics were similar in the early (n = 49) and control (n = 48) groups. Early group had fewer ERCPs (15% vs 29%, P = 0.038), faster time to surgery (16 h vs 43 h, P < 0.005), and shorter 30-day LOS (50 h vs 77 h, RR 0.68 95% CI 0.65 - 0.71, P < 0.005). Complication rates were 6% in early group versus 2% in controls (P = 0.613), which included recurrence/progression of pancreatitis (2 early, 1 control) and a cystic duct stump leak (early). On Bayesian analysis, early cholecystectomy has a 99% probability of reducing 30-day LOS, 93% probability of decreasing ERCP use, and 72% probability of increasing complications. CONCLUSION: In patients with predicted mild gallstone pancreatitis, cholecystectomy within 24 hours of admission reduced rate of ERCPs, time to surgery, and 30-day length-of-stay. Minor complications may be increased with early cholecystectomy. Identification of patients with predicted mild gallstone pancreatitis in whom early cholecystectomy is safe warrants further investigation.

Post-Trial Sustainability and Scalability of the Benefits of a Medical Home for High-Risk Children with Medical Complexity.

OBJECTIVE: To assess the sustainability of the benefits relative to usual care of a medical home providing comprehensive care for high-risk children with medical complexity (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrollment) after we made comprehensive care our standard practice and expanded the program. STUDY DESIGN: We conducted pre-post comparisons of the rate of children with serious illness (death, PICU admission, or >7-day hospitalization) and health-system costs observed after program expansion (March 2014-June 2015) to those during the clinical trial (March 2011-August 2013) for each of the trial's treatment groups (usual care, n = 96, and comprehensive care, n = 105; primary analyses), and among all children given comprehensive care (nPost-trial = 233, including trial usual care children who transitioned to comprehensive care post-trial and newly enrolled medically complex children, and nTrial = 105; secondary analyses). We also analyzed the findings for the trial patients as a 2-phase stepped-wedge study. RESULTS: In intent-to-treat analyses, rates of children with serious illness and costs were reduced or unchanged post-trial vs trial for the trial's usual care group (rate ratio [RR], 0.36; 95% CI, 0.20-0.64; cost ratio [CR], 0.68; 95% CI, 0.28-1.68), the trial's comprehensive care group (RR, 0.74; 95% CI, 0.39-1.41; CR, 0.67; 95% CI, 0.51-0.89), and among all children given comprehensive care (RR, 0.97; 95% CI, 0.61-1.52; CR, 0.75; 95% CI, 0.61-0.93). Conservative stepped-wedge analyses identified overall benefits with comprehensive care across both study periods (RR, 0.46; 95% CI, 0.30-0.72; CR, 0.64; 95% CI, 0.43-0.99). CONCLUSIONS: Major benefits of comprehensive care did not diminish with post-trial program expansion.

Neonatal Intensive Care Variation in Medicaid-Insured Newborns: A Population-Based Study.

OBJECTIVE: To assess the contribution of maternal and newborn characteristics to variation in neonatal intensive care use across regions and hospitals. STUDY DESIGN: This was a retrospective population-based live birth cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 2 subcohorts: very low birth weight (VLBW) singletons and late preterm singletons. Crude and risk-adjusted neonatal intensive care unit (NICU) admission rates, intensive and intermediate special care days, and imaging procedures were calculated across Neonatal Intensive Care Regions (n = 21) and hospitals (n = 100). Total Medicaid payments were calculated. RESULTS: Overall, 11.5% of live born, 91.7% of VLBW, and 37.6% of infants born late preterm were admitted to a NICU, receiving an average of 2 days, 58 days, and 5 days of special care with payments per newborn inpatient episode of $5231, $128 075, and $10 837, respectively. There was little variation across regions and hospitals in VLBW NICU admissions but marked variation for NICU admissions in late preterm newborn infants and for special care days and imaging rates in all cohorts. The variation decreased slightly after health risk adjustment. There was moderate substitution of intermediate for intensive care days across hospitals (Pearson r VLBW -0.63 P < .001; late preterm newborn -0.53 P < .001). CONCLUSIONS: Across all risk groups, the variation in NICU use was poorly explained by differences in newborn illness levels and is likely to indicate varying practice styles. Although the "right" rates are uncertain, it is unlikely that all of these use patterns represent effective and efficient care.

Between-hospital variation in treatment and outcomes in extremely preterm infants.

BACKGROUND: Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS: We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS: Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS: Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.).

Rationale and Design of a Statewide Cohort to examine efficient resource utilization for patients with Intracerebral hemorrhage (EnRICH).

BACKGROUND: Intracerebral hemorrhage is a devastating disease with no specific treatment modalities. A significant proportion of patients with intracerebral hemorrhage are transferred to large stroke treatment centers, such as Comprehensive Stroke Centers, because of perceived need for higher level of care. However, evidence of improvement in patient-centered outcomes for these patients treated at larger stroke treatment centers as compared to community hospitals is lacking. METHODS / DESIGN: "Efficient Resource Utilization for Patients with Intracerebral Hemorrhage (EnRICH)" is a prospective, multisite, state-wide, cohort study designed to assess the impact of level of care on long-term patient-centered outcomes for patients with primary / non-traumatic intracerebral hemorrhage. The study is funded by the Texas state legislature via the Lone Star Stroke Research Consortium. It is being implemented via major hub hospitals in large metropolitan cities across the state of Texas. Each hub has an extensive network of "spoke" hospitals, which are connected to the hub via traditional clinical and administrative arrangements, or by telemedicine technologies. This infrastructure provides a unique opportunity to track outcomes for intracerebral hemorrhage patients managed across a health system at various levels of care. Eligible patients are enrolled during hospitalization and are followed for functional, quality of life, cognitive, resource utilization, and dependency outcomes at 30 and 90 days post discharge. As a secondary aim, an economic analysis of the incremental cost-effectiveness of treating intracerebral hemorrhage patients at higher levels of care will be conducted. DISCUSSION: Findings from EnRICH will provide much needed evidence of the effectiveness and efficiency of regionalized care for intracerebral hemorrhage patients. Such evidence is required to inform policy and streamline clinical decision-making.

Nationwide Estimates of 30-Day Readmission in Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: Readmission within 30 days of hospital discharge for ischemic stroke is an important quality of care metric. We aimed to provide nationwide estimates of 30-day readmission in the United States, describe important reasons for readmission, and sought to explore factors associated with 30-day readmission, particularly the association with recanalization therapy. METHODS: We conducted a weighted analysis of the 2013 Nationwide Readmission Database to represent all US hospitalizations. Adult patients with acute ischemic stroke including those who received intravenous tissue-type plasminogen activator and intra-arterial therapy were identified using International Classification of Diseases-Ninth Revision codes. Readmissions were defined as any readmission during the 30-day post-index hospitalization discharge period for the eligible patient population. Proportions and 95% confidence intervals for overall 30-day readmissions and for unplanned and potentially preventable readmissions are reported. Survey design logistic regression models were fit for determining crude and adjusted odds ratios and 95% confidence interval for association between recanalization therapy and 30-day readmission. RESULTS: Of the 319 317 patients with acute ischemic stroke, 12.1% (95% confidence interval, 11.9-12.3) were readmitted. Of these, 89.6% were unplanned and 12.9% were potentially preventable. More than 20% of all readmissions were attributable to acute cerebrovascular disease. Readmitted patients were older and had a higher comorbidity burden. After controlling for age, sex, insurance status, and comorbidities, patients who underwent recanalization therapy had significantly lower odds of 30-day readmission (odds ratio, 0.82; 95% confidence interval, 0.77-0.89). CONCLUSIONS: Up to 12% of patients with ischemic stroke get readmitted within 30 days post-discharge period, and recanalization therapy is associated with 11% to 23% lower odds of 30-day readmission.

Measuring the Value of a Clinical Practice Guideline for Children With Perforated Appendicitis.

OBJECTIVE: To determine the incremental cost-effectiveness of a clinical practice guideline (CPG) compared with "usual care" for treatment of perforated appendicitis in children. Secondary objective was to compare cost analyses using hospital accounting system data versus data in the Pediatric Health Information System (PHIS). BACKGROUND: Value-based surgical care (outcomes relative to costs) is frequently touted, but outcomes and costs are rarely measured together. METHODS: During an 18-month period, 122 children with perforated appendicitis at a tertiary referral children's hospital were treated using an evidence-based CPG. Clinical outcomes and costs for the CPG cohort were compared with patients in the 30-month period before CPG implementation (n = 191 children). RESULTS: With CPG-directed care, intra-abdominal abscess rate decreased from 0.24 to 0.10 (adjusted risk ratio 0.44, 95% confidence interval [CI] 0.26-0.75). The rate of any adverse event decreased from 0.30 to 0.23 (adjusted risk ratio 0.82, 95% CI 0.58-1.17). Mean total hospital costs per patient (hospital accounting system) decreased from $16,466 to $10,528 (adjusted absolute difference-$5451, 95% CI -$7755 to -$3147), leading to estimated adjusted total savings of $665,022 during the study period. Costs obtained from the PHIS database also showed reduction with CPG-directed care (-$6669, 95% CI -$8949 to -$4389 per patient). In Bayesian cost-effectiveness analyses, likelihood that CPG was the dominant strategy was 91%. CONCLUSIONS: An evidence-based CPG increased the value of surgical care for children with perforated appendicitis by improving outcomes and lowering costs. Hospital cost accounting data and pre-existing cost data within the PHIS database provided similar results.

Outcomes of Preterm Infants following Discussions about Withdrawal or Withholding of Life Support.

OBJECTIVES: To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. STUDY DESIGN: This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. RESULTS: WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. CONCLUSIONS: Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration: clinicaltrials.gov Identifier: NCT00614744.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

IMPORTANCE: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants.

OBJECTIVE: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. STUDY DESIGN: We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. RESULTS: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. CONCLUSIONS: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

Infant Outcomes after Periviable Birth: External Validation of the Neonatal Research Network Estimator with the BEAM Trial.

Objective The objective of this study was to use data from the 20-center beneficial effect of antenatal magnesium sulfate (BEAM) trial to assess the external validity of the Neonatal Research Network (NRN) estimator, a widely employed web-based counseling tool to estimate the probability of an adverse outcome for periviable infants given intensive care. Study Design The probability of different adverse outcomes predicted from the NRN estimator was compared with observed rates at 18 to 22 months for ventilated, nonanomalous infants born at 23 to 25 weeks and assessed in BEAM as in the NRN. Results were assessed using rigorous validation methods for prediction models. Results Among 289 eligible infants, 26% died, 40% died or had profound neurodevelopmental impairment (PNDI), and 71% died or had NDI. The area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI], 0.63-0.78) for death, 0.64 (95% CI, 0.56-0.71) for death or NDI, and 0.71 (95% CI, 0.65-0.78) for death or PNDI. Observed and predicted rates were somewhat different for death or NDI but quite similar for death and for death or PNDI in different risk groups. Brier scores for accuracy were favorable (0.17-0.22) for all outcomes. Conclusion Our results provide external validation of the NRN estimator for assessing the probability of adverse outcomes at 18 to 22 months for periviable infants given intensive care.

Childhood outcomes after hypothermia for neonatal encephalopathy.

BACKGROUND: We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. METHODS: In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. RESULTS: Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80). CONCLUSIONS: The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).