Surgical Necrotizing Enterocolitis and Spontaneous Intestinal Perforation Lead to Severe Growth Failure in Infants.

OBJECTIVE: We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure. SUMMARY BACKGROUND DATA: Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited. METHODS: This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight <-2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ2 test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables. RESULTS: Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P=0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2). CONCLUSIONS: This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months.

Survey of vitamin D supplementation practices in extremely preterm infants.

BACKGROUND: Most extremely preterm (EP) infants are vitamin D deficient (serum 25-hydroxyvitamin D levels below 20 ng/mL), and optimal supplementation practices for EP infants remain unknown. Our objective is to assess current vitamin D supplementation practices in U.S. neonatal intensive care units (NICU) for EP infants to provide baseline information for the design of future clinical trials. METHODS: We conducted an online survey to study vitamin D intake and supplementation practices in U.S. NICUs caring for EP infants. Descriptive statistics compared responses by affiliation and level of care. RESULTS: We analyzed responses from 253 NICUs, representing the majority of academic and level IV centers. Nearly all centers (97%) provided enteral vitamin D supplementation during the NICU stay, with 400 IU/day as the most common dosage (77%). Over half (56%) used feeding volume to initiate supplementation, with 71% of centers starting after achieving at least 120 ml/kg/day. Additionally, 94% of NICUs reported prescribing a vitamin D supplementation at discharge. CONCLUSIONS: Most NICUs in the U.S. supplement EP infants with 400 IU/day of enteral vitamin D. Clinical trials of vitamin D supplementation comparing the most common regimen to earlier and higher doses are needed to identify adequate regimens for EP infants. IMPACT: Despite the prevalence of vitamin D deficiency in extremely preterm (EP) infants at birth, optimal levels and supplementation strategies remain debated. Recent studies have suggested benefits of early high-dose vitamin D supplementation (800 IU/day) for reducing complications like bronchopulmonary dysplasia, infections, and disability. There is US center variation in timing and dose of vitamin D supplementation, being the most common regimen 400 IU/d started after established feedings (≥120 ml/kg/day). These findings inform and highlight the need for clinical trials of usual vs. early, higher-dose vitamin D supplementation to advance clinical outcomes and define desirable blood levels of EP infants.

Randomized Controlled Trial of Enteral Vitamin D Supplementation (ViDES) in Infants <28 Weeks Gestational Age or <1000 Grams Birth Weight: Study Protocol.

Background: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. Methods: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 grams birth weight at a large academic center in the United States.Infants are stratified by birth weight and randomized within 96 hours after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth.We hypothesize that the higher and early vitamin D dose (800 IU/d with early feeding) compared to placebo plus routine dose (400 IU/d with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at one month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes) and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes.The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. Discussion: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterminfants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. Trial registration: ClinicalTrials.gov registered on July 14, 2022 (NCT05459298).

Randomized controlled trial of enteral vitamin D supplementation (ViDES) in infants <28 weeks gestational age or <1000 g birth weight: study protocol.

BACKGROUND: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. METHODS: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 g birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 h after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/day with early feeding) compared to placebo plus routine dose (400 IU/day with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at 1 month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes), and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. DISCUSSION: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterm infants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. TRIAL REGISTRATION: ClinicalTrials.gov NCT05459298. Registered on July 14, 2022.

Hospital-Level NICU Capacity, Utilization, and 30-Day Outcomes in Texas.

Importance: Risk-adjusted neonatal intensive care unit (NICU) utilization and outcomes vary markedly across regions and hospitals. The causes of this variation are poorly understood. Objective: To assess the association of hospital-level NICU bed capacity with utilization and outcomes in newborn cohorts with differing levels of health risk. Design, Setting, and Participants: This population-based retrospective cohort study included all Medicaid-insured live births in Texas from 2010 to 2014 using linked vital records and maternal and newborn claims data. Participants were Medicaid-insured singleton live births (LBs) with birth weights of at least 400 g and gestational ages between 22 and 44 weeks. Newborns were grouped into 3 cohorts: very low birth weight (VLBW; <1500 g), late preterm (LPT; 34-36 weeks' gestation), and nonpreterm newborns (NPT; ≥37 weeks' gestation). Data analysis was conducted from January 2022 to October 2023. Exposure: Hospital NICU capacity measured as reported NICU beds/100 LBs, adjusted (ie, allocated) for transfers. Main Outcomes and Measures: NICU admissions and special care days; inpatient mortality and 30-day postdischarge adverse events (ie, mortality, emergency department visit, admission, observation stay). Results: The overall cohort of 874 280 single LBs included 9938 VLBW (5054 [50.9%] female; mean [SD] birth weight, 1028.9 [289.6] g; mean [SD] gestational age, 27.6 [2.6] wk), 63 160 LPT (33 684 [53.3%] female; mean [SD] birth weight, 2664.0 [409.4] g; mean [SD] gestational age, 35.4 [0.8] wk), and 801 182 NPT (407 977 [50.9%] female; mean [SD] birth weight, 3318.7 [383.4] g; mean [SD] gestational age, 38.9 [1.0] wk) LBs. Median (IQR) NICU capacity was 0.84 (0.57-1.30) allocated beds/100 LB/year. For VLBW newborns, NICU capacity was not associated with the risk of NICU admission or number of special care days. For LPT newborns, birth in hospitals with the highest compared with the lowest category of capacity was associated with a 17% higher risk of NICU admission (adjusted risk ratio [aRR], 1.17; 95% CI, 1.01-1.33). For NPT newborns, risk of NICU admission was 55% higher (aRR, 1.55; 95% CI, 1.22-1.97) in the highest- vs the lowest-capacity hospitals. The number of special care days for LPT and NPT newborns was 21% (aRR, 1.21; 95% CI,1.08-1.36) and 37% (aRR, 1.37; 95% CI, 1.08-1.74) higher in the highest vs lowest capacity hospitals, respectively. Among LPT and NPT newborns, NICU capacity was associated with higher inpatient mortality and 30-day postdischarge adverse events. Conclusions and Relevance: In this cohort study of Medicaid-insured newborns in Texas, greater hospital NICU bed supply was associated with increased NICU utilization in newborns born LPT and NPT. Higher capacity was not associated with lower risk of adverse events. These findings raise important questions about how the NICU is used for newborns with lower risk.

Evaluation of negative binomial and zero-inflated negative binomial models for the analysis of zero-inflated count data: application to the telemedicine for children with medical complexity trial.

BACKGROUND: Two characteristics of commonly used outcomes in medical research are zero inflation and non-negative integers; examples include the number of hospital admissions or emergency department visits, where the majority of patients will have zero counts. Zero-inflated regression models were devised to analyze this type of data. However, the performance of zero-inflated regression models or the properties of data best suited for these analyses have not been thoroughly investigated. METHODS: We conducted a simulation study to evaluate the performance of two generalized linear models, negative binomial and zero-inflated negative binomial, for analyzing zero-inflated count data. Simulation scenarios assumed a randomized controlled trial design and varied the true underlying distribution, sample size, and rate of zero inflation. We compared the models in terms of bias, mean squared error, and coverage. Additionally, we used logistic regression to determine which data properties are most important for predicting the best-fitting model. RESULTS: We first found that, regardless of the rate of zero inflation, there was little difference between the conventional negative binomial and its zero-inflated counterpart in terms of bias of the marginal treatment group coefficient. Second, even when the outcome was simulated from a zero-inflated distribution, a negative binomial model was favored above its ZI counterpart in terms of the Akaike Information Criterion. Third, the mean and skewness of the non-zero part of the data were stronger predictors of model preference than the percentage of zero counts. These results were not affected by the sample size, which ranged from 60 to 800. CONCLUSIONS: We recommend that the rate of zero inflation and overdispersion in the outcome should not be the sole and main justification for choosing zero-inflated regression models. Investigators should also consider other data characteristics when choosing a model for count data. In addition, if the performance of the NB and ZINB regression models is reasonably comparable even with ZI outcomes, we advocate the use of the NB regression model due to its clear and straightforward interpretation of the results.

Automated Large Vessel Occlusion Detection Software and Thrombectomy Treatment Times: A Cluster Randomized Clinical Trial.

Importance: The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical. Objective: To determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows. Design, Setting, and Participants: This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion criteria included patients presenting as transfers from an outside hospital (n = 158), in-hospital stroke (n = 39), and patients treated with EVT through randomization in a large core clinical trial (n = 3). Intervention: Artificial intelligence (AI)-enabled automated LVO detection from CT angiogram coupled with secure messaging was activated at the 4 CSCs in a random-stepped fashion. Once activated, clinicians and radiologists received real-time alerts to their mobile phones notifying them of possible LVO within minutes of CT imaging completion. Main Outcomes and Measures: Primary outcome was the effect of AI-enabled LVO detection on door-to-groin (DTG) time and was measured using a mixed-effects linear regression model, which included a random effect for cluster (CSC) and a fixed effect for exposure status (pre-AI vs post-AI). Secondary outcomes included time from hospital arrival to intravenous tissue plasminogen activator (IV tPA) bolus in eligible patients, time from initiation of CT scan to start of EVT, and hospital length of stay. In exploratory analysis, the study team evaluated the impact of AI implementation on 90-day modified Rankin Scale disability outcomes. Results: Among 243 patients who met inclusion criteria, 140 were treated during the unexposed period and 103 during the exposed period. Median age for the complete cohort was 70 (IQR, 58-79) years and 122 were female (50%). Median National Institutes of Health Stroke Scale score at presentation was 17 (IQR, 11-22) and the median DTG preexposure was 100 (IQR, 81-116) minutes. In mixed-effects linear regression, implementation of the AI algorithm was associated with a reduction in DTG time by 11.2 minutes (95% CI, -18.22 to -4.2). Time from CT scan initiation to EVT start fell by 9.8 minutes (95% CI, -16.9 to -2.6). There were no differences in IV tPA treatment times nor hospital length of stay. In multivariable logistic regression adjusted for age, National Institutes of Health Stroke scale score, and the Alberta Stroke Program Early CT Score, there was no difference in likelihood of functional independence (modified Rankin Scale score, 0-2; odds ratio, 1.3; 95% CI, 0.42-4.0). Conclusions and Relevance: Automated LVO detection coupled with secure mobile phone application-based communication improved in-hospital acute ischemic stroke workflows. Software implementation was associated with clinically meaningful reductions in EVT treatment times. Trial Registration: ClinicalTrials.gov Identifier: NCT05838456.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

N-of-1 trials: The epitome of personalized medicine?

Observational studies are notoriously susceptible to bias, and parallel-group randomized trials are important to identify the best overall treatment for eligible patients. Yet, such trials can be expected to be a misleading indicator of the best treatment for some subgroups or individual patients. In selected circumstances, patients can be treated in n-of-1 trials to address the inherent heterogeneity of treatment response in clinical populations. Such trials help to accomplish the ultimate goal of all biomedical research, to optimize the care of individual patients.

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).

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.

N-of-1 Trials vs. Usual Care in Children With Hypertension: A Pilot Randomized Clinical Trial.

BACKGROUND: Blood pressure (BP) is often inadequately controlled in children treated for hypertension, and personalized (n-of-1) trials show promise for tailoring treatment choices. We assessed whether patients whose treatment choices are informed by an n-of-1 trial have improved BP control compared to usual care. METHODS: A randomized clinical trial was conducted in a pediatric hypertension clinic in Houston from April 2018 to September 2020. Hypertensive adolescents and young adults 10-22 years old were randomized 1:1 to a strategy of n-of-1 trial using ambulatory BP monitoring to inform treatment choice or usual care, with treatment selected by physician preference. The primary outcome was the proportion of patients with ambulatory BP control at 6 months in a Bayesian analysis. RESULTS: Among 49 participants (23 randomized to n-of-1 trials and 26 to usual care), mean age was 15.6 years. Using skeptical priors, we found a 69% probability that n-of-1 trials increased BP control at 6 months (Bayesian odds ratio (OR) 1.24 (95% credible interval (CrI) 0.51, 2.97), and 74% probability using neutral informed priors (OR 1.45 (95% CrI 0.48, 4.53)). Systolic BP was reduced in both groups, with a 93% probability of greater reduction in the n-of-1 trial group (mean difference between groups = -3.6 mm Hg (95% CrI -8.3, 1.28). There was no significant difference in side effect experience or caregiver satisfaction. CONCLUSIONS: Among hypertensive adolescents and young adults, n-of-1 trials with ambulatory BP monitoring likely increased the probability of BP control. A large trial is needed to assess their use in clinical practice. CLINICALTRIALS.GOV: NCT03461003. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; NCT03461003.

Informed Consent for Placebo-Controlled Trials: Do Ethics and Science Conflict?

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled trials, and we explore the fundamental ethical and scientific complexities involved with each.

Outcome prediction in newborn infants: Past, present, and future.

The perinatal and neonatal periods are the periods of considerable organ development and maturation. Perinatal and neonatal illnesses can result in mortality and morbidities that burden families and the healthcare system. Outcome prediction is essential for informing perinatal and intensive care management, prognosis, and post-discharge interventions. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) research databases include hospital and neurodevelopment follow-up outcomes of infants with various underlying diseases and conditions receiving intensive care, providing a unique opportunity to assess outcome risk prediction. The NRN has developed outcome risk prediction tools for use in infants with various diseases and conditions that allow data-driven, transparent discussions to inform family-focused communications and clinical management. This review presents the published neonatal outcome risk prediction research from the NRN, their present clinical utility, and possible future directions for advanced individualized risk prediction.

Special considerations in randomized trials investigating neonatal surgical treatments.

Randomized controlled trials (RCTs) are challenging, but are the studies most likely to change practice and benefit patients. RCTs investigating neonatal surgical therapies are rare. The Necrotizing Enterocolitis Surgery Trial (NEST) was the first surgical RCT conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and multiple lessons were learned. NEST was conducted over a 7.25-year enrollment period and the primary outcome was death or neurodevelopmental impairment (NDI) at 18-22 months corrected age. Surgical investigators designing clinical trials involving neonatal surgical treatments have many considerations to include, including how to study eligible but non-randomized patients, heterogeneity of treatment effect, use of frequentist and Bayesian analyses, assessment of generalizability, and anticipating criticisms during peer review. Surgeons are encouraged to embrace these challenges and seek innovative methods to acquire evidence that will be used to improve patient outcomes.

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..

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study.

Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, Setting, and Participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main Outcomes and Measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and Relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial Registration: ClinicalTrials.gov Identifier: NCT01192776.

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.

Damage control laparotomy in trauma: a pilot randomized controlled trial. The DCL trial.

BACKGROUND: Although widely used in treating severe abdominal trauma, damage control laparotomy (DCL) has not been assessed in any randomized controlled trial. We conducted a pilot trial among patients for whom our surgeons had equipoise and hypothesized that definitive laparotomy (DEF) would reduce major abdominal complications (MAC) or death within 30 days compared with DCL. METHODS: Eligible patients undergoing emergency laparotomy were randomized during surgery to DCL or DEF from July 2016 to May 2019. The primary outcome was MAC or death within 30 days. Prespecified frequentist and Bayesian analyses were performed. RESULTS: Of 489 eligible patients, 39 patients were randomized (DCL 18, DEF 21) and included. Groups were similar in demographics and mechanism of injury. The DEF group had a higher Injury Severity Score (DEF median 34 (IQR 20, 43) vs DCL 29 (IQR 22, 41)) and received more prerandomization blood products (DEF median red blood cells 8 units (IQR 6, 11) vs DCL 6 units (IQR 2, 11)). In unadjusted analyses, the DEF group had more MAC or death within 30 days (1.71, 95% CI 0.81 to 3.63, p=0.159) due to more deaths within 30 days (DEF 33% vs DCL 0%, p=0.010). Adjustment for Injury Severity Score and prerandomization blood products reduced the risk ratio for MAC or death within 30 days to 1.54 (95% CI 0.71 to 3.32, p=0.274). The Bayesian probability that DEF increased MAC or death within 30 days was 85% in unadjusted analyses and 66% in adjusted analyses. CONCLUSION: The findings of our single center pilot trial were inconclusive. Outcomes were not worse with DCL and, in fact, may have been better. A randomized clinical trial of DCL is feasible and a larger, multicenter trial is needed to compare DCL and DEF for patients with severe abdominal trauma. LEVEL OF EVIDENCE: Level II.