Robert DiGeronimo

Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group

Objective:To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes.Study Design:This is a descriptive study evaluating the data collected prospectively in the Children’s Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children’s hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks’ gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010–July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge.Result:High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%.Conclusion:Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.

High-frequency nasal ventilation for 21 d maintains gas exchange with lower respiratory pressures and promotes alveolarization in preterm lambs

Background:Short-term high-frequency nasal ventilation (HFNV) of preterm neonates provides acceptable gas exchange compared to endotracheal intubation and intermittent mandatory ventilation (IMV). Whether long-term HFNV will provide acceptable gas exchange is unknown. We hypothesized that HFNV for up to 21 d would lead to acceptable gas exchange at lower inspired oxygen (O2) levels and airway pressures compared to intubation and IMV.Methods:Preterm lambs were exposed to antenatal steroids and treated with perinatal surfactant and postnatal caffeine. Lambs were intubated and resuscitated by IMV. At ~3u2009h of age, half of the lambs were switched to noninvasive HFNV. Support was for 3 or 21 d. By design, Pao2 and Paco2 were not different between groups.Results:At 3 d (n = 5) and 21 d (n = 4) of HFNV, fractional inspired O2 (FiO2), peak inspiratory pressure (PIP), mean airway, intratracheal, and positive end-expiratory pressures, oxygenation index, and alveolar–arterial gradient were significantly lower than matched periods of intubation and IMV. Pao2/FiO2 ratio was significantly higher at 3 and 21 d of HFNV compared to matched intubation and IMV. HFNV led to better alveolarization at 3 and 21 d.Conclusion:Long-term HFNV provides acceptable gas exchange at lower inspired O2 levels and respiratory pressures compared to intubation and IMV.

A Family-Based Paradigm to Identify Candidate Chromosomal Regions for Isolated Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non‐syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family‐based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high‐density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2–q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family‐based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non‐coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.

Short-term outcomes for preterm infants with surgical necrotizing enterocolitis.

Objective:To characterize the population and short-term outcomes in preterm infants with surgical necrotizing enterocolitis (NEC).Study Design:Preterm infants with surgical NEC were identified from 27 hospitals over 3 years using the Children’s Hospitals Neonatal Database; infants with gastroschisis, volvulus, major congenital heart disease or surgical NEC that resolved prior to referral were excluded. Patient characteristics and pre-discharge morbidities were stratified by gestational age (<28 vs 280/7 to 366/7 weeks’ gestation).Result:Of the 753 eligible infants, 60% were born at <28 weeks’ gestation. The median age at referral was 14 days; only 2 infants were inborn. Male gender (61%) was overrepresented, whereas antenatal steroid exposure was low (46%). Although only 11% had NEC totalis, hospital mortality (<28 weeks’ gestation: 41%; 280/7 to 366/7 weeks’ gestation: 32%, P=0.02), short bowel syndrome (SBS)/intestinal failure (IF) (20% vs 26%, P=0.06) and the composite of mortality or SBS/IF (50% vs 49%, P=0.7) were prevalent. Also, white matter injury (11.7% vs 6.6%, P=0.02) and grade 3 to 4 intraventricular hemorrhages (23% vs 2.7%, P<0.01) were commonly diagnosed. After referral, the median length of hospitalization was longer for survivors (106 days; interquartile range (IQR) 79, 152) relative to non-survivors (2 days; IQR 1,17; P<0.001). These survivors were prescribed parenteral nutrition infrequently after hospital discharge (<28 weeks’: 5.2%; 280/7 to 366/7 weeks’: 9.9%, P=0.048).Conclusion:After referral for surgical NEC, the short-term outcomes are grave, particularly for infants born <28 weeks gestation. Although analyses to predict outcomes are urgently needed, these data suggest that affected infants are at a high risk for lengthy hospitalizations and adverse medical and neuro-developmental abnormalities.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial

Background:Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t1/2). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia.Study design:Thirty infants (n = 10/arm) ≥36u2009wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 μg/kg), or high dose (10 μg/kg) given intravenously within 12u2009h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics.Results:Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 μg/kg, t1/2 was 24 and 32u2009h, and the area under the curve (AUCinf) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t1/2 was 26 and 35u2009h, and AUCinf was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01).Conclusion:Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Potential and Actual Neonatal Organ and Tissue Donation After Circulatory Determination of Death

IMPORTANCEnThe need for transplants continues to exceed organ and tissue donor availability. Although recent surgical advances have resulted in successful transplants using very small pediatric donors, including neonates, the actual practice of neonatal organ donation after circulatory determination of death (DCDD) remains uncommon.nnnOBJECTIVEnTo describe the percentage of neonates potentially eligible for DCDD, including those who underwent successful donation, and reasons for ineligibility in those who did not in a single neonatal intensive care unit (NICU).nnnDESIGN, SETTING, AND PARTICIPANTSnWe obtained data from the Childrens Hospital Neonatal Database and Intermountain Donor Services (IDS) organ procurement records. The 136 deaths that occurred in the NICU of the Primary Childrens Hospital, Salt Lake City, Utah, from January 1, 2010, through May 7, 2013, were reviewed retrospectively from January 12 through July 1, 2014, to determine potential eligibility for DCDD as determined by IDS minimum eligibility criteria (requirement of life-sustaining interventions and weight >2 kg). For patients who did not undergo DCDD, we reviewed records to determine the reasons for ineligibility.nnnMAIN OUTCOMES AND MEASURESnPotential eligibility for DCDD among neonates who died in the study NICU.nnnRESULTSnOf 136 deaths in the NICU, 60 (44.1%) met criteria for DCDD; however, fewer than 10% were referred appropriately to the regional organ procurement organization for evaluation. Forty-five neonates (33.1%) ultimately died within 90 minutes of withdrawal of life-sustaining interventions and thus would have been eligible for organ donation based on warm ischemic time. The most common causes of death among the 60 potentially eligible neonatal donors were neonatal encephalopathy (nu2009=u200917) and multiple congenital anomalies (nu2009=u200914). Nonreferral or late referral by the medical team was the most frequent reason for donor ineligibility, including 49 neonates (36.0%). Overall, only 4 neonates (2.9%) underwent successful DCDD.nnnCONCLUSIONS AND RELEVANCEnAlthough almost half of all neonatal deaths identified met minimum IDS criteria, most of these patients were not referred or were referred too late for evaluation. Although small size remains the primary reason for exclusion from DCDD, improved education with regard to criteria and the importance of timely referral by neonatologists and other members of the NICU team would likely result in a significant increase of future donations.

Intercenter Cost Variation for Perinatal Hypoxic-Ischemic Encephalopathy in the Era of Therapeutic Hypothermia.

OBJECTIVEnTo quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across childrens hospitals.nnnSTUDY DESIGNnProspectively collected data from the Childrens Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes.nnnRESULTSnOf the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was

Nutritional Practices and Growth in Premature Infants After Surgical Necrotizing Enterocolitis

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Mechanical stretch induces lung α-epithelial Na + channel expression

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Do normal head ultrasounds need repeating in infants less than 30 weeks gestation

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