Dongli Song

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy.

BACKGROUND Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial. METHODS We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score. RESULTS Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome. CONCLUSIONS This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy.

Optimizing Therapeutic Hypothermia for Neonatal Encephalopathy

OBJECTIVE: Therapeutic hypothermia (TH) for neonatal encephalopathy is becoming widely available in clinical practice. The goal of this collaborative was to create and implement an evidence-based standard-of-care approach to neonatal encephalopathy, deliver consistent care, and optimize outcomes. METHODS: The quality improvement process identified and used the Model for Improvement as a framework for improvement efforts. This was a Vermont Oxford Network Collaborative focused on optimizing TH in the treatment of neonatal encephalopathy. By using an evidence-based approach, Potentially Better Practices were developed by the topic expert, modified by the collaborative, and implemented at each hospital. These included the following: timely identification of at-risk infants, coordination with referring hospitals to ensure TH was available within 6 hours after birth, staff education for both local and referring hospitals, nonsedated MRI, incorporating amplitude-integrated EEG into a TH protocol, and ensuring standard neurodevelopmental follow-up of infants. Each center used these practices to develop a matrix for implementation. RESULTS: Local self-assessments directed the implementation and adaptation of the Potentially Better Practices at each center. Resources, based on common identified barriers, were developed and shared among the group. CONCLUSIONS: The implementation of a TH program to improve the consistency of care for patients in NICUs is feasible using standard-quality improvement methodology. The successful introduction of new interventions such as TH to the NICU culture requires a collaborative multidisciplinary team, use of a systematic quality improvement process, and perseverance.

Oxygen Saturation Nomogram in Newborns Screened for Critical Congenital Heart Disease

OBJECTIVE: To establish simultaneous pre- and postductal oxygen saturation nomograms in asymptomatic newborns when screening for critical congenital heart disease (CCHD) at ∼24 hours after birth. METHODS: Asymptomatic term and late preterm newborns admitted to the newborn nursery were screened with simultaneous pre- and postductal oxygen saturation measurements at ∼24 hours after birth. The screening program was implemented in a stepwise fashion in 3 different affiliated institutions. Data were collected prospectively from July 2009 to March 2012 in all 3 centers. RESULTS: We screened 13 714 healthy newborns at a median age of 25 hours. The mean preductal saturation was 98.29% (95% confidence interval [CI]: 98.27–98.31), median 98%, and mean postductal saturation was 98.57% (95% CI: 98.55–98.60), median 99%. The mean difference between the pre- and postductal saturation was −0.29% (95% CI: −0.31 to −0.27) with P < .00005. Its clinical relevance to CCHD screening remains to be determined. The postductal saturation was equal to preductal saturation in 38% and greater than preductal saturation in 40% of the screens. CONCLUSIONS: We have established simultaneous pre- and postductal oxygen saturation nomograms at ∼24 hours after birth based on >13 000 asymptomatic newborns. Such nomograms are important to optimize screening thresholds and methodology for detecting CCHD.

Duration of Cord Clamping and Neonatal Outcomes in Very Preterm Infants

Background Delayed cord clamping (DCC, ≥30s) increases blood volume in newborns and is associated with fewer blood transfusions and short-term neonatal complications. The optimal timing of cord clamping for very preterm infants should maximize placental transfusion without interfering with stabilization and resuscitation. Aim We compared the effect of different durations of DCC, 30-45s vs. 60-75s, on delivery room (DR) and neonatal outcomes in preterm infants <32 weeks gestational age (GA). Methods This is a single-center prospective observational study. Data were collected prospectively from eligible infants from two groups: 30-45s DCC group (January 2008 to February 2011, n = 187) and 60-75s DCC group (March 2011 to April 2014, n = 166). Results The 60-75s DCC group compared to the 30-45s DCC group had higher hematocrits at <2 hours (49.2% vs. 47.4%, p = 0.02). In infants <28 weeks GA, the 12–36 hours hematocrit was higher in the 60-75s DCC group compared to the 30-45s DCC group (47.9% vs. 42.1%, p = 0.002). The 60-75s DCC group had reductions in DR intubation (11% vs. 22%, p = 0.004), hypothermia on admission (1% vs. 5%, p = 0.01), surfactant therapy (13% vs. 28%, p = 0.001), intubation in the first 24 hours (20% vs. 34%, p = 0.004), any intubation (27% vs. 40%, p = 0.007), and any red blood cell transfusion (20% vs. 33%, p = 0.008) during the hospitalization compared to the 30-45s DCC group. These reductions remained significant after adjusting for GA, gender and >48 hours of antenatal steroid exposure. There was no difference between the two groups in neonatal death, intraventricular hemorrhage, chronic lung disease, late onset sepsis, necrotizing enterocolitis and severe retinopathy of prematurity. Conclusion In this study cohort increasing DCC duration from 30-45s to 60-75s is associated with decreased hypothermia on admission, neonatal respiratory interventions and red blood cell transfusions without increase in neonatal mortality and morbidities.

Perfusion index in healthy newborns during critical congenital heart disease screening at 24 hours: retrospective observational study from the USA

Objective To describe the distribution of perfusion index (PI) in asymptomatic newborns at 24 hours of life when screening for critical congenital heart disease (CCHD) using an automated data selection method. Design This is a retrospective observational study. Setting Newborn nursery in a California public hospital with ~3500 deliveries annually. Methods We developed an automated programme to select the PI values from CCHD screens. Included were term and late preterm infants who were screened for CCHD from November 2013 to January 2014 and from May 2015 to July 2015. PI measurements were downloaded every 2 s from the pulse oximeter and median PI were calculated for each oxygen saturation screen in our cohort. Results We included data from 2768 oxygen saturation screens. Each screen had a median of 29 data points (IQR 17 to 49). The median PI in our study cohort was 1.8 (95% CI 1.8 to 1.9) with IQR 1.2 to 2.7. The median preductal PI was significantly higher than the median postductal (1.9 vs 1.8, p=0.03) although this difference may not be clinically significant. Conclusion Using an automated data selection method, the median PI in asymptomatic newborns at 24 hours of life is 1.8 with a narrow IQR of 1.2 to 2.7. This automated data selection method may improve accuracy and precision compared with manual data collection method. Further studies are needed to establish external validity of this automated data selection method and its clinical application for CCHD screening.

Homecare and Healthcare Utilization Errors Post–Neonatal Intensive Care Unit Discharge

Background: High-risk infants transitioning from the neonatal intensive care unit (NICU) to home represent a vulnerable population, given their complex care requirements. Little is known about errors during this period. Purpose: Identify and describe homecare and healthcare utilization errors in high-risk infants following NICU discharge. Methods: This was a prospective observational cohort study of homecare (feeding, medication, and equipment) and healthcare utilization (appointment) errors in infants discharged from a regional NICU between 2011 and 2015. Chi-square test and Wilcoxon rank-sum test were used to compare infant and maternal demographics between infants with and without errors. Results: A total of 363 errors were identified in 241 infants during 635 home visits. The median number of visits was 2. No significance was found between infant and maternal demographics in those with or without errors. Implications of Practice: High-risk infants have complex care needs and can benefit from regular follow-up services. Home visits provide an opportunity to identify, intervene, and resolve homecare and healthcare utilization errors. Implications of Research: Further research is needed to evaluate the prevalence and cause of homecare errors in high-risk infants and how healthcare resources and infant health outcomes are affected by those errors. Preventive measures and mitigating interventions that best address homecare errors require further development and subsequent description.

Microdeletion of chromosome 15q24.3-25.2 and orofacial clefting.

We report a case of de novo microdeletion of 15q24.3-q25.2 in an infant with orofacial cleft and general hypotonia and suggest that this may be a critical region in orofacial development. In addition, this case highlights the usefulness of comparative genomic microarray in the evaluation of children with congenital anomalies with such defects.