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Objective: More than half of all infants with neonatal hypoxic ischemic encephalopathy (HIE) are graded as mild and do not meet current criteria for therapeutic hypothermia. These infants are often not enrolled in follow-up, and hence our knowledge of their long-term outcome is sparse. We wished to compare 5-year outcomes in a group of infants with mild, moderate, and severe HIE, graded with both early EEG and clinical assessment, none of whom were treated with therapeutic hypothermia., Methods: Term infants with HIE and a healthy comparison group were recruited at birth. Both groups had early continuous EEG recordings. Cognitive and motor outcome was assessed at 5 years., Results: Outcome was available in 53 infants with HIE and 30 infants in the comparison group at 5 years. Infants with mild HIE at birth (n = 22) had significantly lower full-scale IQ, verbal IQ, and performance IQ than comparison infants (n = 30) at 5 years (P = .001, .001, and 0.004, respectively). No difference in cognitive measures was seen between infants with mild and moderate grades HIE. Intact survival at 5 years varied across EEG grade HIE at 6 hours after birth; 75% in mild, 46% in moderate, 43% in major abnormalities, and 0% with inactive EEGs, compared with 97% in the comparison group., Conclusions: Survivors of mild HIE, graded clinically or by early EEG, have higher rates of disability than their peers and have cognitive outcomes similar to that of children with moderate encephalopathy in an uncooled HIE cohort., (Copyright © 2016 by the American Academy of Pediatrics.)

Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants. Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.

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.

The death or near death of a presumably healthy newborn in the delivery room is uncommon. We report here 6 cases of apparent life-threatening events (ALTEs) in the delivery room during the first 2 hours of life. In each case, the incident occurred in a healthy infant who was in a prone position on his or her mother's abdomen during early skin-to-skin contact. In most cases, the mother was primiparous, and in all cases the mother and infant were not observed during the initiation of skin-to-skin contact and breastfeeding. There are many benefits of early skin-to-skin contact and breastfeeding in the delivery room. However, in view of the risk of a rare but significant ALTE, we suggest that surveillance of newborns is needed. Although many ALTEs are apparently caused by obstruction, we suggest that a standardized investigational workup be performed after an ALTE.

Objective: Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods., Methods: In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37°C (range: 36.5-37.5°C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5°C (range: 33-34°C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability., Results: A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P=.001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09-0.54]; number needed to treat: 4 [95% CI: 3-9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n=77; P=.005; odds ratio: 0.17 [95% CI: 0.05-0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group., Conclusion: Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group.

Objective: The objective of this study was to determine whether Apgar scores at 10 minutes are associated with death or disability in early childhood after perinatal hypoxic-ischemic encephalopathy., Methods: This was a secondary analysis of infants who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hypothermia trial. Infants who were born at >or=36 weeks' gestation and had clinical and/or biochemical abnormalities at birth and encephalopathy at <6 hours were studied. Logistic regression and classification and regression-tree analysis were used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome, adjusting for covariates. Death or disability (moderate or severe) at 18 to 22 months of age was the measured outcome., Results: Twenty of 208 infants were excluded (missing data). More than 90% of the infants had Apgar scores of 0 to 2 at 1 minute, and Apgar scores at 5 and 10 minutes shifted to progressively higher values; at 10 minutes, 27% of infants had Apgar scores of 0 to 2. After adjustment, each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability. Death or disability occurred in 76%, 82%, and 80% of infants with 10-minute Apgar scores of 0, 1, and 2, respectively. Classification and regression-tree analysis indicated that Apgar scores at 10 minutes were discriminators of outcome., Conclusions: Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with hypoxic-ischemic encephalopathy. Death or moderate/severe disability is common but not uniform with Apgar scores of <3; caution is needed before adopting a specific time interval to guide duration of resuscitation.

Background: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial., Objective: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age., Design/methods: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups., Results: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories., Conclusions: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

Objectives: Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants., Patients and Methods: Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33 degrees C to 34 degrees C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth., Results: Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137-767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88-327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58-1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65-1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 microg/kg per h., Conclusions: Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 microg/kg per h.

Objective: The goals were to identify predictor variables and to develop scoring systems and classification trees to predict death/disability or death in infants with hypoxic-ischemic encephalopathy., Methods: Secondary analysis of data from the multicenter, randomized, controlled, National Institute of Child Health and Human Development Neonatal Research Network trial of hypothermia in hypoxic-ischemic encephalopathy was performed. Data for 205 neonates diagnosed as having hypoxic-ischemic encephalopathy were studied. Logistic regression analysis was performed by using clinical and laboratory variables available within 6 hours of birth, with death or moderate/severe disability at 18 to 22 months or death as the outcomes. By using the identified variables and odds ratios, scoring systems to predict death/disability or death were developed, weighting each predictor in proportion to its odds ratio. In addition, classification and regression tree analysis was performed, with recursive partitioning and automatic selection of optimal cutoff points for variables. Correct classification rates for the scoring systems, classification and regression tree models, and early neurologic examination were compared., Results: Correct classification rates were 78% for death/disability and 71% for death with the scoring systems, 80% and 77%, respectively, with the classification and regression tree models, and 67% and 73% with severe encephalopathy in early neurologic examination. Correct classification rates were similar in the hypothermia and control groups., Conclusions: Among neonates diagnosed as having hypoxic-ischemic encephalopathy, the classification and regression tree model, but not the scoring system, was superior to early neurologic examination in predicting death/disability. The 3 models were comparable in predicting death. Only a few components of the early neurologic examination were associated with poor outcomes. These scoring systems and classification trees, if validated, may help in assessments of prognosis and may prove useful for risk-stratification of infants with hypoxic-ischemic encephalopathy for clinical trials.

Objective: Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) is a difficult task. Magnetic resonance imaging, particularly diffusion imaging, holds promise in this regard as it is more sensitive to brain injury than any other available imaging modality. Previous studies have suggested that abnormal signal intensity in the posterior limb of the internal capsule (PLIC), detectable on inversion-recovery T1-weighted imaging, is a strong predictor of outcome. The aim of this study was to assess the relationship between apparent diffusion coefficient (ADC) values from the PLIC, measured by diffusion imaging, and neuromotor outcome in term infants with HIE., Methods: Twenty-eight term infants with a clinical diagnosis of HIE underwent magnetic resonance imaging as soon as practicable after birth (mean age: 5.6 days), including diffusion-weighted imaging, from which ADC values in the PLIC were measured. Motor outcome was assessed in 12 of 16 survivors., Results: The ADC value in the PLIC was significantly associated with survival in term infants with HIE. For survivors, the mean ADC value in the PLIC was 0.89 +/- 0.17 microm2/ms, whereas the mean ADC value for nonsurvivors was 0.75 +/- 0.17 microm2/ms (t = 2.25). Among survivors, the ADC value in the PLIC was also associated with neuromotor outcome (F = 5.60)., Conclusion: The ADC value in the PLIC is an indicator of ischemic injury and may be of use as an objective prognostic marker for infants with HIE.

Objective: To assess the safety of selective head cooling in birth-asphyxiated term newborn infants while maintaining the rectal temperature at 35.0 degrees C or 34.5 degrees C., Methods: Twenty-six term infants with Apgar