Therapeutic Hypothermia For Hypoxic-ischemic Encephalopathy Research Articles

Practice Variations for Therapeutic Hypothermia in Neonates with Hypoxic-ischemic Encephalopathy: An International Survey

To evaluate variations in management of therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE) among international clinical sites and to identify areas for harmonization. An electronic survey was sent to Children's Hospitals Neonatal Consortium site sponsors, Canadian Neonatal Network site investigators, members of the Newborn Brain Society, and American Academy of Pediatrics Neonatology chiefs. One hundred five sites responded, with most from high-income regions (n=95). Groupings were adapted from the United Nations regional groups: US (n=52 sites); Canada (n=20); Western Europe and other states excluding Canada and US Group (WEOG, n=18); and non-WEOG (central and eastern Europe, Asia, Africa, Latin America, and Caribbean, n=15). Regional variations were seen in the eligibility criteria for TH, such as the minimum gestational age, grading of HIE severity, use of electroencephalography, and the frequency of providing TH for mild HIE. Active TH during transport varied among regions and was less likely in smaller volume sites. Amplitude-integrated electroencephalogram and/or continuous electroencephalogram to determine eligibility for TH was used by most sites in WEOG and non-WEOG but infrequently by the US and Canada Groups. For sedation during TH, morphine was most frequently used as first choice but there was relatively high (33%) use of dexmedetomidine in the US Group. Timing of brain magnetic resonance imaging and neurodevelopmental follow-up were variable. Neurodevelopmental follow occurred earlier and more frequently, although for a shorter duration, in the non-WEOG. We found significant variations in practices for TH for HIE across regions internationally. Future guidelines should incorporate resource availability in a global perspective.

Oral Clonidine-Based Strategy to Reduce Opiate Use During Cooling for Neonatal Encephalopathy: An Observational Study

To determine whether an enteral, clonidine-based sedation strategy (CLON) during therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy would decrease opiate use while maintaining similar short-term safety and efficacy profiles to a morphine-based strategy (MOR). This was a single-center, observational study conducted at a level IV neonatal intensive care unit from January 1, 2017, to October 1, 2021. From April 13, 2020, to August 13, 2020, we transitioned from MOR to CLON. Thus, patients receiving TH for hypoxic-ischemic encephalopathy were grouped to MOR (before April 13, 2020) and CLON (after August 13, 2020). We calculated the total and rescue morphine milligram equivalent/kg (primary outcome) and frequency of hemodynamic changes (secondary outcome) for both groups. The MOR and CLON groups (74 and 25 neonates, respectively) had similar baseline characteristics and need for rescue sedative intravenous infusion (21.6% MOR and 20% CLON). Both morphine milligram equivalent/kg and need for rescue opiates (combined bolus and infusions) were greater in MOR than CLON (P<.001). As days in TH advanced, a lower percentage of patients receiving CLON needed rescue opiates (92% on day 1 to 68% on day 3). Patients receiving MOR received a greater cumulative dose of dopamine and more frequently required a second inotrope and hydrocortisone for hypotension. MOR had a lower respiratory rate during TH (P=.01 vs CLON). Our CLON protocol is noninferior to MOR, maintaining perceived effectiveness and hemodynamic safety, with an apparently reduced need for opiates and inotropes.

Expiratory braking defines the breathing patterns of asphyxiated neonates during therapeutic hypothermia.

Although neonatal breathing patterns vary after perinatal asphyxia, whether they change during therapeutic hypothermia (TH) remains unclear. We characterized breathing patterns in infants during TH for hypoxic-ischemic encephalopathy (HIE) and normothermia after rewarming. In seventeen spontaneously breathing infants receiving TH for HIE and in three who did not receive TH, we analyzed respiratory flow and esophageal pressure tracings for respiratory timing variables, pulmonary mechanics and respiratory effort. Breaths were classified as braked (inspiratory:expiratory ratio ≥1.5) and unbraked (<1.5). According to the expiratory flow shape braked breaths were chategorized into early peak expiratory flow, late peak expiratory flow, slow flow, and post-inspiratory hold flow (PiHF). The most braked breaths had lower rates, larger tidal volume but lower minute ventilation, inspiratory airway resistance and respiratory effort, except for the PiHF, which had higher resistance and respiratory effort. The braked pattern predominated during TH, but not during normothermia or in the uncooled infants. We speculate that during TH for HIE low respiratory rates favor neonatal braked breathing to preserve lung volume. Given the generally low respiratory effort, it seems reasonable to leave spontaneous breathing unassisted. However, if the PiHF pattern predominates, ventilatory support may be required.

Association Between Seizures and Neurodevelopmental Outcome at Two and Five Years in Asphyxiated Newborns With Therapeutic Hypothermia

ObjectiveTo investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. MethodsRetrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. ResultsSeventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. ConclusionThe presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders.

Therapeutic hypothermia after perinatal asphyxia in Vietnam: medium-term outcomes at 18 months – a prospective cohort study

AimTo determine neurodevelopmental outcome at 18 months after therapeutic hypothermia for hypoxic-ischaemic encephalopathy (HIE) infants in Vietnam, a low-middle-income country.MethodProspective cohort study investigating outcomes at 18 months in severely asphyxiated...

A novel clinical risk scoring system for neurodevelopmental outcomes among survivors of neonatal hypoxic-ischemic encephalopathy (HIE)

ObjectiveWe aimed to develop a risk scoring system as a predictor of 24-month neurodevelopmental outcomes (cognitive, language, and motor) for neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). MethodsThis was a chart review of infants with HIE treated with therapeutic hypothermia who were admitted to the Neonatal Intensive Care Unit (NICU) at the University of Michigan between 2009 and 2019 and followed in the neonatal developmental clinic until 24 months of age. We examined bivariate associations between the neonatal characteristics and Bayley-III scores. We then performed stepwise logistic regression. To create the risk scores, a participant was given one point for each of the factors included in the final model. ResultsFifty-five infants were included. The final model for Bayley cognitive abnormality included abnormal neonatal neurologic exam (p < 0.0001), white matter/watershed MRI abnormality (p = 0.01), 5-min Apgar score (p = 0.02), and EEG-confirmed seizures (p = 0.04). The model for language abnormality included abnormal neurologic exam (p = 0.0002), seizures (p = 0.007), clinical severity of HIE (p = 0.06), and basal ganglia/thalamus MRI abnormality (p = 0.17). The model for motor abnormality included seizures (p = 0.03), abnormal neurologic exam (p = 0.06) and basal ganglia/thalamus MRI abnormality (p = 0.02). The positive predictive values for the risk scores were 60 %, 85 % and 71 %, respectively, for the Bayley-III cognitive, language and motor domains. ConclusionOur study identifies early clinical features that differentially predict domains of neurodevelopmental outcome and associated risk scores that may be of value to both clinicians and families. This novel scoring system should next be validated in a larger, prospective study.

Acute Kidney Injury and Abnormalities on Brain Magnetic Resonance Imaging or Death in Infants with Hypoxic-Ischemic Encephalopathy: A Case-Control Study.

This study aimed to analyze the association between acute kidney injury (AKI) and abnormalities on brain magnetic resonance imaging (MRI) or death in neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). This is a retrospective case-control analysis of 380 neonates born at ≥35 weeks' gestation treated with therapeutic hypothermia for HIE. Death or abnormal brain MRI using the basal ganglia watershed scoring system was compared between neonates with and without AKI. A total of 51 (13.4%) neonates had AKI. Infants with AKI had higher rates of the composite of death or abnormal brain MRI (74.5 vs. 38.3%; p < 0.001). Rate of death (21.6 vs. 5.5%; p < 0.001) and severe abnormalities on MRI or death (43.1 vs. 19.1%; p < 0.001) were also higher in neonates with AKI. AKI is strongly associated with abnormalities on brain MRI or death in neonates with HIE. Identification of AKI in this patient population may be helpful in guiding clinical management and predicting potential neurodevelopmental impairment. · Neonates with HIE are at increased risk for AKI.. · AKI is associated with hypoxic-ischemic injury on brain MRI or death among neonates with HIE.. · Identification of AKI in infants with HIE may help predict neurodevelopmental impairment..

A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE. We included full articles and book chapters published in English on PubMed with references to "hypoxic ischemic encephalopathy", "birth asphyxia", "therapeutic hypothermia", or "neonatal encephalopathy". We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials. Despite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration. TH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.

The Feasibility of Telemedicine in the Implementation and Management of Therapeutic Hypothermia for Infants with Neonatal Hypoxic-Ischemic Encephalopathy in a Resource-Limited Country.

Background Telemedicine is widely used in neonatal services in developed countries, though its outcomes in low- and middle-income countries are controversial. Lack of expertise and/or facilities, however, has limited its use in developing countries and around areas of military conflicts. We aim to study the implementation and management of therapeutic hypothermia (TH) in infants with hypoxic-ischemic encephalopathy (HIE) with the help of telemedicine in a resource-limited country. Methodology This is a retrospective study, evaluating patients who received TH, guided by telemedicine, through a mobile app (Telegram), an application that allows sharing and archiving of information with other beneficial features. We assessed the feasibility of utilizing telemedicine in guiding the application of TH to infants affected with HIE in the North-West of Syria between July 2020 and July 2021. Feasibility was measured by parameters related to the time gaps between initiation of consultation and treatment and clinical short-term outcomes. Results Out of 5,545 newborn infants delivered during the study period, 22 patients were eligible for TH guided by telemedicine. Patients were referred for consultation at a median (interquartile range [IQR]) of 137 (35-165) minutes of life. A median (IQR) of 12 (3-18) minutes elapsed between the call for a consultation and the consultant response and a median (IQR) of 30 (0-42) minutes elapsed between seeking the consultation and the initiation of cooling therapy. Eighteen patients completed cooling for 72 hours. The patients' temperatures were within the target range (33-34°C) most of the time (84.1%). Conclusion Telemedicine is a feasible method to guide the implementation TH for HIE in resource-limited areas. The short-term success rate is relatively high; however, further studies with a larger population are needed to confirm these findings.

Left Ventricular Dysfunction Persists in the First Week after Re-Warming following Therapeutic Hypothermia for Hypoxic-Ischaemic Encephalopathy

Objectives: The aim of this study was to assess serial myocardial function in newborn infants receiving therapeutic hypothermia (TH) as treatment for moderate to severe hypoxic-ischaemic encephalopathy (HIE). Methods: Serial echocardiography was performed in 20 term infants receiving TH on days 1–3 and again after re-warming. Left ventricular (LV) fractional shortening, LV cardiac output, and tissue Doppler imaging-derived myocardial velocities and myocardial performance index were measured. Similar assessments were obtained from 20 well term infants within 48 h of birth. Results: LV fractional shortening (LVFS) was similar between cases and controls during all measurements (25.3% vs. 27.4%). The mean LV cardiac output on day 1 was significantly lower in cases (109 mL/kg/min) than in controls (162 mL/kg/min) but increased after re-warming (145 mL/kg/min). All myocardial velocities were significantly lower in cases on day 1, increased during TH, but LV indices remained consistently lower compared to controls even after re-warming. LV myocardial performance index was higher in cases compared to controls on day 1, improved during TH but remained abnormal after re-warming. The right ventricular myocardial performance index was similar between cases and controls. Conclusion: Among infants affected by moderate to severe HIE, LV function appears to be more affected than right ventricular function with LV dysfunction persisting after completion of TH. LVFS was not useful to determine dysfunction in this cohort.

Interventions for the management of Pain and Sedation in Newborns undergoing Therapeutic hypothermia for hypoxic-ischemic encephalopathy (IPSNUT): protocol of a systematic review

BackgroundClinical research has shown that therapeutic hypothermia after neonatal hypoxic-ischemic injury improves survival without disability. There is no consensus regarding pain relief or sedation during therapeutic hypothermia in newborns; however, therapeutic hypothermia seems to be associated with pain and stress, and adequate analgesia and sedation are central to maximize the effect of therapeutic hypothermia. Pain needs to be adequately managed in all patients, especially the newborn infant due to the potential short- and long-term negative effects of inadequately treated pain in this population.MethodsWe will perform a systematic review of pharmacological and non-pharmacological interventions for the management of pain and sedation in newborn infants undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy. We will include randomized, quasi-randomized controlled trials and observational studies. The use of pharmacological or non-pharmacological interventions will be compared to other pharmacological and or non-pharmacological interventions or no intervention/placebo. The primary outcomes for this review will be analgesia and sedation assessed with validated pain scales, circulatory instability, mortality to discharge, and moderate-to-severe neurodevelopmental disability. We will search the following databases: CINAHL, ClinicalTrials.gov, Cochrane Library, Embase, PubMed, Scopus, and Web of Science. Two independent researchers will screen the records for inclusion, extract data using a data extraction form, and assess the risk of bias in the included trials.DiscussionThe result of this review will summarize the knowledge regarding the management of pain and sedation in infants treated with therapeutic hypothermia and potentially provide clinicians with guidance on the effective and safe methods.Systematic review registrationPROSPERO CRD42020205755

Association between multi-organ dysfunction and adverse outcome in infants with hypoxic ischemic encephalopathy.

To evaluate multi-organ dysfunction (MOD) in newborns treated with therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), and to compare MOD in those with normal/mild magnetic resonance imaging (MRI) findings to those with moderate to severe MRI findings or death. Retrospective single-center observational study of infants treated with TH. A total of 16 parameters across 7 organ systems were analyzed. Primary outcome was death or moderate to severe brain injury on MRI. Of 157 infants treated with TH, 77% had ≥2 organ systems with dysfunction. The number of organ systems with dysfunction was strongly associated with death or moderate-to-severe brain injury (p < 0.0001). Hematologic (68%) and hepatic (65%) dysfunction were most common. Neurologic and renal dysfunction were most strongly associated with the primary outcome (OR 13.5 [6.1-29.8] and 11.2 [4.1-30.3], respectively), while pulmonary hypertension was not. MOD is prevalent in infants undergoing TH for HIE, and the association between MOD and adverse outcomes may impact clinical care and counseling.

Opioid exposure during therapeutic hypothermia and short-term outcomes in neonatal encephalopathy.

To assess the association between opioid exposure during therapeutic hypothermia (TH) for perinatal hypoxic-ischemic encephalopathy (HIE) and in-hospital outcomes. In this retrospective cohort study, linked data were accessed on infants ≥36 weeks gestation, who underwent TH for HIE, born from 2010-2016 in 23 Neonatal Intensive Care Units participating in Children's Hospitals Neonatal Consortium and Pediatric Health Information Systems. We excluded infants who received opioids for >5 days. The cohort (n = 1484) was categorized as No opioid [240(16.2%)], Low opioid (1-2 days) [574 (38.7%)] and High opioid group (HOG, 3-5 days) [670 (45.2%)]. After adjusting for HIE severity, opioids were not associated with abnormal MRI, but were associated with decreased likelihood of complete oral feeds at discharge. HOG had increased likelihood of prolonged hospital stay and ventilation. Opioid exposure during TH was not associated with abnormal MRI; its association with adverse short-term outcomes suggests need for cautious empiric use.

Dexmedetomidine Versus Fentanyl for Neonates With Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia.

Therapeutic hypothermia reduces the risk of death and major disability in neonates with moderate-to-severe hypoxic ischemic encephalopathy (HIE). Opioids and benzodiazepines are used to manage agitation but contribute to hemodynamic and respiratory instability. The objective of this study was to evaluate the safety and efficacy of dexmedetomidine (DEX) compared with fentanyl (FENT) in neonates with HIE undergoing therapeutic hypothermia. This was a retrospective, single-center study comparing outcomes in neonates with HIE undergoing therapeutic hypothermia who received FENT to those who received DEX. A total of 45 neonates were included (FENT, n = 19; DEX, n = 26). The DEX group had a decreased need for sedative bolus doses during therapeutic hypothermia compared with the FENT group; however, there was no difference in number of uncontrolled agitation scores or need for additional scheduled sedatives. The DEX group had a shorter time to discontinuation of sedatives after rewarming compared with the FENT group (0.52 versus 5 days, respectively; p = 0.001), shorter time to extubation after birth (3.1 versus 11.3 days, respectively; p = 0.004), and earlier time to resumption of feeds (8.5 versus 13 days, respectively; p = 0.03). A non-statistically significant reduction in seizures was noted (3 versus 7 subjects, respectively; p = 0.07). There was no difference in baseline characteristics, mortality, or adverse effects. The use of DEX during therapeutic hypothermia for HIE appears to provide comparable control of agitation to FENT with a reduced need for additional sedatives and may lead to an earlier time to extubation and discontinuation of sedatives.

Alterations in the Stool Microbiome in Newborns Undergoing Mild Therapeutic Hypothermia after Hypoxic-Ischemic Encephalopathy

Background: Hypoxic-ischemic encephalopathy (HIE) is associated with brain injury in newborns and may lead to disability or death. Mild therapeutic hypothermia (TH) is an effective neuroprotective intervention and an established standard of care in western countries. The gut microbiome, the genomic and physicochemical contribution of the gut microbiota, serves important functions and is increasingly recognized as a major influencer on development. The impact of HIE and TH on the evolving gut microbiota of the newborn remains to be elucidated. Objective: The objective of this study was to carry out an exploratory study on the effects of HIE and TH on the gut microbiome in term neonates. Methods and Results: Stool samples were obtained from 28 newborns with HIE (median age 68 h) undergoing TH on the neonatal unit (HIE TH group), with a follow-on stool sample available for 20 of these babies (median age 151 h). For comparison, a single stool specimen was obtained from 19 healthy newborns on the postnatal ward (median age 34 h). The microbiota composition was determined using established microbial DNA extraction and 16S rRNA gene sequencing methodology. There was no difference in the mode of delivery or the method of feeding the newborns, once established, between the 2 groups. All the infants in the HIE TH group had received antibiotics compared to only one of the controls. A lower α-diversity, quantified by the Shannon diversity index, was noted in the microbiota of the HIE TH group in comparison to the control group. The HIE TH group had a higher mean relative abundance (MRA) of facultative anaerobes and aerobes such as Staphylococcus species and a lower MRA of strict anaerobes, such as members of the Bacteroides genus, compared to the control. Also, there was a significant reduction in the MRA of the genus Bifidobacterium in the HIE TH group. Although the mode of delivery exerts a profound influence on the gut microbiota of the newborn, distance-based redundancy analysis showed that TH may exert an independent influence. This study could not determine the independent contribution of the use of antibiotics or the neonatal intensive care unit environment. Conclusion: In this study, we demonstrate an alteration in the microbiota composition in newborns undergoing TH for HIE.

Effect of dexmedetomidine on heart rate in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia

Sedation is recommended to optimize neuroprotection in neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Dexmedetomidine is an alternative agent to opioids, which are commonly used but have adverse effects. Both TH and dexmedetomidine can cause bradycardia. In this study, we describe our experience with dexmedetomidine and fentanyl in neonates undergoing TH for HIE, with a focus on heart rate (HR). We performed a retrospective chart review from 2011-2019 at a level IV NICU comparing sedation with dexmedetomidine (n = 14), fentanyl (n = 120), or both (n = 32) during TH for HIE. HR trends were compared based on sedation and gestational age. Neonates were included if they underwent TH and received sedation and were excluded if cooling was initiated past 24hours (h) from birth or if they required ECMO. Of the 166 neonates included, 46 received dexmedetomidine, 14 as monotherapy and 32 in combination with fentanyl. Mean hourly HR from 12-36 h after birth was significantly lower for infants on dexmedetomidine versus fentanyl monotherapy (91±9 vs. 103±11 bpm, p < 0.002). Dexmedetomidine was decreased or discontinued in 22 (47.8%) neonates, most commonly due to inadequate sedation with a low HR. Lower gestational age was associated with higher HR but no significant difference in dexmedetomidine-related HR trends. Despite an association with lower HR, dexmedetomidine may be successfully used in neonates with HIE undergoing TH. Implementation of a standardized protocol may facilitate dexmedetomidine titration in this population.

Clonidine for sedation in infants during therapeutic hypothermia with neonatal encephalopathy: pilot study.

Objective:To determine a safe dose of clonidine (CLON) to be used in infants with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH).Study Design:A pilot prospective study was performed to determine the effect of CLON on autonomic parameters, the pharmacokinetics (PK) of CLON, and the amount of morphine (MOR) given “as needed” for shivering and agitation in a cohort of infants (n=12) with HIE undergoing TH compared to a historical control group (n=28).Results:The CLON group received less “as needed” MOR than the MOR-only group for agitation/shivering (p < 0.001), and the CLON vs MOR-only group spent 92% vs 79% of cooling time at the target core body temperature (CBT; p = 0.03, CLON vs MOR).Conclusions:Intravenous CLON (1mcg/kg Q8h) is well tolerated in infants treated with TH for HIE. CLON stabilizes CBT in the ideal range during cooling which may be optimal for neuroprotection.

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the National Neonatal Research Database

BackgroundTherapeutic hypothermia is standard of care for babies with moderate/severe hypoxic-ischaemic encephalopathy and is increasingly used for mild encephalopathy.ObjectiveDescribe temporal trends in the clinical condition of babies diagnosed with hypoxic-ischaemic...

Predictive Models of Neurodevelopmental Outcomes After Neonatal Hypoxic-Ischemic Encephalopathy.

To develop predictive models for death or neurodevelopmental impairment (NDI) after neonatal hypoxic-ischemic encephalopathy (HIE) from data readily available at the time of NICU admission ("early") or discharge ("cumulative"). In this retrospective cohort analysis, we used data from the Children's Hospitals Neonatal Consortium Database (2010-2016). Infants born at ≥35 weeks' gestation and treated with therapeutic hypothermia for HIE at 11 participating sites were included; infants without Bayley Scales of Infant Development scores documented after 11 months of age were excluded. The primary outcome was death or NDI. Multivariable models were generated with 80% of the cohort; validation was performed in the remaining 20%. The primary outcome occurred in 242 of 486 infants; 180 died and 62 infants surviving to follow-up had NDI. HIE severity, epinephrine administration in the delivery room, and respiratory support and fraction of inspired oxygen of 0.21 at admission were significant in the early model. Severity of EEG findings was combined with HIE severity for the cumulative model, and additional significant variables included the use of steroids for blood pressure management and significant brain injury on MRI. Discovery models revealed areas under the curve of 0.852 for the early model and of 0.861 for the cumulative model, and both models performed well in the validation cohort (goodness-of-fit χ2: P = .24 and .06, respectively). Establishing reliable predictive models will enable clinicians to more accurately evaluate HIE severity and may allow for more targeted early therapies for those at highest risk of death or NDI.