To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE).
...Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2.
Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 42%) compared with the late TT group (n = 289 58%) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, −2.8 95% CI, −6.1 to 0.5, language −3.3 95% CI, −7.4 to 0.8, and motor −3.5 95% CI, −7.3 to 0.3).
In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age.
High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta.clinicaltrials.gov/study/NCT02811263.
Abstract 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.
IMPORTANCE: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have ...not demonstrated a decrease in donor exposure. OBJECTIVES: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. DESIGN, SETTING, AND PARTICIPANTS: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. INTERVENTIONS: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. MAIN OUTCOMES AND MEASURES: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. RESULTS: A total of 936 patients (488 male 52.1%) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean SD, 3.5 4.0 vs 5.2 4.4), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean SD, 47.6 60.4 vs 76.3 68.2 mL), with a mean difference of −25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean SD, 1.6 1.7 vs 2.4 2.0), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean SD hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% 5.5% vs 30.4% 4.6% (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01378273
Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has ...proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.
Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and ...thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine-mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related impairment of adult learning.
Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes ...or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14
CD16
(double-positive) and CD14
CD16
(single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at
(
)
,
, and
compared with those collected at
. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.
Newborns with hypoxic-ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities ...correlate with MRI brain injury and with response to treatment.
Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system.
Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality.
Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.
To describe high/low daily blood pressures (BP) and variability in BP management with vasoactive infusions (VI) and/or hydrocortisone (HC) in extremely preterm infants.
Analysis of data from 24-27 ...weeks' gestation infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Daily high/low BPs, the use of VI and/or HC, and adverse outcomes were compared descriptively and using regression models.
936 infants were included; 64% untreated, 20% VI, 3% HC, and 13% VI + HC. BP ranges are described for the 602 untreated infants. Considerable inter- and intra-center variability was demonstrated in the rate of VI and/or HC use and the lowest BP on the day of VI or HC initiation.
Despite published expert opinion guidance regarding BP management in extremely preterm infants, our results suggest a continued lack of consensus result in both inter- and intra-center variability in practice. Well-designed studies in the field are urgently needed.
Extremely low gestational age neonates born <28 weeks gestation are at risk for chronic disease. We sought to describe the prevalence of kidney outcomes by gestational age and determine risk factors ...for their development.
The Recombinant Erythropoietin for Protection of Infant Renal Disease (REPAIReD) study examined kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo NeuroProtection Trial (PENUT) study. Kidney function, urine albumin, and BP were measured at 2-year (24±2 months) corrected gestational age. We compared outcomes across gestational age categories and evaluated associations between kidney-related outcomes and neonatal and maternal characteristics. The primary outcome was eGFR <90 ml/min per 1.73 m
(CKD); secondary outcomes were spot urine albumin-creatinine ratio ≥30 mg/g (albuminuria) and either systolic BP or diastolic BP >90th percentile for height, age, and sex.
A total of 832 survived to 2 years, and 565 (68%) had at least one outcome measured. Overall, 297 (53%) had one abnormal kidney outcome; 61 (18%) had an eGFR <90 ml/min per 1.73 m
, 155 (36%) had albuminuria, 65 (22%) had elevated systolic BP, and 128 (44%) had elevated diastolic BP. Gestational age (odds ratio, 0.94; 95% confidence interval, 0.89 to 0.99), birth weight
-score (odds ratio, 0.92; 95% confidence interval, 0.85 to 0.98), and prenatal steroids (odds ratio, 1.23; 95% confidence interval, 1.08 to 1.39) were associated with an eGFR <90 ml/min per 1.73 m
. An elevated systolic BP was associated with indomethacin use (odds ratio, 1.18; 95% confidence interval, 1.04 to 1.33) and Black race (odds ratio, 1.19; 95% confidence interval, 1.01 to 1.39); elevated diastolic BP was associated with male sex (odds ratio, 1.29; 95% confidence interval, 1.12 to 1.49), severe AKI (odds ratio, 1.24; 95% confidence interval, 1.04 to 1.48), and indomethacin use (odds ratio, 1.16; 95% confidence interval, 1.01 to 1.33).
Approximately 18% of extremely low gestational age neonates have CKD, 36% have albuminuria, 22% have an elevated systolic BP, and 44% have an elevated diastolic BP at 2 years of age. Gestational age, birthweight
-score, and prenatal steroids were associated with CKD. Male sex, Black race, indomethacin use, and severe AKI were associated with elevated BP.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_19_CJN15011121.mp3.
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