Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth?

Infants with moderate to severe neonatal encephalopathy (NE) benefit significantly from therapeutic hypothermia, with reduced risk of death or disability. However, the need for therapeutic hypothermia for infants with milder NE remains unclear. It has been suggested that these infants should not be offered therapeutic hypothermia as they may not be at risk for adverse neurodevelopmental outcome and that the balance of risk against potential benefit is unknown. Several key questions need to be answered including first, whether one can define NE in the first 6 h after birth so as to accurately distinguish infants with brain injury who may be at risk for adverse neurodevelopmental consequences. Second, will treatment of infants with mild NE with therapeutic hypothermia improve or even worsen neurological outcomes? Although alternate treatment protocols for mild NE may be feasible, the use of the current approach combined with rigorous avoidance of hyperthermia and initiation of hypothermia as early as possible after birth may promote optimal outcomes. Animal experimental data support the potential for greater benefit for mild HIE compared with moderate to severe HIE. This review will summarize current knowledge of mild NE and the challenges to a trial in this population

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). Main Outcomes and Measures The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Conclusions and Relevance Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness

Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy: A Randomized Clinical Trial

Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models

Feasibility of EEG Phase-Amplitude Coupling to Stratify Encephalopathy Severity in Neonatal HIE Using Short Time Window

Goal: It is challenging to clinically discern the severity of neonatal hypoxic ischemic encephalopathy (HIE) within hours after birth in time for therapeutic decision-making for hypothermia. The goal of this study was to determine the shortest duration of the EEG based PAC index to provide real-time guidance for clinical decision-making for neonates with HIE. Methods: Neonates were recruited from a single-center Level III NICU between 2017 and 2019. A time-dependent, PAC-frequency-averaged index, tPACm, was calculated to characterize intrinsic coupling between the amplitudes of 12–30 Hz and the phases of 1–2 Hz oscillation from 6-h EEG data at electrode P3 during the first day of life, using different sizes of moving windows including 10 s, 20 s, 1 min, 2 min, 5 min, 10 min, 20 min, 30 min, 60 min, and 120 min. Time-dependent receiver operating characteristic (ROC) curves were generated to examine the performance of the accurate window tPACm as a neurophysiologic biomarker. Results: A total of 33 neonates (mild-HIE, n = 15 and moderate/severe HIE, n = 18) were enrolled. Mixed effects models demonstrated that tPACm between the two groups was significantly different with window time segments of 3–120 min. By observing the estimates of group differences in tPACm across different window sizes, we found 20 min was the shortest window size to optimally distinguish the two groups (p m with a 20 min EEG time window to differentiate the severity of HIE and facilitate earlier diagnosis and treatment initiation

Should therapeutic hypothermia be offered to babies With mild neonatal encephalopathy in the first 6 hours after birth?

Infants with moderate to severe neonatal encephalopathy (NE) benefit significantly from therapeutic hypothermia, with reduced risk of death or disability. However, the need for therapeutic hypothermia for infants with milder NE remains unclear. It has been suggested that these infants should not be offered therapeutic hypothermia as they may not be at risk for adverse neurodevelopmental outcome and that the balance of risk against potential benefit is unknown. Several key questions need to be answered including first, whether one can define NE in the first 6 h after birth so as to accurately distinguish infants with brain injury who may be at risk for adverse neurodevelopmental consequences. Second, will treatment of infants with mild NE with therapeutic hypothermia improve or even worsen neurological outcomes? Although alternate treatment protocols for mild NE may be feasible, the use of the current approach combined with rigorous avoidance of hyperthermia and initiation of hypothermia as early as possible after birth may promote optimal outcomes. Animal experimental data support the potential for greater benefit for mild HIE compared with moderate to severe HIE. This review will summarize current knowledge of mild NE and the challenges to a trial in this population