Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy

Background Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH.Methods This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates & GE;34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15).Findings Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per degrees C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per degrees C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (& beta; (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl x mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. Interpretation Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE.Funding This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).Copyright & COPY; 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The objective of this study was to evaluate the association between cerebral oxygen metabolism (CMRO2) and neurodevelopmental outcomes at 18 months in neonates with hypoxic ischemic encephalopathy (HIE), and to assess CMRO2 as a potential diagnostic for HIE. The study found that CMRO2 was significantly associated with cognitive and motor outcomes and outperformed conventional clinical evaluations in predicting these outcomes in mild to moderate HIE. This provides a promising, objective, physiologically-based diagnostic for HIE.