PMID- 37392599
OWN - NLM
STAT- MEDLINE
DCOM- 20230814
LR  - 20230930
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 94
DP  - 2023 Aug
TI  - Association of cerebral metabolic rate following therapeutic hypothermia with 
      18-month neurodevelopmental outcomes after neonatal hypoxic ischemic 
      encephalopathy.
PG  - 104673
LID - S2352-3964(23)00238-4 [pii]
LID - 10.1016/j.ebiom.2023.104673 [doi]
LID - 104673
AB  - 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 (CMRO(2)) in the days after 
      TH is associated with 18-month neurodevelopmental outcomes as the first step in 
      evaluating CMRO(2)'s potential as a diagnostic for HIE. Secondary objectives were 
      to compare associations with clinical exams and characterise the relationship 
      between CMRO(2) 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 >/=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. CMRO(2) 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. CMRO(2) 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. CMRO(2) 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 mm(2)/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 
      CMRO(2) in the NICU during C and RW showed dramatic changes and potential to 
      assess individual response to TH. CMRO(2) 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).
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Sutin, Jason
AU  - Sutin J
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA; Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA. 
      Electronic address: Jason.Sutin@childrens.harvard.edu.
FAU - Vyas, Rutvi
AU  - Vyas R
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA.
FAU - Feldman, Henry A
AU  - Feldman HA
AD  - Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Department of 
      Pediatrics, Institutional Centers for Clinical and Translational Research, Boston 
      Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA.
FAU - Ferradal, Silvina
AU  - Ferradal S
AD  - Department of Intelligent Systems Engineering, Indiana University Bloomington, 
      107 S Indiana Ave., Bloomington, IN 47405, USA.
FAU - Hsiao, Chuan-Heng
AU  - Hsiao CH
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA.
FAU - Zampolli, Lucca
AU  - Zampolli L
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA.
FAU - Pierce, Lara J
AU  - Pierce LJ
AD  - Department of Psychology, York University, 198 York Blvd., North York, ON M3J 
      2S5, Canada.
FAU - Nelson, Charles A
AU  - Nelson CA
AD  - Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Division of 
      Developmental Medicine, Department of Pediatrics, Boston Children's Hospital, 300 
      Longwood Ave., Boston, MA 02115, USA.
FAU - Morton, Sarah U
AU  - Morton SU
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA; Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
FAU - Hay, Susanne
AU  - Hay S
AD  - Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Department of 
      Neonatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 
      02215, USA.
FAU - El-Dib, Mohamed
AU  - El-Dib M
AD  - Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Division of 
      Newborn Medicine, Department of Pediatrics, Brigham and Women's Hospital, 75 
      Francis St., Boston, MA 02115, USA.
FAU - Soul, Janet S
AU  - Soul JS
AD  - Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Department of 
      Neurology, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA.
FAU - Lin, Pei-Yi
AU  - Lin PY
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA; Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
FAU - Grant, Patricia E
AU  - Grant PE
AD  - Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's 
      Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Division of Newborn Medicine, 
      Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA; Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; 
      Department of Radiology, Boston Children's Hospital, 300 Longwood Ave., Boston, 
      MA 02115, USA.
LA  - eng
GR  - P50 HD105351/HD/NICHD NIH HHS/United States
GR  - R01 HD076258/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Observational Study
DEP - 20230629
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Infant, Newborn
MH  - Infant
MH  - Pregnancy
MH  - Humans
MH  - Female
MH  - Young Adult
MH  - Adult
MH  - Cohort Studies
MH  - Prospective Studies
MH  - *Hypoxia-Ischemia, Brain/diagnosis/etiology/therapy
MH  - *Infant, Newborn, Diseases
MH  - Oxygen/metabolism
MH  - *Hypothermia, Induced/methods
PMC - PMC10338207
OTO - NOTNLM
OT  - Cerebral blood flow
OT  - Cerebral metabolic rate of oxygen consumption
OT  - Diffuse correlation spectroscopy
OT  - Hypoxic ischemic encephalopathy
OT  - Infants
OT  - Near-infrared spectroscopy
OT  - Neonates
OT  - Neurodevelopmental outcome
OT  - Perinatal asphyxia
OT  - Therapeutic hypothermia
COIS- Declaration of interests The authors declare no conflict of interest.
EDAT- 2023/07/02 01:10
MHDA- 2023/08/14 06:43
PMCR- 2023/06/29
CRDT- 2023/07/01 18:05
PHST- 2023/01/12 00:00 [received]
PHST- 2023/06/02 00:00 [revised]
PHST- 2023/06/06 00:00 [accepted]
PHST- 2023/08/14 06:43 [medline]
PHST- 2023/07/02 01:10 [pubmed]
PHST- 2023/07/01 18:05 [entrez]
PHST- 2023/06/29 00:00 [pmc-release]
AID - S2352-3964(23)00238-4 [pii]
AID - 104673 [pii]
AID - 10.1016/j.ebiom.2023.104673 [doi]
PST - ppublish
SO  - EBioMedicine. 2023 Aug;94:104673. doi: 10.1016/j.ebiom.2023.104673. Epub 2023 Jun 
      29.