Diminished Cerebral Oxygen Extraction and Metabolic Rate in Neonates With Hypoxic Ischemic Encephalopathy

Abstract

Background: Hypoxic ischemic encephalopathy (HIE), which is associated with perinatal disruption of cerebral oxygen supply and utilization, is a leading cause of neonatal mortality and severe neurological impairment in childhood. The present study investigated whether key physiological parameters of cerebral oxygen utilization, specifically oxygen extraction fraction (OEF), cerebral blood flow, and cerebral metabolic rate of oxygen (CMRO₂), were altered in neonates with HIE, and whether these parameters were associated with clinical indices.

Methods: In this case-control study, neonates with HIE and healthy control newborns were enrolled from the Johns Hopkins Children's Center and the Children's Hospital at the University of Maryland Medical Center. The brain's hemodynamic and metabolic parameters of OEF, cerebral blood flow, and CMRO₂ were measured with noncontrast magnetic resonance imaging and were compared between neonates with HIE and controls. We studied the relationships between the brain's physiological parameters and the presence of structural brain lesions and Apgar scores in neonates with HIE and controls. Additionally, we investigated the associations between these physiological parameters and the length of stay in the neonatal intensive care unit among neonates with HIE.

Results: Forty-two neonates with HIE and 54 control neonates were included. Neonates with HIE exhibited lower OEF (control, 31.2±5.2% versus HIE, 28.3±7.3%; P=0.02) and CMRO₂ (control, 50.4±17.3 μmol/min per 100 grams versus HIE, 34.5±13.5 μmol/min per 100 gram; P<0.0001) compared with control neonates, whereas cerebral blood flow showed no significant difference (control, 15.9±3.9 mL/min per 100 grams versus HIE, 15.2±4.6 mL/min per 100 grams; P=0.61). OEF and CMRO₂ were correlated with 1-minute and 5-minute Apgar scores (P<0.05). Among neonates with HIE, lower OEF was associated with a longer neonatal intensive care unit stay (P=0.003).

Conclusions: These findings suggest that cerebral oxygen utilization is compromised in neonates with HIE. The physiological parameters of OEF and CMRO₂ may serve as useful biomarkers for evaluating cerebral injury and planning treatment in HIE.

Keywords: brain injuries; hypoxia-ischemia, brain; infant, newborn; oxygen consumption.

Figure 1:

Flowchart of participant recruitment. (A) Enrollment of neonates with HIE. (B) Recruitment of healthy control neonates. JHCC = Johns Hopkins Children’s Center, UMMC = University of Maryland Medical Center, HIE = hypoxic ischemic encephalopathy, ΔR₂ = width of the 95% confidence interval of the estimated transverse relaxation rate of blood.

Figure 2:

Representative data from a neonate with HIE. (A) Illustration of the labeling slab and imaging slice of TRUST MRI. (B) TRUST utilized control-label subtraction to isolate pure blood signal in the superior sagittal sinus (SSS), which decayed with increasing effective echo time (eTE). (C) The SSS signal was fitted as a monoexponential function of eTEs to derive the OEF value. (D) Time-of-flight angiogram showing the brain’s feeding arteries: internal carotid arteries (ICAs) and vertebral arteries (VAs). The blue bars indicate the positions of the phase-contrast MRI scans. (E) Each phase-contrast scan generated a magnitude image and a velocity map of the target artery (yellow arrow). HIE = hypoxic ischemic encephalopathy, TRUST = T₂-relaxation-under-spin-tagging, SSS = superior sagittal sinus, eTE = effective echo time, OEF = oxygen extraction fraction, ICA = internal carotid artery, VA = vertebral artery.

Figure 3:

Comparison between neonates with HIE and control neonates. (A) Neonates with HIE exhibited significantly lower OEF than the control group. (B) CBF did not show a significant difference between HIE and control groups. (C) Neonates with HIE had reduced CMRO₂ compared to the controls. p values were adjusted for multiple comparisons using Bonferroni correction. HIE = hypoxic ischemic encephalopathy, OEF = oxygen extraction fraction, CBF = cerebral blood flow, CMRO₂ = cerebral metabolic rate of oxygen.

Figure 4:

Subgroup analyses by stratifying neonates with HIE based on the presence of structural brain lesions or a history of seizure disorders prior to the MRI scan. (A) HIE neonates with structural brain lesions exhibited reduced OEF compared to controls. (B) Neonates with HIE had lower CMRO₂ than controls, regardless of the presence of structural brain lesions. (C) HIE neonates with a history of seizure disorders showed reduced OEF compared to both controls and HIE neonates without seizure disorders. (D) Compared to controls, HIE neonates exhibited lower CMRO₂, regardless of a history of seizure disorders. p values were obtained using post-hoc Tukey’s multiple comparison tests. HIE = hypoxic ischemic encephalopathy, OEF = oxygen extraction fraction, CMRO₂ = cerebral metabolic rate of oxygen.

Figure 5:

Associations of the Apgar scores with OEF and CMRO₂. (A-C) Associations between OEF and the Apgar scores. (D-F) Associations between CMRO₂ and the Apgar scores. p values were adjusted for multiple comparisons using Bonferroni correction. HIE = hypoxic ischemic encephalopathy, OEF = oxygen extraction fraction, CMRO₂ = cerebral metabolic rate of oxygen.

Figure 6:

Scatterplots depicting the relationships between NICU LoS and OEF, as well as GA at birth among neonates with HIE. (A) A lower OEF was associated with longer NICU LoS. (B) A smaller GA at birth was associated with longer NICU LoS. The dashed lines represent the fitted lines. NICU = neonatal intensive care unit, LoS = length of stay, HIE = hypoxic ischemic encephalopathy, OEF = oxygen extraction fraction, GA = gestational age.