INTRODUCTION

Hypoxic ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and neurological disabilities, affecting 1.5 newborns per 1000 live birth¹. Although the introduction of therapeutic hypothermia has reduced the risk of death and disability in neonates with HIE, over 40% of neonates with moderate or severe HIE still suffer from death, disability or neurodevelopmental delay, suggesting the need for adjuvant therapies². Because HIE is associated with the disruption of the brain’s oxygen supply, the assessment of cerebral oxygen metabolism may provide useful biomarkers to identify the risk of permanent neurologic injury and determine the necessity of adjuvant treatments in HIE. Cerebral oxygen metabolism is characterized by physiological parameters including oxygen-extraction-fraction (OEF), cerebral-blood-flow (CBF) and cerebral-metabolic-rate-of-oxygen (CMRO₂). In this study, we aimed to evaluate these physiological parameters in neonates with HIE in comparison with healthy newborns and examine whether these parameters could predict short-term clinical outcome.

METHODS

Participants: In this IRB-approved study, we included 42 neonates with HIE (20 females, birth-age 38.9±1.7weeks) and 52 control neonates (26 females, birth-age 39.0±1.0weeks). Table 1 lists the characteristics of the participants.
MRI Experiments: All neonates were scanned on 3T Siemens Skyra or Trio systems. Global OEF was evaluated using T₂-relaxation-under-spin-tagging (TRUST) MRI, which is a PET-validated technique³ and has been optimized for neonatal applications⁴. To quantify global CBF, phase-contrast MRI was employed to measure the total blood flow in the brain’s feeding arteries in a subset of neonates (35 HIE and 20 control)⁵. Arterial-oxygenation (Y_a) of each neonate was assessed by an MRI-compatible pulse oximeter.
Data Processing: The TRUST data were processed to obtain global venous-oxygenation (Y_v)^3,4. Global CBF was calculated as the total arterial blood flow normalized by the brain mass. Global OEF and CMRO₂ were computed as: $$OEF=(Y_a-Y_v)/Y_a\times100\%$$
$$CMRO_2=(Y_a-Y_v){\times}CBF{\times}C_h$$
where C_h=8.97μmol O₂/ml for a hematocrit of 0.44⁶. MRI images of neonates with HIE were graded by a board-certified neuroradiologist using the National-Institute-of-Child-Health-and-Human-Development (NICHD) score⁷.
Statistical Analysis: Linear regression analyses were used to compare OEF, CBF and CMRO₂ between neonates with HIE and healthy controls, with postmenstrual-age at the MRI scan and sex as covariates. We further stratified neonates with HIE based on their Sarnat scores (a clinical rating of neonatal HIE severity) or the presence of structural brain lesions (NICHD>0) and employed analysis-of-covariance (ANCOVA) followed by Tukey’s tests to compare OEF, CBF and CMRO₂ across the control group and the HIE subgroups. Finally, we utilized linear regression (adjusted for birth-age and sex) to examine whether OEF, CBF or CMRO₂ can predict NICU length-of-stay (LoS) in neonates with HIE, a metric for short-term clinical outcome.

RESULTS AND DISCUSSION

Figure 1 depicts representative TRUST and phase-contrast data of a neonate with HIE.
As shown in Figure 2, compared to control neonates, neonates with HIE exhibited diminished OEF (P=0.01) and CMRO₂ (P<0.0001), suggesting impaired cerebral oxygen metabolism. CBF showed no significant difference (P=0.12).
When stratifying neonates with HIE based on the Sarnat score (Figure 3A-C), ANCOVA revealed significant group differences in OEF (P<0.0001), CBF (P=0.02) and CMRO₂ (P<0.0001). Specifically, neonates with severe HIE had reduced OEF compared to other groups (Figure 3A), while all HIE subgroups had lower CMRO₂ than the control group (Figure 3C). When categorizing the neonates with HIE based on the presence of structural brain lesions (Figure 3D-F), significant group differences were found in OEF (P=0.003) and CMRO₂ (P=0.0001), but not in CBF (P=0.07). HIE neonates with structural brain lesions exhibited lower OEF compared to both the controls (P=0.002) and HIE neonates without brain lesions (P=0.048). Compared to control neonates, CMRO₂ was diminished in HIE neonates with (P<0.001) or without (P<0.001) structural brain lesions. These results suggest that CMRO₂ is sensitive to mild brain impairments even when there are no abnormalities in structural MRI. On the other hand, reduction in OEF is mostly seen in neonates with more severe brain injury.
Finally, we found that a lower OEF predicted a longer NICU LoS (P=0.004, Figure 4A). NICU LoS was positively associated with CBF (P=0.02, Figure 4B) but not with CMRO₂ (P=0.37, Figure 4C). It is worth noting that NICU LoS was not associated with Sarnat score (P=0.33) or the presence of structural brain lesions (P=0.12), indicating that physiological parameters such as OEF can provide additional information (beyond standard clinical indices) for treatment planning in HIE.

CONCLUSION

This work demonstrated that the brain’s OEF and CMRO₂ were diminished in neonates with HIE. Furthermore, a lower OEF predicted longer stay in NICU. These findings suggest that physiological biomarkers such as OEF and CMRO₂ may be useful in cerebral injury evaluation and treatment planning for HIE.

Acknowledgements

No acknowledgement found.

References

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