Heart rate variability during therapeutic hypothermia in neonatal encephalopathy

Background and Purpose: Continuous monitoring of autonomic nervous system (ANS) responses during therapeutic hypothermia (TH) in neonates offers important markers for hypoxic-ischemic encephalopathy. Heart rate variability (HRV) indices, which reflect ANS activity, are particularly informative during TH. The high frequency component of HRV—a marker of parasympathetic tone—is known to increase with cooling [1], promoting the recovery of cerebral tissues and circulatory functions; However, only few studies have reported a comparative analysis of HRV changes throughout the entire cooling and subsequent rewarming periods, especially in the context of adverse brain injury outcomes. We hypothesized that infants with brain injury would exhibit a blunted HRV response to TH.

Methodology: EKG was collected from infants who underwent TH for neonatal encephalopathy at Brigham and Women’s Hospital, MA. Post-TH brain injury was assessed using Weeke et al.’s MRI-based grading (PMID:29246356). A Weeke score >3 was considered ‘brain injury’. The R-to-R interval was extracted and cleaned using automated algorithms and visual examinations, and analyzed across high (HF=0.2-2Hz), low (LF=0.04-0.2Hz), and very-low frequency (VLF=0.01-0.04Hz) bands using a wavelet transform technique. HF indices were combined into 1-hour medians and further grouped into 6-hour bins for the cooling stage and 3-hour bins for the rewarming stage. A mixed model was used to account for repeated measures in each bin.

Results: We analyzed 43 infants in this report. Absolute HF values were log10-transformed to achieve normality. In both groups, we found the anticipated increases in HF during cooling, and in heart rate during rewarming. In the brain injury group, we found a consistently lower log10HF, while their relative HF (e.g., HF/[Total Power] or LF/HF ratio) was not different from the normal group. Both groups exhibited a gradual increase in Total Power, LF, and VLF during cooling, and a decrease upon rewarming. Although visually subtle, the brain injury group maintained a statistically higher heart rate throughout TH.

Conclusion/Impact: We report HRV indices and heart rate changes during therapeutic hypothermia, confirming the anticipated responses to cooling and rewarming. Cooling-induced HF increases suggested enhanced parasympathetic activity in both brain injury and normal groups. However, the brain injury group showed consistently lower HF levels and higher heart rates, suggesting diminished parasympathetic tone and its capacity. Insignificant differences in relative HF power may be due to a proportional increase in Total Power during cooling. Future work will incorporate cerebral oxygenation, and covariates that can induce parasympathetic withdrawal, such as modes of ventilation. This work provides additional insights into HRV changes during TH and their possible association with brain injury outcomes.

Bibliography:
[1] R. M. Goulding et al., “Heart rate variability in hypoxic ischemic encephalopathy during therapeutic hypothermia.,” Pediatr. Res., vol.81, no.4, pp.609–615, Apr. 2017