Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia–ischaemia in near‐term fetal sheep

Abstract

Key points •Therapeutic hypothermia needs to be started as early as possible in the first 6 h after acute injury caused by hypoxia–ischaemia (HI), but the severity and timing of HI are often unclear. In this study we evaluated whether measures of heart rate variability (HRV) might provide early biomarkers of HI. •The duration but not magnitude of suppression of HRV power and conversely increased sample entropy of the heart rate were associated with severity of HI, such that changes in the first 3 h did not discriminate between groups. •Relative changes in HRV power bands showed different patterns between groups and therefore may have the potential to evaluate the severity of HI. •Aberrant fetal heart rate patterns and increased arginine vasopressin levels in the first hour after moderate and severe HI were correlated with loss of EEG power after 3 days’ recovery, suggesting potential utility as early biomarkers of outcome. Abstract Therapeutic hypothermia is partially neuroprotective after acute injury caused by hypoxia–ischaemia (HI), likely because the timing and severity of HI are often unclear, making timely recruitment for treatment challenging. We evaluated the utility of changes in heart rate variability (HRV) after HI as biomarkers of the timing and severity of acute HI. Chronically instrumented fetal sheep at 0.85 gestational age were exposed to different durations of umbilical cord occlusion to produce mild (n = 6), moderate (n = 8) or severe HI (n = 8) or to sham occlusion (n = 5). Heart rate (HR) and HRV indices were assessed until 72 h after HI. All HI groups showed suppressed very low frequency HRV power and elevated sample entropy for the first 3 h; more prolonged changes were associated with greater severity of HI. Analysis of relative changes in spectral power showed that the moderate and severe groups showed a shift towards higher HRV frequencies, which was most marked after severe HI. This shift was associated with abnormal rhythmic HR patterns including sinusoidal patterns in the first hour after HI, and with elevated plasma levels of arginine vasopressin, which were correlated with subsequent loss of EEG power by day 3. In conclusion, absolute changes in HRV power in the first 3 h after acute HI were not significantly related to the severity of HI. The intriguing relative shift in spectral power towards higher frequencies likely reflects greater autonomic dysfunction after severe HI. However, sinusoidal HR patterns and elevated vasopressin levels may have utility as biomarkers of severe HI.

Peripheral chemoreflex control of fetal heart rate decelerations overwhelms the baroreflex during brief umbilical cord occlusions in fetal sheep

“…2016 a ; Kasai et al . 2019). At this gestation, the neural maturation of fetal sheep is broadly comparable to the term human neonate (Barlow, 1969).…”

“…This study utilised chronically instrumented near-term fetal sheep at 0.85 of gestation, which allows for continuous monitoring of multiple cardiovascular and neurophysiological parameters simultaneously, without the confounding effects of anaesthetics. Thirty-three Romney/Suffolk fetal sheep were sourced from the University farm and surgically instrumented at 121 ± 1 days of gestational (term = 147 days), similarly to previous reports (Lear et al 2016a;Kasai et al 2019).…”

Heart Rate Variability in the Perinatal Period: A Critical and Conceptual Review

“…Interesting results came also from animal models of fetal inflammation. Studies on models of hypoxic-ischemic events in ovine fetuses showed that many fHRV metrics changed in the hours after the event: VLF decreased, whereas SampEn, HF, and RMSSD increased (Frasch et al, 2016;Kasai et al, 2019). Besides, the rise in RMSSD correlated positively with interleukin (IL)-1β levels (Frasch et al, 2016), whereas lipopolysaccharides administration showed that multidimensional fHRV metrics (i.e., both linear and non-linear) could predict the fetal inflammatory response (Durosier et al, 2015;Herry et al, 2016).…”

Trust the heart to save the brain: changes in heart rate patterns have the potential to be a biomarker for hypoxic ischaemic brain injury

“…In demonstrating a role for heart rate pattern and/or arginine vasopressin as an early biomarker of hypoxic ischaemic injury, Kasai et al .’s article builds on a wealth of work from this group, and others, in determining the physiological basis of hypoxic ischaemic injury and translates this knowledge into a potential biomarker available to be applied in clinical practice.…”

“…Could the heart rate pattern of the newborn provide the elusive biomarker for detection of an infant in the latent stage of brain injury following HI? A study by Kasai et al (2019) in this issue of The Journal of Physiology investigated the relationship between sinusoidal heart rate patterns or elevated vasopressin levels in fetal sheep following mild, moderate or severe umbilical cord occlusion resulting in hypoxic ischaemic injury. Sinusoidal HR patterns and increased vasopressin levels were frequently seen in the first hours following severe HI insults in fetal sheep.…”