The effects of dexamethasone on post‐asphyxial cerebral oxygenation in the preterm fetal sheep

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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.

Section: Discussionmentioning

confidence: 97%

Section: Figure 3 Spectral Power and Sample Entropy Of Fetal Heart Rmentioning

confidence: 99%

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

Kasai

Lear

Davidson

et al. 2019

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“…), and this was associated with increased EEG activity and seizure activity, and evidence of uncoupling of CBF and cerebral metabolism as well as exacerbated hyperglycaemia (Lear et al . ). In contrast, when dexamethasone was given 4 h pre‐HI, there was a significant increase in neural injury, including induction of cystic lesions, despite evidence of reduced cytotoxic oedema during HI (Lear et al .…”

Section: The Global Burden Of Hypoxic–ischaemic Brain Injurymentioning

confidence: 97%

“…In preterm fetal sheep, increasing plasma glucose to similar levels to those seen after dexamethasone produced the same severe cystic injury patterns as seen with dexamethasone (Lear et al . , ). Given that post‐HI dexamethasone was associated with more modest injury (Koome et al .…”

Section: The Global Burden Of Hypoxic–ischaemic Brain Injurymentioning

confidence: 99%

The fetus at the tipping point: modifying the outcome of fetal asphyxia

Dhillon

Lear

Galinsky

et al. 2018

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Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia-ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia-ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia-ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia.

“…), and this may relate to uncoupling of cerebral blood flow and metabolism and/or hyperglycaemia (Lear et al . ). Pre‐treatment of near‐term fetal sheep with glucocorticoids 48 h before cerebral ischaemia induced by carotid artery occlusion did not provide neuroprotection (Elitt et al .…”

Section: Introductionmentioning

confidence: 97%

Sex, drugs and rock and roll: tales from preterm fetal life

Bennet

2017

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Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.