A working model for hypothermic neuroprotection

Wassink, Guido; Davidson, J.; Lear, Christopher A.; Juul, Sandra E.; Northington, Frances J.; Bennet, Laura; Gunn, Alistair J.

doi:10.1113/jp274928

Cited by 67 publications

(88 citation statements)

References 121 publications

(137 reference statements)

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“…This study evaluated the potential utility of FHRV as a biomarker of the severity of HI in near‐term fetal sheep within the established therapeutic window for hypothermia of the first 6 h after HI (Wassink et al . ). VLF spectral power of FHRV was consistently suppressed after all severities of HI.…”

Section: Discussionmentioning

confidence: 97%

“…; Wassink et al . ). Consistent with the previous finding of delayed suppression of FHRV in preterm fetal sheep after severe HI leading to brain stem injury (George et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Wassink et al . ). Moreover, in some cases it is likely that HI was initiated well before birth, further reducing the time for intervention.…”

Section: Introductionmentioning

confidence: 97%

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

Kasai

Lear

Davidson

et al. 2019

The Journal of Physiology

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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.

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Section: Discussionmentioning

confidence: 97%

“…; Wassink et al . ). Consistent with the previous finding of delayed suppression of FHRV in preterm fetal sheep after severe HI leading to brain stem injury (George et al .…”

Section: Discussionmentioning

confidence: 97%

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

Kasai

Lear

Davidson

et al. 2019

The Journal of Physiology

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“…rEpo is reported to have potent, potentially beneficial, anti‐apoptotic, anti‐oxidant and anti‐inflammation effects in models of inflammatory and HI induced perinatal brain injury (Wassink et al . ). Moreover, it promotes the proliferation, maturation and differentiation of oligodendrocytes and neurons, and could promote neurorepair after HI.…”

Section: Introductionmentioning

confidence: 97%

“…These findings parallel previous experience with therapeutic hypothermia where optimal neuroprotection is achieved when cooling is started as early as possible during the latent phase and continued until secondary events such as seizures have resolved, after approximately 72 h (Wassink et al . ).…”

Section: Introductionmentioning

confidence: 97%

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Wassink

Davidson

Fraser

et al. 2020

The Journal of Physiology

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Key points Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether the combination of high‐dose rEpo therapy with therapeutic hypothermia can further improve outcomes. Hypothermia and rEpo independently improved neuronal survival, with greater improvement with hypothermia, and similarly reduced numbers of caspase‐3 positive cells and reactive microglia after 7 days recovery. Hypothermia, but not rEpo, was associated with markedly improved EEG power, whereas both interventions improved recovery of EEG frequency. There was no significant improvement in any outcome after combined rEpo and hypothermia compared with hypothermia alone, and of concern, the combination was associated with increased numbers of cortical caspase‐3‐positive cells compared with ischaemia‐hypothermia. These data suggest that the mechanisms of neuroprotection with hypothermia and rEpo overlap and, thus, high‐dose rEpo infusion does not appear to be an effective adjunct therapy for therapeutic hypothermia. Abstract Therapeutic hypothermia for hypoxic‐ischaemic encephalopathy (HIE) provides incomplete neuroprotection. Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether adjunct rEpo therapy with therapeutic hypothermia can further improve outcomes. Near‐term fetal sheep received sham‐ischaemia (n = 9) or global cerebral ischaemia for 30 min (ischaemia‐vehicle, n = 8), followed by intravenous infusion of rEpo (ischaemia‐Epo, n = 8; 5000 U/kg loading dose, then 833.3 U/kg/h), cerebral hypothermia (ischaemia‐hypothermia, n = 8), or rEpo plus hypothermia (ischaemia‐Epo‐hypothermia, n = 8), from 3 to 72 h post ischaemia. Fetal brains were collected 7 days after cerebral ischaemia. Cerebral ischaemia was associated with severe neuronal loss and microglial induction in the parasagittal cortex and subcortical regions. Hypothermia reduced overall neuronal loss, cortical caspase‐3 and reactive microglia in the striatum and cortex, with greater recovery of electroencephalographic (EEG) power and spectral edge (SEF) from 48 h onwards. rEpo independently improved neuronal survival in the parasagittal cortex, hippocampal CA4 and thalamus, and reduced cortical caspase‐3 and activated microglia in striatal and cortical areas, with greater SEF from 120 h onwards. However, ischaemia‐Epo‐hypothermia did not further improve outcomes compared with ischaemia‐hypothermia and was associated with increased numbers of cortical caspase‐3‐positive cells. These findings suggest that although delayed, prolonged treatment with both hypothermia and rEpo are independently neuroprotective, they have overlapping anti‐inflammatory and anti‐apoptotic mechanisms, such that the delayed, high‐dose rEpo infusion for 3 days did not materially augment neuroprotection with therapeutic hypothermia.

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Long‐term effect of indomethacin on a rat model of neonatal hypoxia ischemic encephalopathy through behavioral tests

Tepe,

Satar,

Ozdemir

et al. 2023

Intl J of Devlp Neuroscience

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BackgroundMany medical experts prescribe indomethacin because of its anti‐inflammatory, analgesic, tocolytic, and duct closure effects. This article presents an evaluation of the enduring impact of indomethacin on neonatal rats with hypoxic–ischemic (HI) insults, employing behavioral tests as a method of assessment.MethodsThe experiment was conducted on male Wistar‐Albino rats weighing 10 to 15 g, aged between seven and 10 days. The rats were divided into three groups using a random allocation method as follows: hypoxic ischemic encephalopathy (HIE) group, HIE treated with indomethacin group (INDO), and Sham group. A left common carotid artery ligation and hypoxia model was applied in both the HIE and INDO groups. The INDO group was treated with 4 mg/kg intraperitoneal indomethacin every 24 h for 3 days, while the Sham and HIE groups were given dimethylsulfoxide (DMSO). After 72 h, five rats from each group were sacrificed and brain tissue samples were stained with 2,3,5‐Triphenyltetrazolium chloride (TCC) for infarct‐volume measurement. Seven rats from each group were taken to the behavioral laboratory in the sixth postnatal week (PND42) and six from each group were sacrificed for the Evans blue (EB) experiment for blood–brain barrier (BBB) integrity evaluation. The open field (OF) test and Morris water maze (MWM) tests were performed. After behavioral tests, brain tissue were obtained and stained with TCC to assess the infarct volume.ResultsThe significant increase in the time spent in the central area and the frequency of crossing to the center in the INDO group compared with the HIE group indicated that indomethacin decreased anxiety‐like behavior (p < 0.001, p < 0.05). However, the MWM test revealed that indomethacin did not positively affect learning and memory performance (p > 0.05). Additionally, indomethacin significantly reduced infarct volume and neuropathological grading in adolescence (p < 0.05), although not statistically significant in the early period. Moreover, the EB experiment demonstrated that indomethacin effectively increased BBB integrity (p < 0.05).ConclusionsIn this study, we have shown for the first time that indomethacin treatment can reduce levels of anxiety‐like behavior and enhance levels of exploratory behavior in a neonatal rat model with HIE. It is necessary to determine whether nonsteroidal anti‐inflammatory agents, such as indomethacin, should be used for adjuvant therapy in newborns with HIE.

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A working model for hypothermic neuroprotection

Cited by 67 publications

References 121 publications

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

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

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Long‐term effect of indomethacin on a rat model of neonatal hypoxia ischemic encephalopathy through behavioral tests

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