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

2020 ◽  
Vol 598 (5) ◽  
pp. 999-1015 ◽  
Author(s):  
Guido Wassink ◽  
Joanne O. Davidson ◽  
Mhoyra Fraser ◽  
Caroline A. Yuill ◽  
Laura Bennet ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Cerebral Ischaemia ◽  
Additive Effects ◽  
Fetal Sheep ◽  
Near Term ◽  
Global Cerebral Ischaemia

scholarly journals Connexin hemichannel blockade improves survival of striatal GABA-ergic neurons after global cerebral ischaemia in term-equivalent fetal sheep

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Robert Galinsky ◽  
Joanne O. Davidson ◽  
Christopher A. Lear ◽  
Laura Bennet ◽  
Colin R. Green ◽  
...  
Keyword(s):  
Cerebral Ischaemia ◽  
Fetal Sheep ◽  
Connexin Hemichannel ◽  
Global Cerebral Ischaemia

Spontaneous Pre-Existing Hypoxia Does Not Affect Brain Damage after Global Cerebral Ischaemia in Late-Gestation Fetal Sheep

2014 ◽  
Vol 37 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Joanne O. Davidson ◽  
Caroline A. Yuill ◽  
Guido Wassink ◽  
Laura Bennet ◽  
Alistair J. Gunn
Keyword(s):  
Cerebral Ischaemia ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Significant Loss ◽  
Late Gestation ◽  
Sleep State ◽  
Fetal Sheep ◽  
Bilateral Carotid ◽  
Global Cerebral Ischaemia ◽  
Bilateral Carotid Artery

There is considerable evidence that a mild, non-injurious insult can protect (precondition) against a subsequent injurious insult. Typically, protection is seen when the gap between insults is several days to a week. However, the effect of mild but persistent hypoxia is unknown. In this study we examined the hypothesis that mild pre-existing hypoxia (PaO2 <17 mm Hg) would reduce neural injury in chronically instrumented late-gestation (0.85 gestation) fetal sheep exposed to 30 min of global cerebral ischaemia induced by bilateral carotid artery occlusion (normoxia: n = 9 vs. pre-existing hypoxia: n = 9) or normoxia plus sham ischaemia (sham controls: n = 9). Histopathology was assessed after 7 days of recovery. Fetuses with pre-existing hypoxia had lower PaO2 values (16.1 ± 0.6 vs. 26.0 ± 1.1 mm Hg) and were lighter at post-mortem (4,033 ± 412 vs. 5,261 ± 238 g) compared to normoxic fetuses. Cerebral ischaemia was associated with secondary cortical oedema and seizures, reduced final EEG power, loss of sleep state cycling, and significant loss of neurons and oligodendrocytes, with no significant effect of pre-existing hypoxia. Pre-existing hypoxia was associated with a significantly attenuated rise in mean arterial pressure between 18 and 36 h and slower resolution of cortical oedema between 96 and 150 h after ischaemia. These data suggest that chronic hypoxia is not associated with a significant preconditioning effect.

scholarly journals Deleterious Effects of High Dose Connexin 43 Mimetic Peptide Infusion After Cerebral Ischaemia in Near-Term Fetal Sheep

2012 ◽  
Vol 13 (5) ◽  
pp. 6303-6319 ◽  
Author(s):  
Joanne O. Davidson ◽  
Colin R. Green ◽  
Louise F. B. Nicholson ◽  
Laura Bennet ◽  
Alistair J. Gunn
Keyword(s):  
Cerebral Ischaemia ◽  
Connexin 43 ◽  
High Dose ◽  
Fetal Sheep ◽  
Mimetic Peptide ◽  
Near Term

scholarly journals The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep

2020 ◽  
Vol 21 (9) ◽  
pp. 3042 ◽  
Author(s):  
Simerdeep K. Dhillon ◽  
Guido Wassink ◽  
Christopher A. Lear ◽  
Joanne O. Davidson ◽  
Nicholas H.G. Holford ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Combined Treatment ◽  
Full Term ◽  
Prolonged Treatment ◽  
High Dose ◽  
Recombinant Erythropoietin ◽  
Fetal Sheep ◽  
Gestation Age ◽  
Near Term

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.

scholarly journals Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep

2018 ◽  
Vol 39 (11) ◽  
pp. 2246-2257 ◽  
Author(s):  
Joanne O Davidson ◽  
Guido Wassink ◽  
Vittoria Draghi ◽  
Simerdeep K Dhillon ◽  
Laura Bennet ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Optimal Rate ◽  
Global Cerebral Ischemia ◽  
Preclinical Studies ◽  
Critical Determinant ◽  
Fetal Sheep ◽  
Eeg Power ◽  
Near Term ◽  
Ischemic Encephalopathy

The optimal rate of rewarming after therapeutic hypothermia for neonatal hypoxic–ischemic encephalopathy is unknown, although it is widely suggested that slow rewarming is beneficial. Some preclinical studies suggest better outcomes with slower rewarming, but did not control for the duration of hypothermia. In this study, near-term fetal sheep (0.85 gestation) received 30 min cerebral ischemia followed by normothermia, 48 h hypothermia with rapid rewarming over 1 h, 48-h hypothermia with slow rewarming over 24 h, or 72-h hypothermia with rapid rewarming. Slow rewarming after 48 h of hypothermia improved recovery of EEG power compared with rapid rewarming ( p < 0.05), but was not different from rapid rewarming after 72 h of hypothermia. At seven days recovery, neuronal survival was partially improved by both fast and slow rewarming after 48-h hypothermia, but less than 72-h hypothermia in the cortex and CA4 ( p < 0.05). In conclusion, although electrographic recovery was partially improved by slow rewarming over 24 h following cerebral hypothermia for 48 h, optimal neuroprotection was seen with hypothermia for 72 h with rapid rewarming, suggesting that the overall duration of cooling was the critical determinant of outcomes after therapeutic hypothermia.

scholarly journals How Long is Too Long for Cerebral Cooling after Ischemia in Fetal Sheep?

2015 ◽  
Vol 35 (5) ◽  
pp. 751-758 ◽  
Author(s):  
Joanne O Davidson ◽  
Guido Wassink ◽  
Caroline A Yuill ◽  
Frank G Zhang ◽  
Laura Bennet ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Neuronal Survival ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Fetal Sheep ◽  
Bilateral Carotid ◽  
Hypothermia Group ◽  
Near Term

Therapeutic hypothermia can partially reduce long-term death and disability in neonates after hypoxic-ischemic encephalopathy. The aim of this study was to determine whether prolonging the duration of cooling from 3 days to 5 days could further improve outcomes of cerebral ischemia in near-term fetal sheep. Fetal sheep (0.85 gestation) received 30 minutes bilateral carotid artery occlusion followed by 3 days of normothermia ( n = 8), 3 days of hypothermia ( n = 8), or 5 days of hypothermia ( n = 8) started 3 hours after ischemia. Sham controls received sham ischemia followed by normothermia ( n = 8). Cerebral ischemia was associated with profound loss of electroencephalography power and spectral edge, with greater and more rapid recovery in both hypothermia groups ( P < 0.05). Ischemia was associated with severe loss of neurons in the cortex, hippocampus and thalamus ( P < 0.05), with a significant improvement in both hypothermia groups. However, the ischemia-3-day hypothermia group showed greater neuronal survival in the cortex and dentate gyrus compared with ischemia-5-day hypothermia ( P < 0.05). Ischemia was associated with induction of iba1-positive microglia, which was attenuated in both hypothermia groups ( P < 0.05). Extending the duration of delayed therapeutic hypothermia from 3 to 5 days did not improve outcomes after severe ischemia, and was associated with reduced neuronal survival in some regions.

scholarly journals Time scales of autonomic information flow in near-term fetal sheep

2012 ◽  
Vol 3 ◽  
Author(s):  
M. G. Frasch ◽  
B. Frank ◽  
M. Last ◽  
T. Müller
Keyword(s):  
Time Scales ◽  
Information Flow ◽  
Fetal Sheep ◽  
Near Term

scholarly journals Loss of interneurons and disruption of perineuronal nets in the cerebral cortex following hypoxia-ischaemia in near-term fetal sheep

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Tania M. Fowke ◽  
Robert Galinsky ◽  
Joanne O. Davidson ◽  
Guido Wassink ◽  
Rashika N. Karunasinghe ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Perineuronal Nets ◽  
Fetal Sheep ◽  
Near Term
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