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 Window of Opportunity of Cerebral Hypothermia for Postischemic White Matter Injury in the Near-Term Fetal Sheep

2004 ◽  
Vol 24 (8) ◽  
pp. 877-886 ◽  
Author(s):  
Vincent Roelfsema ◽  
Laura Bennet ◽  
Sherly George ◽  
David Wu ◽  
Jian Guan ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Basic Protein ◽  
White Matter Injury ◽  
Window Of Opportunity ◽  
Reactive Microglia ◽  
Fetal Sheep ◽  
Near Term ◽  
Protein Density

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4±0.1°C to between 30 and 33°C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41±20 vs 18±11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14±12 vs 91±51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4±6 vs 38±18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24±12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.

scholarly journals Dopamine does not limit fetal cerebrovascular responses to hypoxia

2007 ◽  
Vol 102 (1) ◽  
pp. 130-134 ◽  
Author(s):  
Dennis E. Mayock ◽  
Rachel Bennett ◽  
Roderick D. Robinson ◽  
Christine A. Gleason
Keyword(s):  
Infusion Rate ◽  
Perfusion Pressure ◽  
High Dose ◽  
Fetal Hypoxia ◽  
Fetal Sheep ◽  
Dopamine Infusion ◽  
Cerebrovascular Resistance ◽  
Arterial Blood ◽  
Cerebral Vasodilatation ◽  
Near Term

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 μg·kg−1·min−1 while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 ± 14.1% and CVR decreased 38.9 ± 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 μg·kg−1·min−1, begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 μg·kg−1·min−1. Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 μg·kg−1·min−1. This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.

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 Non-Additive Effects of Delayed Connexin Hemichannel Blockade and Hypothermia after Cerebral Ischemia in Near-Term Fetal Sheep

2015 ◽  
Vol 35 (12) ◽  
pp. 2052-2061 ◽  
Author(s):  
Joanne O Davidson ◽  
Alexandra L Rout ◽  
Guido Wassink ◽  
Caroline A Yuill ◽  
Frank G Zhang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Activity ◽  
Recovery Period ◽  
Fetal Sheep ◽  
Treatment Groups ◽  
Intracerebroventricular Infusion ◽  
Eeg Power ◽  
Near Term ◽  
Connexin Hemichannel ◽  
Ischemic Encephalopathy

Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia ( n = 8), hypothermia for 3 days ( n = 8), connexin hemichannel blockade (50 umol/L intracerebroventricular over 1 hour followed by 50 umol/L over 24 hours, n = 8) or hypothermia plus hemichannel blockade ( n = 7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology ( P < 0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.

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

Erythropoietin Concentrations in Cerebrospinal Fluid of Nonhuman Primates and Fetal Sheep following High-Dose Recombinant Erythropoietin

Neonatology ◽  
2004 ◽  
Vol 85 (2) ◽  
pp. 138-144 ◽  
Author(s):  
Sandra E. Juul ◽  
Ronald J. McPherson ◽  
Francis X. Farrell ◽  
Linda Jolliffe ◽  
Dana J. Ness ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Nonhuman Primates ◽  
High Dose ◽  
Recombinant Erythropoietin ◽  
Fetal Sheep
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