Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Bennet, Laura; Galinsky, Robert; Draghi, Vittoria; Lear, Christopher A.; Davidson, J.; Unsworth, Charles P.; Gunn, Alistair J.

doi:10.1113/jp275627

Cited by 39 publications

(60 citation statements)

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“…Both animal and human data show that sex-based analysis will provide important insights about the differential response of boys and girls to treatment regimens. For example, in a preterm fetal sheep model of asphyxia, male fetuses given magnesium sulfate after umbilical cord occlusion showed a greater reduction in seizures than female fetuses 40. A similar analysis of the sexual dimorphic effect of magnesium sulfate in humans has not been done, but could lead to more precise therapy for fetuses expected to be born preterm 39 41.…”

Section: Discussionmentioning

confidence: 99%

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

Garfinkle

Yoon

Alvaro

et al. 2019

Arch Dis Child Fetal Neonatal Ed

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ObjectiveTo examine the differences and trends of outcomes of preterm boys and girls born at <29 weeks’ gestation.DesignA retrospective cohort study.SettingData collected by the Canadian Neonatal Network.PatientsNeonates born at <29 weeks’ gestation between January 2007 and December 2016.Main outcome measuresWe examined rate differences in mortality, major morbidities (bronchopulmonary dysplasia, severe brain injury, retinopathy of prematurity, necrotising enterocolitis and late-onset sepsis) and care practices (antenatal steroids, magnesium sulfate, maternal antibiotics, ventilation and surfactant administration) between boys and girls and evaluated trends in these rate differences over the study period. Our primary outcome was a composite of mortality and any one of the five morbidities.ResultsOur study included 8219 boys and 6934 girls with median gestational age of 26 (IQR 25–28) weeks. The composite of death or major morbidity was more common in boys (adjusted risk ratio 1.07, 95% CI 1.05 to 1.10) and remained higher in boys over the study period. The gap between boys and girls for mortality, however, decreased over time: the slope for boys was −0.043 (95% CI −0.071 to −0.015) and for girls was −0.012 (95% CI −0.045 to 0.020) (p=0.04). All other morbidities remained higher in boys. Care practices changed at similar rates between the sexes.ConclusionThe difference between the mortality rates for boys and girls decreased over the study period but the difference between rates of the major morbidities was unchanged. More research is needed to understand biological differences and outcome disparities.

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Section: Discussionmentioning

confidence: 99%

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

Garfinkle

Yoon

Alvaro

et al. 2019

Arch Dis Child Fetal Neonatal Ed

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“…Romney-Suffolk cross fetal sheep were instrumented on gestation day 99 (preterm, n = 36) or at day 125 (near-term, n = 25) (full term 147 days). All the surgical procedures were performed using aseptic techniques, as previously described [7,[19][20][21]. Fetal instrumentation at both gestations included brachial artery catheters for blood pressure measurement and preductal blood sample collection, and brachial vein catheters for drug infusion.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we report an analysis of pharmacokinetic models of combined first-order and mixed-order elimination, first-order and saturable EPO-R-mediated clearance and rEPO treatment-induced changes in EPO-R to describe rEPO elimination. We examined the effect of an increase in fetal size, maturation, exposure to global asphyxia, cerebral ischemia, therapeutic hypothermia and exogenous rEPO treatment on the pharmacokinetics of high-dose rEPO in well-established fetal sheep models [7,[19][20][21][22]. Finally, we compared the pharmacokinetics of high-dose rEPO in preterm fetal sheep given an i.v.…”

Section: Introductionmentioning

confidence: 99%

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

Dhillon

Wassink

Lear

et al. 2020

IJMS

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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.

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“…On day 103-104 of gestation, animals were randomly assigned to either sham asphyxia (n = 8), asphyxia + vehicle (n = 7) or asphyxia + GDQ (n = 7) groups. Umbilical cord occlusion (UCO) was induced at 07.30 hours by rapid complete inflation of the umbilical cord occluder for 25 minutes or until blood pressure fell below 8 mmHg or there was fetal asystole 29,30 . Sham control animals received no occlusion.…”

mentioning

confidence: 99%

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

Cho

Zeng

Anekal

et al. 2020

Sci Rep

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In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.Preterm birth is closely associated with long-term neurodevelopmental disability 1 . While survival rates among preterm infants have significantly improved, rates of neonatal morbidity remain high with 50% of extremely preterm infants displaying cognitive and behavioural difficulties 2-4 . The etiology of preterm brain injury is multifactorial 5 , however a key contributing factor is the greater occurrence of acute hypoxic ischemic encephalopathy (HIE) in moderately preterm infants compared to term 6 . Therapeutic mild hypothermia is now standard care for term newborns after moderate to severe HIE 7 . Despite its benefits, mild hypothermia is not recommended for preterm infants <35 weeks gestational age 8,9 . Thus, there is a considerable unmet need for neuroprotective therapies for preterm infants with acute HIE.Growing evidence suggests that inflammation plays a critical role in the pathogenesis of HIE and immunomodulatory drugs have therapeutic promise 10 . Toll-like receptors (TLRs) are key regulators of the initial inflammatory response to HI, and while implicated in brain injury, they can be neuroprotective via tolerance (pre-conditioning) and immunomodulation 11 . The TLR7 signaling pathway can modulate both pro-and anti-inflammatory responses in central and peripheral immune cells 12-15 , with the potential to reduce inflammatory injury within the CNS [16][17][18] . We have previously shown that pre-conditioning with the inflammatory mediator lipopolysaccharide (LPS) ...

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Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Cited by 39 publications

References 100 publications

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

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

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

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