Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years

Natalucci, Giancarlo; Latal, Beatrice; Koller, Brigitte; Rüegger, Christoph M.; Sick, Beate; Held, Leonhard; Bucher, Hans Ulrich; Fauchère, Jean‐Claude

doi:10.1001/jama.2016.5504

Cited by 121 publications

(109 citation statements)

References 37 publications

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“…Indeed, an association of age with the severity of injury has shown mixed results in human studies. In a recent study of early prophylactic high-dose EPO in very preterm infants, there were no statistically significant differences in neurodevelopmental outcomes at 2 years, despite positive changes in MRI at earlier ages between the placebo- and EPO-treated groups [38]. …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

et al. 2017

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The neonatal brain is highly susceptible to oxidative stress as developing endogenous antioxidant mechanisms are overwhelmed. In the neonate, superoxide dismutase (SOD) overexpression worsens hypoxic-ischemic injury due to H₂O₂ accumulation in the brain. Erythropoietin (EPO) is upregulated in 2 phases after HI, early (4 h) and late (7 days), and exogenous EPO has been effective in reducing the injury, possibly through reducing oxidative stress. We hypothesized that exogenous EPO would limit injury from excess H₂O₂ seen in SOD1-overexpressing mice, and thus enhance recovery after HI. We firstwanted to confirm our previous findings in postnatal day 7 (P7) SOD-tg (CD1) mice using a P9 model of the Vannucci procedure of HI with SOD-tg mice from a different background strain (C57Bl/6), and then determine the efficacy of EPO treatment in this strain and their wild-type (WT) littermates. Thus, mice overexpressing copper/zinc SOD1 were subjected to HI, modified for the P9 mouse, and recombinant EPO (5 U/g) or vehicle (saline) was administered intraperitoneally 3 times: at 0 h, 24 h, and 5 days. Injury was assessed 7 days after HI. In addition, protein expression for EPO and EPO receptor was assessed in the cortex and hippocampus 24 h after HI. With the moderate insult, the SOD-tg mice had greater injury than the WT overall, confirming our previous results, as did the hippocampus and striatum when analyzed separately, but not the cortex or thalamus. EPO treatment worsened injury in SOD-tg overall and in the WT and SOD-tg hippocampus and striatum. With the more severe insult, all groups had greater injury than with the moderate insult, but differences between SOD-tg and WT were no longer observed and EPO treatment had no effect. Increased protein expression of EPO was observed in the cortex of SOD-tg mice given recombinant human EPO compared to SOD-tg given vehicle. This study confirms our previous results showing greater injury with SOD overexpression in the neonatal brain after HI at P7 in a different strain. These results also suggest that EPO treatment cannot ameliorate the damage seen in situations where there is excess H₂O₂ accumulation, and it may exacerbate injury in settings of extreme oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

et al. 2017

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“…We believe that early EPO administration is necessary to target pathways of VIBI and prevent injury manifestation. However, the only clinical trial in which preterm infants were administered the first dose of high-dose EPO within the first 3 h of birth has presented discouraging 2-year follow-up results showing no differences in neurodevelopmental outcomes between EPO and placebo groups [52] . Indeed, the therapeutic time window of EPO administration needs to be ascertained before the full neuroprotective potential of EPO for VIBI can be established.…”

Section: Discussionmentioning

confidence: 99%

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

et al. 2017

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Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.

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“…Moreover, rEpo application seems to improve white matter integrity (assessed by MRI) and neurocognitive outcomes (in retrospective and prospective investigations) [147,148,[150][151][152][153] . Other studies did not reveal any positive effects of rEpo therapy [154] . This might again be due to different doses and application regimes, ranging from high-dose application for a few days to lower doses for several weeks.…”

Section: Hormonesmentioning

confidence: 84%

Hyperoxia and the Immature Brain

et al. 2016

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Despite major advances in obstetrics and neonatal intensive care, preterm infants frequently suffer from neurological impairments in later life. Preterm and also full-term neonates are generally susceptible to injury caused by reactive oxygen species due to the immaturity of endogenous radical scavenging systems. It is well known that high oxygen levels experienced during the critical phase of maturation can profoundly influence developmental processes. Supraphysiological oxygen concentrations used for resuscitation or in the care of critically ill infants are known to have deleterious effects on the developing lung and retina, contributing to the pathophysiology of neonatal diseases like bronchopulmonary dysplasia and retinopathy of prematurity. Moreover, experimental work from the last decade suggests that hyperoxia also leads to neuronal and glial cell death, contributing to the injury of white and grey matter observed in preterm infants. During the critical phase of brain maturation, hyperoxia can alter developmental processes, resulting in the disruption of neural plasticity and myelination. However, oxygen therapy can often not be avoided in neonatal intensive care. Therefore, in situations requiring oxygen supplementation, in addition to the development of appropriate monitoring systems, protective and/or regenerative strategies are highly warranted. Here, we summarise the clinical and experimental evidence as well as potential therapeutic strategies, providing an overview of the pathophysiology of oxygen exposure on the developing central nervous system and its impact on neonatal brain injury.

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Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years

Cited by 121 publications

References 37 publications

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

Hyperoxia and the Immature Brain

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