An Approach to Using Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

Fauchère, Jean‐Claude; Dame, Christof; Vonthein, Reinhard; Koller, Brigitte; Arri, S. J.; Wolf, Martin; Bucher, Hans Ulrich

doi:10.1542/peds.2007-2591

Cited by 149 publications

(127 citation statements)

References 50 publications

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“…The mechanisms behind the reduced incidence of NEC and sepsis are not fully understood; however, rhEPO protects epithelial barrier function and protects intestine from excessive autophagy and apoptosis, and this, as well as rhEPO's immunomodulation actions, might provide beneficial effects in preventing NEC and sepsis 49, 50. Furthermore, there were no adverse effects such as thrombosis, hypertension, polycythemia, or polyplastocytosis observed, which is in line with previous reports,20, 37 suggesting that the current protocol of repeated low‐dose rhEPO treatment in this study is protective and safe.…”

Section: Discussionsupporting

confidence: 86%

“…The rates for mortality and morbidities, including ICH and NEC, were not significantly changed by early rhEPO treatment 23. Other recent studies showed that early high‐dose rhEPO (2,500–3,000U/kg) administered once in very preterm infants did not increase the incidence or severity of ROP 20, 37. In the current study, low‐dose rhEPO (500U/kg) treatment decreased the risk of NEC and sepsis and did not increase the risk of ROP or BPD.…”

Section: Discussionsupporting

confidence: 54%

“…This high‐dose rhEPO in rodents was equivalent to that in preterm infants given at a high dose of 1,000 to 2,500U/kg 20. Based on those results from neonatal rodent brain injury models, clinical studies showed that high‐dose rhEPO (2,500–3,000U/kg) administered after birth was well tolerated in preterm and term infants14, 20, 33, 37, 42 and conferred neuroprotection 16, 36. In a previous study using low‐dose rhEPO to prevent anemia in preterm infants, it was observed that preterm infants with rhEPO treatment also had significant neurodevelopmental improvement 38.…”

Section: Discussionmentioning

confidence: 86%

“…Recent experimental34, 35 and clinical17, 36, 37, 38 studies indicate that rhEPO is a promising candidate for very preterm infants with brain injury and that it improves neurodevelopment and reduces the risk of neurodevelopmental disability. However, the safe dose range, timing, and duration of rhEPO administration still require careful exploration and consideration.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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ObjectiveTo evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants.MethodsA total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age.ResultsDeath and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed.InterpretationRepeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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“…Very recently, two safety studies have been concluded in very preterm infants and infants with extremely low birth weight. 120,121 In both studies, high-dose EPO was found well tolerated, causing no excess morbidity or mortality. A dose range of 1000 to 3000 IU/kg was found to yield neuroprotective serum levels.…”

Section: Erythropoietin As Neuroprotective/ Neuroregenerative Treatmementioning

confidence: 85%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

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Erythropoiesis-Stimulating Agent Administration and Survival After Severe Traumatic Brain Injury

Talving

Lustenberger²,

Inaba³

et al. 2012

Arch Surg

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To validate previous findings of the effects of erythropoiesis-stimulating agent (ESA) administration following severe traumatic brain injury. Design: Prospective observational study of all patients with severe traumatic brain injury admitted to the surgical intensive care unit (SICU) at our institution from January 1, 2009, to December 31, 2010 (head Abbreviated Injury Scale score Ն3). Propensity scores were calculated to match patients who received ESA within 30 days after admission to patients who did not receive ESA. Patients: A total of 566 patients with severe traumatic brain injury were admitted to the SICU. After matching in a 1:1 ratio, 75 matched pairs were analyzed. Main Outcome Measures: ⌬ Glasgow Coma Scale score (difference between admission and SICU discharge), in-hospital morbidity, and mortality. Results: Patients who received ESA and control subjects who did not receive ESA had similar age, mechanisms of injury, vital signs on admission, Abbreviated Injury Scale scores, Injury Severity Scores, and specific intracranial injuries. Patients who received ESA experienced significantly longer lengths of stay in the SICU (mean [SD], 16.1 [1.3] days vs 8.6 [0.8] days; PϽ.001) and comparable SICUfree days. There was no statistically significant difference in the incidence of major in-hospital complications including deep venous thrombosis and pulmonary embolism when comparing the 2 study cohorts. The ⌬ Glasgow Coma Scale mean [standard error of the mean] score was 3.0 [0.4] and 2.4 [0.5] in patients who received ESA and those who did not, respectively (P=.33). However, in-hospital mortality was significantly lower for patients who received ESA compared with those who did not (9.3% vs 25.3%; odds ratio, 0.25; 95% CI, 0.08-0.75; P=.012). Conclusions: Erythropoiesis-stimulating agent administration demonstrates a significant survival advantage without an increase in morbidity in patients with severe traumatic brain injury.

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An Approach to Using Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

Cited by 149 publications

References 50 publications

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

Erythropoiesis-Stimulating Agent Administration and Survival After Severe Traumatic Brain Injury

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