A Phase I/II Trial of High-Dose Erythropoietin in Extremely Low Birth Weight Infants: Pharmacokinetics and Safety

Juul, Sandra E.; McPherson, Ronald J.; Bauer, Larry A.; Ledbetter, Kelly J.; Gleason, Christine A.; Mayock, Dennis E.

doi:10.1542/peds.2007-2711

Cited by 173 publications

(163 citation statements)

References 41 publications

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“…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: 99%

“…Animal experiments showed that high‐dose rhEPO (10,000–30,000U/kg) decreases both short‐term and long‐term brain injury, but it must be given at the time of, or very soon after, brain injury 12, 45. 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.…”

Section: Discussionmentioning

confidence: 99%

“…The side effects of rhEPO in very preterm infants have drawn much concern, especially because rhEPO has been reported to promote angiogenesis and ROP 47. However, studies in the current literature show conflicting results with regard to ROP being associated with the use of rhEPO in preterm infants 17, 20, 22, 23, 48. In a recent review of 27 studies with a total of 2,209 preterm infants, early administration of rhEPO reduced the risk associated with increased blood transfusion, but there was a tendency, although not significant, for an increase in the risk of ROP.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models,12, 13 and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants 8, 14, 15, 16, 17. In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment 17, 18, 19, 20. The neuroprotective effect of rhEPO was suggested to be through acting against apoptosis, inflammation, and neurotoxicity and by acting as an antioxidant in protecting white matter from injury and in promoting neural regeneration, injury repair, and normal development 5…”

mentioning

confidence: 99%

“…It has been shown that serum rhEPO concentrations are positively correlated with the degree of maturation during mental development in preterm infants,21 and high‐dose rhEPO (2,500U/kg) is well tolerated by preterm infants, causing no excess morbidity or mortality 14, 20. However, it is still a significant concern to use high‐dose rhEPO in very preterm infants because this might increase the potential risk of ROP 19, 22, 23.…”

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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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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Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age

Leuchter

Gui

Poncet

et al. 2014

JAMA

132

100

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A Phase I/II Trial of High-Dose Erythropoietin in Extremely Low Birth Weight Infants: Pharmacokinetics and Safety

Abstract: Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants, causing no excess morbidity or mortality. Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels.

Cited by 173 publications

References 41 publications

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

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

Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age

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