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Erythropoietin as a NeonatalNeuroprotective AgentSandra Juul, MD, PhD*

Author DisclosureDr Juul has disclosedno nancialrelationships relevantto this article. Thiscommentary doescontain a discussionof an unapproved/investigative use of a

commercial product/device.

Objectives After completing this article, readers should be able to:1. Review the historical use of erythropoietin (Epo) to treat anemia.2. Describe the rationale for Epo use in neonatal brain disease.3. Delineate the potential risks and benets associated with Epo use in neonatal

populations.

AbstractBrain injury is common in critically ill preterm and term infants. To date, no proventherapies are available for preterm infants who experience intracranial hemorrhage or white matter injury. Hypothermia appears to improve the outcome of term or near-terminfants who have perinatal asphyxia, but only among those who have mild-to-moderate

injury. This article provides an overview of a novel approach to neuroprotection: high-dose recombinant erythropoietin (rEpo). This treatment has potential for stand-alone useor as an adjunct to hypothermia. Experimental and clinical data supporting the use of erythropoietin (Epo) as a neuroprotective agent for neonates who have brain injury arediscussed.

Introduction A circulating hematopoietic factor initiallywas posited by Carnot and DeFlandre in 1906 aftertheobservation that blood transfused from a rabbit that hada hemorrhage could stimulate redcell production in another rabbit. (1) Seventy-one years later, a 30.4-kDa glycoproteinerythropoietic factor was isolated from the urine of patients who had aplastic anemia. (2) Theavailability of this factor allowed for the structural analysis of Epo, which led to its cloning in1985. (3) This advance precipitated a rapid evolution of events: rEpo was produced, clinicaltrials of rEpo treatment for anemia of chronic renal disease showed benet, (4) and rEpo wasapproved by the United States Food and Drug Administration (FDA) in 1989 (Fig. 1). Fur-ther research into other possible applications of rEpo included its use for anemia of pre-maturity. Between 1991 and 2009, more than 2,700 preterm infants were enrolled in 33randomized, controlled trials to evaluate the safety and efcacy of rEpo as a treatment foranemia of prematurity. Treatment regimens varied widely, with doses ranging from 70 to5,000 U/kg per week and the duration of therapy ranging from 2 weeks to several months.(5)(6)(7) Early neonatal studies used doses extrapolated from adult data, but these dosesshowed little benet. Subsequent studies in neonatal animals and clinical trials demonstratedthat neonates have a threefold higher volume of distribution and more rapid clearance thanadults, necessitating the use of higher per kilogram doses to achieve the same erythropoietic

effects. (8)(9) Later studies, using doses more appropriate forneonates, showed a marked erythropoietic response to exogenousrEpo. (6)(10) The overall effectiveness of rEpo in the preventionof neonatal transfusions varies and depends on the dose used, thedosing interval, and most importantly, the phlebotomy practicesand transfusion guidelines used at any given institution.

Nonhematopoietic Roles of EpoEpo functions by binding to its cell surface homodimer re-ceptor. In the mid-1990s, the expression of functional Eporeceptors (EpoR) on nonerythropoietic cell lines was identied

*Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, Wash.

AbbreviationsBBB: blood-brain barrierEpo: erythropoietinEpoR: erythropoietin receptorFDA: Food and Drug AdministrationrEpo: recombinant erythropoietinROP: retinopathy of prematurity

Article neurology

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and conrmed. (11)(12)(13) During fetal development,EpoR expression is widespread, including not only eryth-rocyte precursors in the marrow, but also liver stromalcells, smooth muscle cells, myocardiocytes, endothelialcells, enterocytes, epithelial cells in the lung, retinal cells,placental tissues, Leydig cells, and cells specic to thecentral nervous system. (11)(13) Because the absenceof Epo or EpoR expression during fetal developmentis lethal, (14) due to severe anemia, the tissue-speciceffects of Epo during development are not obvious.Nonetheless, using tissue-specic gene manipulation, re-searchers have shown that Epo expression is required fornormal neuronal maturation (15) and brain development(16) and that neurons from Epo or EpoR null mutationembryos show increased vulnerability to hypoxia. (17)Epo itself is expressed early in embryonic development,beginning in the yolk sac, progressing to the liver, and

nally, in postnatal life, to the kidneys. Epo also isexpressed by astrocytes in the brain. (18)

Neuroprotective Effects of EpoThe tissue-protective properties of rEpo have been stud-ied most extensively in adult models, although evidencealso supports rEpo treatment as a benecial strategy forneonatal brain injury. Reversal of brain injury is theoret-ically possible because damage continues to occur fordays or even weeks after an acute injury. Mechanisms thatpromote brain death, such as apoptosis, inammation, orglutamate toxicity, all have the potential for reversal in

the period following injury. To be considered as a useful

therapeutic approach, treatmentmust be safe, effective, accessible,affordable, and practical.

In Vitro StudiesIn vitro experiments have shownthat rEpo has direct neuroprotec-tive effects, binding to the cell-surface EpoR homodimer to acti- vate antiapoptotic pathways viaJAK2, STAT 5, and nuclear factor-kappa-B phosphorylation. (19)rEpo improves the viability of neurons cultured in varied noxiousconditions, including hypoxia-ischemia (oxygen glucose depriva-tion), glutamate toxicity, and nitricoxide toxicity. (19)(20)

Epo also has direct effects onoligodendrocytes, the cells hypoth-esized to have critical vulnerability

in the development of white matter injury seen so com-monly in preterm infants. rEpo promotes the maturationand differentiation of oligodendrocytes in culture, (21)protects these cells from interferon-gamma and lipopoly-saccharide toxicity, (22) and improves white matter sur- vival in vivo. (23)

In Vivo StudiesEpo is a large, negatively charged glycoprotein that isunlikely to cross the blood-brain barrier (BBB) readily. Accordingly, early in vivo experiments used intracere-bral injections of rEpo to demonstrate neuroprotection. Although interesting, such a treatment, even if effective, would be unlikely to be adopted for clinical use. In 2000,Brines and associates (24) showed that high doses of rEpo (5,000 U/kg) had protective effects in adult mod-els of brain injury when administered by intraperitoneal

injection. Further study demonstrated that in both adultand perinatal animals, high doses of rEpo could beadministered systemically and result in detectable in-creases in Epo concentrations in spinal uid and brainextract that, based on cell culture results, could be withina neuroprotective range. (25)(26) However, less than 1%of the circulating rEpo crosses the BBB, necessitating theadministration of high doses. Having said this, it isimportant to note that lower doses may cross if the BBBhas been breached. In the ensuing years, hundreds of studies were published, testing a range of rEpo doses upto 30,000 U/kg. Because of concerns that the very

highest range of dosing (20,000 to 30,000 U/kg) may

Figure 1. History of erythropoietin.

neurology erythropoietin neuroprotection

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not be protective and might be injurious, these doses arenot recommended. (27)(28)(29)

When tested in vivo, protective effects important forreducing acute brain injury include decreased apoptosis,(30) inammation, (31) excitotoxicity, (32) and gluta-mate toxicity. (33) rEpo also may be benecial for latebrain recovery because it stimulates neurogenesis, angio-genesis, and migration of regenerating neurons. (17) Ina model of N-methyl-D-aspartate-antagonist MK-801-induced drug toxicity, rEpo conferred 50% neuroprotec-tion due to stimulation of brain-derived neurotrophicfactor and glial cell line-derived neurotrophic factor. (34)Epo is involved directly in prevention of oxidative stress, with generation of antioxidant enzymes, inhibition of nitric oxide production, and decrease of lipid peroxida-tion (Fig. 2). These properties may be relevant in thera-peutic prevention of injury in developing brains of pre-term infants, whose antioxidant systems are immature.Of note, these studies were performed in rodents, and

there are many important differences between the devel-oping rodent and human brain. Further studies are on-going in larger animal models such as piglets and non-human primates. (35)

Clinical TrialsTo date, three clinical trials examining the safety andefcacy of high-dose rEpo as a potential therapy forneonatal brain injury have been published. In a phase Itrial designed to examine safety, newborns born at24 to 31 complete weeks of gestation and weighingless than 1,500 g were randomized into a double-

masked trial comparing rEpo (3,000 U/kg 3 doses,

n 30) with placebo (n 15). (36)Treatments were started by 3 hoursafter birth and administered daily for 3 days. No differences werenoted between groups in any majorproblems of prematurity: retinopa-thy of prematurity (ROP), intracra-nial hemorrhage, sepsis, necrotiz-ing enterocolitis, or lung disease.The follow-up multicenter ran-domized, controlled study is ongo-ing in Switzerland. Another phaseI/II study was completed to evalu-ate the safety and pharmacokineticsof three rEpo doses given to infants who weighed less than 1,000 gduring the rst 3 days after birth.(37) Three rEpo treatment groups(500 U/kg, 1,000 U/kg, and

2,500 U/kg) containing 10 infants in each were com-pared with 30 untreated control infants. The plasma Epoconcentrations achieved using 500 to 1,000 U/kg intra- venously were similar to those obtained from rats givenintraperitoneal or subcutaneous injections of 5,000 U/kg, (26) suggesting that this may be a suitable dosingrange. Safety parameters also were evaluated, and there were no complications noted in the rEpo-treated infants.In the third study, rEpo was evaluated as a neuroprotec-tive treatment for perinatal hypoxia-ischemia in terminfants. (38) A total of 167 term infants who hadmoderate-to-severe hypoxic-ischemic encephalopathy were randomized to either rEpo (n 83) or conventionaltreatment (n 84). rEpo-treated babies received either300 U/kg (n 52) or 500 U/kg (n 31) every other day for 2 weeks. Death or disability occurred in 43.8% of controls compared with 24.6% in the rEpo groups(P 0.017) at 18 months, with no discernible differencebetween rEpo doses. No adverse effects of rEpo were

identied.Other reports suggest rEpo treatment might improve

neurodevelopmental outcome. For example, in a study designed to test the effects of rEpo on erythropoiesis,infants whose birthweights were 1,250 g or less wererandomized to rEpo or control treatment from day 4after birth until 35 weeks corrected gestational age. (39) When all rEpo-treated infants were considered, there wasno difference in neurodevelopmental outcomes at 18 to22 months. However, in preterm infants weighing lessthan 1,000 g treated with rEpo, those whose serum Epoconcentrations were greater than 500 U/mL had higher

Mental Development Index scores than infants whose

Figure 2. Mechanisms of recombinant erythropoietin neuroprotection. NO nitric oxide




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Epo concentrations were less than 500 mU/mL whentested at 18 to 22 months corrected age. (40) Finally,clinical trials of rEpo in adult populations also are begin-ning to identify neuroprotective effects. (41)

Potential Adverse EffectsComplications of rEpo therapy identied in adult popu-lations include polycythemia, rash, seizures, hyperten-sion, shortened time to death, myocardial infarction,congestive heart failure, progression of tumors, andstroke. To date, none of these adverse effects have beenreported in rEpo-treated neonates. In addition, no pro-spective studies of rEpo treatment of neonates havereported group differences in the incidence of neonatalmorbidities, including intraventricular hemorrhage,ROP, necrotizing enterocolitis, chronic lung disease, orlate-onset sepsis. (6)

rEpo is a potent erythropoietic growth factor. Thus,high doses administered for neuroprotective treatmentmight be expected to increase erythropoiesis and possibly megakaryocytopoiesis. In neonatal rats, there was a tran-sient increase in hematocrit following high-dose rEpo,(42) but in preterm infants, although three doses of rEpo increased reticulocytosis, they did not affect hemat-ocrit, likely due to early phlebotomy losses. (37) Theeffect of brief treatments of high-dose rEpo on ironbalance is not known.

The potential contribution of rEpo to the develop-ment of ROP in preterm populations is controversial.Most data come from retrospective studies or meta-analyses of prospective studies for which ROP was not aprimary outcome measure. ROP occurs in two phases,the rst involving a loss of retinal vasculature followingbirth and the second involving uncontrolled prolifera-tion of retinal vessels. EpoR are present on endothelialcells, and rEpo stimulation increases their angiogenicexpression. (43) Early high-dose rEpo theoretically may have a protective effect on the retina by ameliorating the

rst stage of ROP. Alternatively, the angiogenic proper-ties of Epo may prevail, resulting in an increase in ROP.The Cochrane review noting an increase in ROP afterearly rEpo use has raised concerns. (44) In fact, theassociation of anemia with ROP (45) raises the possibleinterpretation that ROP is more directly related to ane-mia and only incidentally related to rEpo used to treatanemia. In addition, because supplemental iron was usedin combination with rEpo in every case, the effect of rEpo alone remains unknown. Other studies have raisedquestions about cumulative dosing of rEpo affectingROP rather than absolute dosing. (46)(47) Still others

question the timing of rEpo dosing relative to the

timing of vascular proliferation in the retina, which gen-erally occurs around 32 weeks corrected gestational age.(45)(47) Animal data suggest timing might be very important. In a mouse model of ROP, early rEpo treat-ment decreased the development of ROP, while latetreatment administered during the proliferative stagecontributed to neovascularization and disease. (45) Incontrast, using a rat model of ROP, no benecial orharmful effects of repeated high-dose rEpo administra-tion (5,000 U/kg 3 doses) on retinal vascularization were observed. (29)

It is of some concern that an extremely high concen-tration of rEpo (40 U/mL) was neurotoxic using an in vitro slice and neuronal culture model of mild hypoxia, as was high-dose rEpo in vivo (20,000 U/kg intraperito-neally 2). (28) These ndings demonstrate that furthertesting of rEpo in the developing brain is warranted. It isreassuring that when used at lower doses in neonatal rats(2,500 or 5,000 U/kg), no such toxicity was noted. In aseries of experiments to test safety, the long-term effectsof high dose rEpo (0, 2,500, or 5,000 U/kg) adminis-tered in the rst postnatal week in three experimentalgroups was assessed: 1) normoxic newborn rats, 2) nor-mal newborn rats exposed to 2 hours of hypoxia (8% O 2 )daily, or 3) animals that underwent unilateral brain injury. (42) rEpo treatment transiently raised the hemato-crit in treated animals. It also prevented hypoxia-induceddelays in geotaxis and growth as well as hypoxia-ischemia-induced learning impairment and substantianigra neuron loss. No adverse long-term behavioral,structural, or immunohistochemical effects were identi-ed. Limitations of this study include the fact that morecomplex behavioral testing comparable to a human in-fant cannot be assessed in rats.

Future DirectionsMore data are needed to dene the optimal timing of

treatment as well as the optimal dose and number of doses of rEpo. Most studies have examined the effectsof very early rEpo administration. Recently, another dos-ing strategy has been proposed by Gonzalez and associ-ates, (48) using two early doses and one additional dose7 days after injury. This may provide additional benet,decreasing late apoptosis. It is important to keep in mindthat the answers to these questions may vary withthe mechanism of injury under discussion. Thus, a dosethat is optimal for neuroprotection to reduce hypoxic-ischemic encephalopathy may not be optimal for pro-phylaxis of white matter disease in extremely low-

birthweight preterm infants.




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There are other exciting developments in this area,investigating Epo analogs such as asialo Epo and car-bamylated Epo as possible alternatives to rEpo. Theseagents may provide more specic neuroprotection with-out the hematopoietic potential of rEpo. Additionalfuture possibilities include the use of rEpo with othertreatment modalities such as hypothermia. To date, hy-pothermia is the only proven benecial therapeutic inter- vention for brain injury in neonates. Hypothermia iscurrently limited to term and near-term infants, and theprotection provided by hypothermia is incomplete.(49)(50) The possibility of improving protection by combininghypothermia with rEpo is being considered inneonatal and adult populations. (41)(51)(52) The FDA placed a temporary hold on rEpo neuroprotection trialsin 2008 but recently reversed this decision, allowing thisimportant research to proceed. Several clinical trials areplanned or underway. This drug has great potential as aneurotherapeutic because it is likely to be effective andsafe, is readily available, is not very costly, and is easy to use.

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609:293512. Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing hu-man fetus. Early Hum Dev. 1998;52:23524913. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immuno-histochemical localization of erythropoietin and its receptor in thedeveloping human brain. Pediatr Dev Pathol. 1999;2:14815814. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of commit-ted erythroid BFU-E and CFU-E progenitors does not requireerythropoietin or the erythropoietin receptor. Cell. 1995;83:596715. Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythro-poietin in the brain. Crit Rev Oncol Hematol. 2007;64:15917116. Yu X, Shacka JJ, Eells JB, et al. Erythropoietin receptor signal-ling is required for normal brain development. Development. 2002;

129:50551617. Tsai PT, Ohab JJ, Kertesz N, et al. A critical role of erythro-poietin receptor in neurogenesis and post-stroke recovery. J Neu- rosci. 2006;26:1269127418. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, SasakiR. A novel site of erythropoietin production. Oxygen-dependentproduction in cultured rat astrocytes. J Biol Chem. 1994;269:194881949319. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuro-protection involves cross-talk between Jak2 and NF-kappa-B sig-nalling cascades. Nature. 2001;412:64164720. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. Eryth-ropoietin receptor is expressed in rat hippocampal and cerebralcortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 1997;76:10511621. Sugawa M, Sakurai Y, Ishikawa-Ieda Y, Suzuki H, Asou H.Effects of erythropoietin on glial cell development; oligodendro-cyte maturation and astrocyte proliferation. Neurosci Res. 2002;44:39140322. Genc K, Genc S, Baskin H, Semin I. Erythropoietin decreasescytotoxicity and nitric oxide formation induced by inammatory stimuli in rat oligodendrocytes. Physiol Res. 2006;55:333823. Vitellaro-Zuccarello L, Mazzetti S, Madaschi L, et al. Chronicerythropoietin-mediated effects on the expression of astrocytemarkers in a rat model of contusive spinal cord injury. Neuroscience.2008;151:45246624. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crossestheblood-brain barrier to protect against experimental brain injury.Proc Natl Acad Sci U S A. 2000;97:1052610531

25. Juul SE, McPherson RJ, Farrell FX, Jolliffe L, Ness DJ, Glea-

American Board of Pediatrics Neonatal-PerinatalMedicine Content Specications

Know the factors regulating erythropoiesisin the fetus and neonate, includingerythropoietin.

Know the management of perinatalasphyxia, including neural protectivestrategies.




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son CA. Erythropoietin concentrations in cerebrospinal uid of nonhuman primates and fetal sheep following high-dose recombi-nant erythropoietin. Biol Neonate. 2004;85:13814426. Statler PA, McPherson RJ, Bauer LA, Kellert BA, Juul SE.Pharmacokinetics of high-dose recombinant erythropoietin inplasma and brain of neonatal rats. Pediatr Res. 2007;61:67167527. Kellert BA, McPherson RJ, Juul SE. A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats. Pediatr Res. 2007;61:45145528. Weber A, Dzietko M, Berns M, et al. Neuronal damage aftermoderate hypoxia and erythropoietin. Neurobiol Dis. 2005;20:59460029. Slusarski J, McPherson RJ, Wallace GN, Juul SE. High-doseerythropoietin does not exacerbate retinopathy of prematurity inrats. Pediatr Res. 2009;66:62563030. Sola A, Rogido M, Lee BH, Genetta T, Wen TC. Erythro-poietin after focal cerebral ischemia activates the Janus kinase-signaltransducer and activator of transcription signaling pathway andimproves brain injury in postnatal day 7 rats. Pediatr Res . 2005;57:48148731. Sun Y, Calvert JW, Zhang JH. Neonatal hypoxia/ischemia isassociated with decreased inammatory mediators after erythro-poietin administration. Stroke. 2005;36:1672167832. Keller M, Yang J, Griesmaier E, et al. Erythropoietin is neuro-protective against NMDA-receptor-mediated excitotoxic brain injury in newborn mice. Neurobiol Dis. 2006;24:35736633. Kawakami M, Iwasaki S, Sato K, Takahashi M. Erythropoietininhibits calcium-induced neurotransmitter release from clonalneuronal cells. Biochem Biophys Res Commun. 2000;279:29329734. Dzietko M, Felderhoff-Mueser U, Sifringer M, et al. Erythro-poietin protects the developing brain against N-methyl-D-aspartate

receptor antagonist neurotoxicity. Neurobiol Dis. 2004;15:17718735. Juul SE, Aylward E, Richards T, McPherson RJ, Kuratani J,Burbacher TM. Prenatal cord clamping in newborn Macaca nem-estrina: a model of perinatal asphyxia. Dev Neurosci. 2007;29:31132036. Fauchere JC, Dame C, Vonthein R, et al. Anapproach to usingrecombinant erythropoietin for neuroprotection in very preterminfants. Pediatrics. 2008;122:37538237. Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA,Mayock DE. A phase I/II trial of high-dose erythropoietin inextremely low birth weight infants: pharmacokinetics and safety.Pediatrics. 2008;122:38339138. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neuro-logic outcomes in newborns with hypoxic-ischemic encephalopa-thy. Pediatrics. 2009;124:e218e226

39. Ohls RK, Ehrenkranz RA, Das A, et al. Neurodevelopmentaloutcome and growth at 18 to 22 months corrected age in ex-tremely low birth weight infants treated with early erythropoietinand iron. Pediatrics. 2004;114:1287129140. Bierer R, Peceny MC, Hartenberger CH, Ohls RK. Erythro-poietin concentrations and neurodevelopmental outcome in pre-term infants. Pediatrics. 2006;118:e635e64041. Tseng MY, Hutchinson PJ, Richards HK, et al. Acute systemicerythropoietin therapy to reduce delayed ischemic decits followinganeurysmal subarachnoid hemorrhage: a phase II randomized,double-blind, placebo-controlled trial. J Neurosurg. 2009;111:17118042. McPherson RJ, Demers EJ, Juul SE. Safety of high-doserecombinant erythropoietin in a neonatal rat model. Neonatology.2007;91:364343. Ribatti D, Presta M, Vacca A, et al. Human erythropoietininduces a pro-angiogenic phenotype in cultured endothelial cells andstimulates neovascularization in vivo. Blood. 1999;93:2627263644. Ohlsson A, Aher SM. Early erythropoietin for preventing redblood cell transfusion in preterm and/or low birth weight infants.Cochrane Database Syst Rev. 2006;3:CD00486345. Chen J, Smith LE. A double-edgedsword: erythropoietin eyedin retinopathy of prematurity. J AAPOS. 2008;12:22122246. Brown MS, Baron AE, France EK, Hamman RF. Associationbetween higher cumulative doses of recombinant erythropoietinand risk for retinopathy of prematurity. J AAPOS. 2006;10:14314947. Suk KK, Dunbar JA, Liu A, et al. Human recombinant eryth-ropoietin and the incidence of retinopathy of prematurity: a multi-ple regression model. J AAPOS. 2008;12:23323848. Gonzalez FF, Abel R, Almi CR, Mu D, Wendland M, Ferriero

DM. Erythropoietin sustains cognitive function and brain volumeafter neonatal stroke. Dev Neurosci. 2009;31:40341149. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective headcooling with mild systemic hypothermia after neonatal encephalop-athy: multicentre randomised trial. Lancet. 2005;365:66367050. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.N Engl J Med. 2005;353:1574158451. Cariou A, Claessens YE, Pene F, et al. Early high-dose eryth-ropoietin therapy and hypothermia after out-of-hospital cardiacarrest: a matched control study. Resuscitation. 2008;76:39740452. Nichol AD, Cooper DJ. Can we improve neurological out-comes in severe traumatic brain injury? Something old (early pro-phylactic hypothermia) and something new (erythropoietin).Injury . 2009;40:471478




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NeoReviews Quiz

5. Since 1991, several randomized clinical trials have been conducted to evaluate the safety and efcacy of recombinant erythropoietin (rEpo) as a treatment for anemia of prematurity. The overall effectiveness of rEpo in the prevention of neonatal blood transfusions has varied. Of the following, the most importantcause of the variability in the effect of rEpo on neonatal blood transfusions is:

A. Institutional phlebotomy policies and transfusion guidelines.B. Lesser volume of distribution of rEpo in neonates relative to adults.C. Slower renal clearance of rEpo in neonates relative to adults.D. Variation in the dosage of rEpo treatment in clinical trials.E. Variation in the duration of rEpo treatment in clinical trials.

6. When bound to cell surface erythropoietin receptor homodimer, rEpo confers neuroprotection by severalmechanisms, as shown by in vitro cell studies and in vivo animal studies. Of the following, the most likelymechanism of rEpo-conferred neuroprotection, as shown in rodent models of brain injury, is rEpo-induced:A. Generation of antioxidant enzymes.B. Inhibition of neuronal apoptosis.C. Inhibition of nitric oxide production.D. Migration of regenerating neurons.E. Suppression of glutamate excitotoxicity.

7. To date, three clinical trials examining the safety and efcacy of rEpo as a potential treatment for neonatalhypoxic-ischemic encephalopathy have been published. One of these studies compared the pharmacokineticsof different doses of rEpo in extremely preterm ( < 1,000 g birthweight) infants during the rst 3 days afterbirth. Of the following, based on plasma concentrations of erythropoietin, the most suitable dosing rangefor intravenous administration of rEpo for neuroprotection in extremely preterm infants is:

A. 75 to 150 U/kg.B. 500 to 1,000 U/kg.C. 2,500 to 5,000 U/kg.D. 10,000 to 20,000 U/kg.E. 20,000 to 30,000 U/kg.

8. Early administration of rEpo has been suggested as a strategy for prevention of neonatal brain injury invery preterm (< 1,500 g birthweight) infants. The potential complications of this treatment, however,warrant consideration. Of the following, according to a Cochrane Database Systematic Review, the most worrisome adverse effect of early rEpo treatment in very preterm infants is an increase in the risk of:

A. Chronic lung disease.B. Intracranial hemorrhage.C. Myocardial infarction.D. Necrotizing enterocolitis.E. Retinopathy of prematurity.




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DOI: 10.1542/neo.11-2-e782010;11;e78-e84 NeoReviews

Sandra JuulErythropoietin as a Neonatal Neuroprotective Agent

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04 erythropoietina como agente neuroprotector

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