Published online August 1, 2008
PEDIATRICS Vol. 122 No. 2 August 2008, pp. 375-382 (doi:10.1542/peds.2007-2591)
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ARTICLE

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

Jean-Claude Fauchère, MDa, Christof Dame, Prof, MDb, Reinhard Vonthein, Drc, Brigitte Koller, RNa, Sandra Arri, MDa, Martin Wolf, PhDa and Hans Ulrich Bucher, Prof, MDa

a Clinic of Neonatology, University Hospital Zurich, Zurich, Switzerland
b Department of Neonatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
c Department of Medical Biometry, University of Tübingen, Tübingen, Germany


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome.

METHODS. This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth.

RESULTS. The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count.

CONCLUSIONS. No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.

Key Words: premature infant • erythropoietin • neurodevelopment • outcome • brain injury • very low birth weight infant • intraventricular hemorrhage • retinopathy of prematurity

Abbreviations: Epo—erythropoietin • rhEpo—recombinant human erythropoietin • EpoR—erythropoietin receptor • ROP—retinopathy of prematurity • IVH—intraventricular hemorrhage • PVL—periventricular leukomalacia • GA—gestational age • THI—total hemoglobin index • TOI—tissue oxygenation index • NIRS—near infrared spectroscopy • OR—odds ratio • CI—confidence interval • IQR—interquartile range • CSF—cerebrospinal fluid • BBB—blood-brain barrier

Novel strategies to protect developing organ systems, in particular the central nervous system, are of greatest interest in neonatal intensive care medicine, because long-term disability remains a major problem in very preterm infants.1 These infants have a significantly increased risk for a delay in psychomotor development and for cognitive deficits.2–4 The most critical period centers around birth, when oxygenation, especially of the brain, may be impaired as a result of respiratory, circulatory, and nutritional disorders.

Erythropoietin (Epo), the primary regulator of red blood cell production, has been shown to be protective against hypoxic-ischemic and inflammatory injuries in a broad range of tissues and organs.5–8 The neuroprotective effects of recombinant human Epo (rhEpo) have been investigated most intensively in neuronal cell cultures; in experimental animal models; and in 3 clinical trials of adult humans with stroke, schizophrenia, or chronic progressive multiple sclerosis.9–11 These mechanisms by which rhEpo exerts its neuroprotective and neurotrophic effects include the inhibition of glutamate release, modulation of intracellular calcium metabolism, induction of antiapoptotic factors, reduction of inflammation, inhibition of nitric oxide–mediated injury, and direct antioxidant effects (for review see refs 5 and 12). Epo achieves its neuroprotective effects by homodimerization of 2 Epo receptors (EpoR) or heterodimerization of the EpoR with the β-subunit common receptor (CD131).13 Recent experimental studies that used a variety of models for neonatal or adult brain injury, and the 3 clinical trials of adult patients highly favor rhEpo as a novel, very effective pharmacologic agent for neuroprotection14,15 (for review, see ref 12).

No clinical study on the use of rhEpo for neuroprotection in human preterm and term neonates has been reported; however, during the past decade, rhEpo has been widely used in preterm infants to prevent or treat the anemia of prematurity.16–18 Although there is still controversy on the efficiency of this treatment and on adverse effects on retinopathy of prematurity (ROP), in general, rhEpo has been considered to be safe and well tolerated in preterm infants (for review see refs 17 and 18). The long-term neurologic outcome of preterm infants who received rhEpo for prevention of blood transfusion for anemia of prematurity has so far been reported in only 3 studies. Newton et al19 did not find relevant differences in the long-term neurodevelopmental outcome of 20 infants who weighed ≤1250 g at birth and were treated with rhEpo (100 or 200 U/kg body weight given intravenously or subcutaneously, 5 times weekly for 6 weeks maximum) in comparison with control subjects. Ohls et al20 showed that extremely low birth weight infants (<1000 g) who were treated with rhEpo (400 U/kg body weight 3 times weekly given intravenously or subcutaneously from 96 hours after birth until the 35th postmenstrual week) did not benefit in neurodevelopmental outcome. In a posthoc analysis, however, the same group reported higher developmental index scores at 18 to 22 months' corrected age for 6 infants with Epo serum concentrations of ≥500 mU/mL compared with those (n = 6) with Epo serum concentrations of <500 mU/mL.21

Conceptually, for proposing rhEpo as a neuroprotective agent, it is important that the EpoR messenger RNA expression in the brain is developmentally downregulated, but upregulated in response to hypoxia.22–24 The rationale for using rhEpo as a neuroprotective agent also includes the consideration that exogenous Epo may compensate for the delayed endogenous Epo synthesis.25 Evidence from animal experiments reveals that rhEpo must be given in high doses at the beginning or within a short (up to 6 hours), critical time period after the onset of brain injury to achieve a significant neuroprotective effect (for review, see refs 5, 9, 26, and 27).

The aim of this study was to investigate the short-term safety of high-dose rhEpo given to very preterm infants immediately after birth and subsequently during the first 2 days, before studying the long-term effect on neurodevelopmental outcome. The primary short-term safety outcome measures were brain injury (intraventricular hemorrhage [IVH] and periventricular leukomalacia [PVL]) and ROP. The secondary safety outcomes were sepsis, necrotizing enterocolitis, persistent ductus arteriosus, apnea of prematurity, and chronic lung disease.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
This single-center phase II clinical trial was designed as a randomized, double-masked, placebo-controlled trial. Very preterm infants who were born between 24 and 31 weeks of gestation from September 2005 through November 2006 and admitted to our NICU were eligible for enrollment. The exclusion criteria were genetically defined syndromes, congenital malformations that adversely affect neurodevelopment, lack of adequate parental information as a result of emergency cesarean section, and language barriers. The patients were randomly assigned within the first 3 hours after birth in a 2:1 allocation in favor of rhEpo. The sequence of patient numbers was assigned by the hospital pharmacy. The study medication (rhEpo or NaCl 0.9%) was randomly assigned to each patient number in advance, using a computer-based random-number generator. Verum (rhEpo) and placebo drug solutions were indistinguishable. Epoietin Beta (3000 U rhEpo/kg body weight at birth, equal to 1 mL solution/kg birth weight; Roche, Basel, Switzerland) or an equivalent volume of normal saline placebo was given intravenously 3 to 6, 12 to 18, and 36 to 42 hours after birth during a period of 10 minutes. No infant was treated later with rhEpo for anemia of prematurity.

Neonatal adaptation was documented using the Apgar score at 1, 5, and 10 minutes and by the Clinical Risk Index for Babies, the latter score being a simple tool to assess neonatal risk on the basis of the variables gestational age (GA), birth weight, congenital malformation, lowest and highest appropriate fraction of inspired oxygen, and worst base deficit within the first 12 hours after birth.28 Moreover, placental histology was performed and Epo concentration in cord blood was determined in duplicate by using the Quantikine human Epo Immunoassay (R&D Systems, Wiesbaden, Germany) following the manufacturer's protocol. The minimal detection limit of the assay was 2.5 mU/mL, and intra-assay variability was <2%.

During the 24 hours after the injection of the study medication, heart rate, transcutaneous arterial oxygen saturation (pulse oximetry arterial oxygen saturation, S9O2), transcutaneous PO2, and arterial blood pressure were monitored. Standardized evaluations including cerebral sonography (at the latest before the second dose of study medication) were performed at day 1, day 7, and 36 weeks' postmenstrual age (or earlier if discharged). IVH was graded according to Ment et al29 and cerebral white matter disease according to de Vries et al30 (persisting periventricular echodensity at 7 days and PVL at 36 postmenstrual weeks). Hematologic examinations were performed at day 1 and day 8 (range: days 7–10). Both eyes were examined by an experienced ophthalmologist to detect ROP. The severity of ROP was graded according to the international classification of ROP.31 Growth (weight, length, and head circumference) was documented before discharge from the hospital.

To assess whether the relatively high dose of rhEpo has any effect on brain oxygenation, we measured oxyhemoglobin, deoxyhemoglobin, total hemoglobin index (THI), and tissue oxygenation index (TOI) using near-infrared spectroscopy (NIRS) (NIRO 300 Hamamatsu, Photonics; Hamamatsu, Japan) in a subset of infants during the second dose. The NIRS sensor, which was placed on the head of each infant, contains 1 light source (with 775-, 810-, 850-, and 910-nm wavelengths) and 1 detector with 3 segments (SI photodiodes). The differences between the baseline before and the five 10-minute intervals after injection (10, 20, 30, 40, and 50 minutes) were calculated in each sample for the NIRS parameters.

Serious adverse events and adverse events were reported continuously to the safety monitoring board. Coordination and data management was provided by the Swiss Neonatal Network and by a study nurse (Ms Koller) who was trained in data management. Data quality was checked, and statistical calculations were performed by an independent person (Vonthein). The trial was approved by the ethical committee of the University Children's Hospital Zurich, by the Ethical Committee of the Canton Zurich (KEK), and by SwissMedics Berne. Written informed consent was obtained from the parents of eligible infants, ideally before birth.

The primary hypothesis of this pilot study was that the rate of survivors without brain injury (IVH and PVL) including retinopathy are not affected by administration of 3 high doses of rhEpo early after birth. This chance was 2:1 in our unit before starting the study; therefore and because of a hope to double this chance, patients were randomly assigned to receive rhEpo in 30 cases and placebo in 15 cases. These numbers were calculated to provide 95% probability of at least 1 event in each arm so that odds ratios (ORs) could be determined. For calculation of the posterior probability of effects of rhEpo on the occurrence of IVH or ROP, a historical control based on consecutive 620 preterm infants who were <32 gestational weeks from the Swiss Neonatal Network was included, yielding incidences for IVH of 23% and for ROP of 19.5%.

Bayes factor (likelihood ratio) was used in lieu of the P value as a measure of the evidential strength.32 Frequencies of traits were compared by OR and exact mid-probability 95% confidence interval (CI) (StatsDirect 2.4.4 [Ltd Altrincham, Cheshire, United Kingdom]). Continuous measurements that seemed to follow a normal distribution were summarized by means, SD, and 95% CIs for the difference of means. Median and interquartile ranges (IQRs) were used to summarize the other variables (JMP IN 5.1 statistical software [SAS Institute, Cary, NC]).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 122 very preterm infants were assessed for eligibility. Of these, 77 were excluded: 56 for not meeting the inclusion criteria and 21 because of parental refusal, leaving a study group of 45 infants who were allocated to the rhEpo group (nt = 30) or to the placebo group (nc = 15). Table 1 summarizes the demographic data. Importantly, the intervention and the control groups were comparable with regard to GA, birth weight and head circumference, gender, pregnancy-related complications, antenatal steroids, mode of delivery, umbilical artery pH, Apgar score, Clinical Risk Index for Babies score, and Epo concentration in cord blood.


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  		TABLE 1 Demographic Data

 
There were 16 (53%) of 30 survivors without IVH, PVL, or ROP in the rhEpo group and 9 (60%) of 15 in the placebo group (Table 2). For 5 infants who had a GA of <26 weeks and belonged to the rhEpo group, withdrawal of intensive care and redirection of care were decided because of severe bilateral IVH (3 infants, in 1 of them IVH was already present before dose 1) or severe pulmonary interstitial emphysema with irreversible global pulmonary insufficiency (2 infants). The charts of these 5 infants were carefully reviewed by the study safety board. In each case, a causal relationship with rhEpo treatment was unlikely. None of the neonates in the control group died.


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  		TABLE 2 Neonatal Morbidity According to Treatment

 
The posterior probability of the hypothesis that rhEpo has an effect on the occurrence of IVH was 0.20 when the previous probability was 0.5 (Bayes factor 4.11; Fig 1). Including historical controls of combined weight, 15, to make the trial balanced, would alter that posterior probability to 0.27 and the Bayes factor to 2.76. Similarly, the posterior probability of rhEpo effect on the occurrence of ROP was 0.36 without and 0.47 with previous information.


Figure 1
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  		FIGURE 1 If-then diagram. Shown is the posterior probability of the null hypothesis of exactly no effect of rhEpo on the occurrence of IVH (fine lines) and ROP (heavy lines) by previous probability, for historical controls who weighed as much as 15 patients in the control group (dashed lines) or without historical controls (solid lines).

 
Continuous monitoring of arterial blood pressure, arterial oxygen saturation, heart rate, cerebral oxygenation (TOI), and cerebral perfusion (THI) did not show any relevant deviation from baseline during injection of rhEpo or placebo, respectively (Fig 2). There was no relevant difference for these parameters between 16 investigated patients who received rhEpo and 10 investigated patients who received placebo at any time before and after drug injection.


Figure 2
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  		FIGURE 2 Mean arterial pressure (MAP), TOI, and THI before and after rhEpo/placebo injection. Box plots show the median, quartiles, and extreme values.

 
Hemoglobin, platelets, and white cell counts were similar at day 8 in both groups. For 39 of 45 patients, Epo concentrations in the umbilical arterial cord blood were determined (Table 3). For 11 (28.2%) of 39 specimens, Epo concentrations were elevated (≥50 mU/mL33).


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  		TABLE 3 Association of Mortality and Morbidity With Fetal Cord Blood Epo Levels

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We report on the first randomized, double-blind, placebo-controlled clinical trial to use high-dose rhEpo as a neuroprotective agent given shortly after birth to very preterm infants. The first objective of this trial was to assess the safety of early high-dose rhEpo administration and whether this intervention alters the incidence of complications that typically are associated with preterm birth (IVH, PVL, ROP, septicemia, necrotizing enterocolitis, bronchopulmonary dysplasia) and, finally, whether complications that are associated with rhEpo treatment in adult humans, such as arterial hypertension and thrombotic events, occur also in preterm infants (Table 4).


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  		TABLE 4 Clinical Status at Discharge According to Treatment

 
The most important finding of this trial is that there were no differences regarding the short-term outcome between both groups. Importantly, any relevant increase in typical adverse effects of rhEpo, in particular ROP,18 were not observed in our patients. The potential drawback of Epo therapy, namely an increase in red cell mass, was not seen in our study, an adverse effect that we did not expect because of the short duration of therapy in a population at risk rather for anemia than for polycythemia. This result is in accordance with the report by Ehrenreich et al,14 who showed that short-term administration of Epo as a neuroprotective agent to patients with stroke did not result in increased hematocrit levels. Other complications of rhEpo treatment, such as arterial hypertension and thrombocytosis, also did not occur. Moreover, no perceptible median group differences in brain perfusion (THI) and cerebral TOI were found (Fig 2).34

A finding that warrants a closer analysis is the higher mortality in rhEpo-treated infants (5 of 30) in comparison with control subjects (0 of 15; Table 2). All 5 deaths occurred in extremely preterm infants with a GA of <26 weeks (extremely low GA). For all of these infants, redirection of care was decided together with the parents. Mechanical ventilation was withdrawn between 6 and 174 hours after birth for either severe bilateral IVH (3 of 5 infants, with 1 infant presenting with IVH before receiving the first dose of rhEpo) or global respiratory insufficiency (2 of 5 with severe bilateral pulmonary interstitial emphysema and air leaks).

Figure 1 shows how previous probabilities of the null hypotheses change after our pilot study. Although it is more probable than not that a high dose of rhEpo does not alter the incidence rates of IVH and ROP in very low birth weight infants, the inclusion of historical controls shifts the assessment toward equipoise, because historical incidences were higher than in the placebo group.

Both the incidence of severe IVH (III–IV; 13%) and the incidence of death as a result of pulmonary insufficiency (9%) in rhEpo-treated infants of extremely low GA were within the range reported in recent international studies: 11% to 25% for severe IVH35–37 and 34% for death as a result of pulmonary insufficiency.38

The optimal dosage and treatment regimen in a neuroprotection approach in neonates is not clear yet. In a study that used high-dose rhEpo for neuroprotection in adult humans with stroke, rhEpo was administered at a dosage of 33333 U (~450 U/kg) during 30 minutes within 5 hours after the onset of symptoms and on the subsequent 2 days.14 In patients with long-term schizophrenia, rhEpo was given as neuroprotectant in a weekly dosage of 40000 U for 3 months.15 Most recently, the effects of 48000 vs 8000 U of rhEpo (12 weeks of weekly followed by 12 weeks of biweekly treatment) were tested in an open-label study of patients with long-term progressive multiple sclerosis.11 In these 3 human trials that used rhEpo as neuroprotectant, treatment was found to be safe and beneficial.

Experimental data on the effects of rhEpo in animal models of neonatal brain injury have been summarized recently.12 On the one hand, escalating dosages from 1000 to 5000 U/kg showed most efficient neuroprotection at Epo concentrations in the cerebrospinal fluid (CSF) between 20 and 200 mU/mL.39–44 On the other hand, recent in vitro and animal experiments of neonatal brain injury that used single or multiple injections of highest rhEpo dosages (up to 30000 U/kg or 40 U/mL in brain slide cultures) showed no additional benefit on neuroprotection or even neurotoxic effects, particularly when combined with mild hypoxia.42,45 Evidence from animal experiments reveals that rhEpo must be given in high doses at the beginning or within a short (up to 6 hours) critical time period after the onset of brain injury to achieve a significant neuroprotective effect26,27 (for review, see refs 5 and 9). Because the highly glycosylated Epo molecule needs to cross the blood-brain barrier (BBB), most likely by a saturable, active transport mechanism,26 intravenous administration is favorable, as suggested by pharmacokinetic analysis. Recent studies in adult rats, fetal sheep, and juvenile or adult nonhuman primates indicated that Epo concentrations in the CSF increase between 1 and 2 hours after systemic (intraperitoneal or intravenous) application of high-dose rhEpo (5000 U/kg) to concentrations of ~100 mU/mL and peak between 3 and 4 hours at concentrations of ~200 mU/mL.26,40 On the basis of a model for predicted concentration-time profiles of Epo in the CSF after single and repetitive rhEpo administration,46 we decided to give 3 doses of 3000 U/kg rhEpo intravenously, yielding Epo concentrations in CSF not higher than 300 mU/mL.

A limitation of our study is the small number of infants included. A larger number would be needed to assess the statistical significance of trends such as those observed for mean arterial pressure and TOI toward lower values in the rhEpo group (Fig 2) and of higher percentages in severe IVH and severe ROP (Table 3). Pooling our results with those of other studies that are under way will help to narrow the CIs.

On the basis of our preliminary results, several aspects may be important for future clinical studies. (1) Potential danger of high-dose rhEpo in infants with IVH: In preterm infants with IVH, the BBB is impaired; consequently, higher amounts of rhEpo may penetrate the brain. An increased uptake of rhEpo around very vulnerable brain capillaries may change their autoregulation if endothelial EpoRs are activated. Importantly, extremely high concentrations of rhEpo may exert adverse effects on neuronal cells and increase the risk for brain damage, in particular in combination with additional factors such as hypoxia and hyperoxia.47 (2) Upregulation of EpoR in extremely preterm infants: As shown in mice, EpoR expression is 10-fold higher in the embryonic brain than in the adult brain and decreases immediately after birth48; therefore, it is very likely that EpoR levels are relatively high in newly born preterm infants. (3) Elevated cord blood Epo levels: In 11 (28.2%) of 39 umbilical cord blood specimens, Epo concentrations were significantly elevated (≥50 mU/mL), indicating possible fetal distress. In 9 of 11 infants, placental insufficiency, pre/eclampsia, amnion infection, or fetal anemia could accounted for increased fetal Epo production, suggesting preconditioning that has been developed slowly over time. In the remaining 2 infants, increased Epo concentrations could have resulted from acute prenatal fetal distress. In our short-term analysis, no consistent pattern between neonatal complications and the presence of increased fetal Epo concentrations or the absolute Epo levels was obvious (Table 3). The observation of possibly less periventricular echodensity in the presence of increased fetal blood Epo concentrations might be of interest when it comes to the analysis of neurodevelopmental outcome.

Upregulation of EpoR and an increase in circulating Epo may also be important aspects for the design of additional studies to investigate the neuroprotective effect of rhEpo in term infants with acute hypoxic-ischemic brain injury, likely in combination with induced brain hypothermia; however, as recently discussed by Bührer et al,47 caution is warranted in hypoxic conditions because various changes occur that may divert Epo from its neuroprotective and restorative actions. These observed changes include (1) a significantly increased transport of blood-borne proteins (eg, Epo) through the BBB,49 exposing the central nervous system to a higher amount of administered rhEpo, (2) an increase in EpoR transcription in neurons,50 and (3) an induction of EpoR by Epo51 with a decreased ratio of heterodimeric CD131/EpoR, leading to an increased binding of Epo to the high-affinity homodimeric EpoR/EpoR, thereby losing its protective action.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our study provides important insights into the safety and short-term outcome of preterm infants who received early high-dose rhEpo for neuroprotection. As independently analyzed by the external safety board and by the Epo trial center, no signs of adverse effects of early high-dose rhEpo treatment in very preterm infants were identified. These results enable us to embark on a larger multicenter study with the aim to determine whether early high-dose administration of rhEpo in very preterm infants finally improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.


   ACKNOWLEDGMENTS
 
This pilot study was supported by the RoFAR Foundation (Roche Foundation for Anemia Research). Epoietin β was kindly provided by Roche (Basel, Switzerland).

We particularly thank the parents who have contributed greatly to this project by consenting to the enrollment of their preterm infant and the NICU staff for their support. We are indebted to the independent data and safety monitoring board (president Theo Gasser, Zurich). We acknowledge the invaluable support and thoughtful comments of Christian Bauer (Zurich), Max Gassmann (Institute of Veterinary Physiology, University of Zurich), Hugo Marti (Max-Planck Institute, Molecular Cell Biology, Bad Nauheim, Germany), Joachim Riethmüller (University of Tübingen, Tübingen, Germany), and numerous other colleagues. We also acknowledge the help by Daniel Fetz of the Pharmacy of the Canton Zurich for preparing the rhEpo and saline vials and for the random assignment of our patients. In large part, the NIRS measurements were performed by Katrin Egli, Andrea Bauschatz, Tanja Karen, and Ruben Barbaro.


   FOOTNOTES
 
Accepted Dec 28, 2007.

Address correspondence to Jean-Claude Fauchère, MD, University Hospital, Clinic of Neonatology, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland. E-mail: jean-claude.fauchere{at}usz.ch

This trial has been registered at www.clinicaltrials.gov (identifier NCT00413946).

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Epo has been shown to be neuroprotective against hypoxic-ischemic and inflammatory injuries in a broad range of tissues and organs. Recent studies using various models for neonatal or adult brain injury highly favor rhEpo as a novel, very effective pharmacologic agent for neuroprotection.

 

What This Study Adds

Our study provides important insights into the safety and short-term outcome of preterm infants who received early high-dose rhEpo for its neuroprotective properties at a time point when their immature brain is at highest risk for damage.

 


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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