OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design.
METHODS: A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting <48 hours after birth. The primary outcome was death or disability. Neurodevelopmental outcomes were assessed at 18 months of age.
RESULTS: Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed.
CONCLUSION: Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.
Dear Editor,
We have read with great interest the results of the recent study by Zhu et al. on the effects of recombinant human erythropoietin (rhEpo) in neonates with moderate hypoxic-ischemic encephalopathy (HIE).1 It is very important that these data have been communicated, since other phase 1 trials aimed at proving a neuroprotective effect of rhEpo in near-term neonates with perinatal asphyxia are either not published (ClinicalTrials.gov No. NCT00945789) or on hold (NCT00719407 and NCT00491413) due to safety concerns on high-dose rhEpo treatment as addressed by the FDA.2 However, the paper of Zhu et al. has several points that need clarification HIE is defined only by the Sarnat score. As these symptoms do not specifically indicate the severity of HIE, additional data on the pH, negative base excess and lactate in the umbilical arterial blood, or at the most critical clinical condition would be very informative. We also miss information on the incidence (and treatment) of seizures and on the hypoxic-ischemic injury of other organs, such as renal and liver insufficiency, or cardiac failure.
It is very important to understand why rhEpo did not reduce the rate of disability in severe HIE. Current experimental data indicate that optimal neuroprotection by rhEpo requires its rapid application after the insult 3 and high expression of the erythropoietin receptor (EpoR).4 Due to the large variation regarding the timepoint of the first rhEpo application in the study by Zhu et al., ranging between 1 and 48 hours after birth, the time period between asphyxia and initiation of rhEpo treatment in severe vs. moderate HIE needs to be presented and to be analyzed regarding the outcome criteria. Current data obtained in experimental models or humans with stroke conclusively indicate that early beginning is required to sustain significant neuroprotection by rhEpo.5-7 This may be due to the fact that high EpoR expression is required for neuroprotection, but can not be achieved in each area of the brain 4, and that EpoR mRNA increases promptly in response to hypoxia 8,9, a phenomenon that has not been totally elucidated on the molecular level yet.
The Epo concentrations in the serum and cerebrospinal fluid (CSF) after subcutaneous application (s.c.) of rhEpo raise also questions. In two phase I/II trials using rhEpo for neuroprotection in very low birth weight infants as well as in the adult stroke trial, rhEpo has been given intravenously (i.v.) in order to rapidly achieve high Epo concentrations in the circulation and in the cerebrospinal fluid.10-12 Although the rationale for i.v. treatment is given by experimental studies 5, it remains unclear whether s.c. application in humans is similarly efficient and/or even safer. Surprisingly, the peak in Epo serum concentrations appears very early (3 hours after s.c. application) in neonates treated by Zhu et al. 1, if compared to adults who also received 300 IU/kg Epoetin- alpha.13 In patients with renal insufficiency, circulating Epo peaks 12 hours after s.c. application of rhEpo 14 and reaches at this time point a bioavailability of about 18-22%.13-15 Thus and concordantly with the previous experimental and clinical data 5,16, the peak of Epo concentrations in the CSF only 3 hours after s.c. rhEpo application is also surprising. We wonder whether the data presented by Zhu et al. rather reflect changes in endogenous Epo concentrations in response to HIE. Since data on rhEpo pharmacology in preterm and term neonates are only very limitedly accessible, the authors should present their results on the pharmacokinetics with regard to the time period between birth and the beginning of rhEpo treatment. Furthermore, the question on differences in Epo concentrations in the CSF and serum depending on the different doses of rhEpo needs to be addressed.
We hope that our discussion helps to improve the scientific disputation on the potential of rhEpo as a neuroprotective agent, particularly if rhEpo is discussed as an alternative to therapeutic hypothermia. In our understanding, further experimental data are still required prior to any clinical study combining rhEpo treatment plus hypothermia for neuroprotection after HIE, since the pharmacology of rhEpo and the regulation of endogenous Epo and EpoR gene expression under such circumstances are unknown.
Sincerely,
Christof Dame (1), Hans-Ulrich Bucher (2), Jean-Claude Fauchère (2) (1) Department of Neonatology, Charite´-Universitätsmedizin Berlin, Germany. (2) Department of Obstetrics, Division of Neonatology, University Hospital Zurich, Switzerland
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Conflict of Interest:
None declared