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
References
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http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm110248.htm.
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Conflict of Interest:
None declared
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