Original ArticleErythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy
Introduction
Perinatal hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal encephalopathy and occurs in one to three per 1000 term births,1, 2 affecting up to 12,000 infants each year in the United States. Therapies remain limited. Hypothermia initiated within 6 hours of birth provides modest improvements in outcome.3, 4, 5, 6, 7 Yet despite this therapy, over 40% of infants with moderate-to-severe HIE die or suffer moderate-to-severe disabilities including cerebral palsy, intellectual impairment, and epilepsy. New neuroprotective therapies are needed to further reduce the unacceptably high risk of adverse outcomes after HIE.
The hematopoietic cytokine erythropoietin (Epo) has neuroprotective and neuroregenerative effects in the brain.8, 9, 10, 11, 12, 13 High doses of Epo administered to neonatal rodents after hypoxic-ischemic brain injury result in improved histologic and functional outcomes and enhanced neurogenesis and repair.14, 15, 16, 17, 18, 19, 20 In a nonhuman primate model of HIE in which hypothermia alone did not significantly improve outcomes, the combined treatment of Epo and hypothermia resulted in a significantly lower rate of death or moderate-to-severe cerebral palsy than did treatment with saline alone (0% versus 43%, P < 0.05).21 Compared with animals treated with saline, those that received both Epo and hypothermia also demonstrated improved long-term motor and cognitive responses, enhanced cerebellar growth, and improved fractional anisotropy on early diffusion tensor imaging.21
Two clinical trials reported that human infants with HIE who received five to seven doses of Epo during the first week of age, in the absence of hypothermia, experienced improved neurological outcomes.22, 23 After hypothermia became the standard of care in the treatment of HIE, we evaluated the safety and pharmacokinetics of combined Epo and hypothermia therapy in a phase I trial and found that multiple doses of Epo ranging from 250 to 2500 U/kg IV appeared safe in the neonatal period.24 However, longer term outcome data have yet to be reported in cooled infants who received high-dose Epo as a neonate. Therefore, we present the neurodevelopmental outcomes of infants with HIE who received high doses of Epo and hypothermia therapy during the first week of age.
We previously reported a phase I safety and pharmacokinetic study of Epo in neonates.24 The current article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial. In an open-label dose-escalation study,24 24 newborns ≥37 weeks of gestational age undergoing hypothermia for HIE received one of the following four Epo doses IV: 250 (n = 3), 500 (n = 6), 1000 (n = 7), and 2500 U/kg per dose (n = 8). We studied these doses to determine which would achieve target plasma Epo levels based on available data from animal studies. We administered up to six doses of Epo every 48 hours, starting by 24 hours of age. Each patient met inclusion and exclusion criteria for encephalopathy and perinatal depression as previously described.24, 25 All patients also underwent standard 72 hours of hypothermia therapy using either whole body (n = 21) or head (n = 3) cooling. All patients received a brain magnetic resonance imaging (MRI) at the completion of hypothermia therapy as part of routine clinical care. A study neuroradiologist (A.J.B.) who was blinded to patient outcomes interpreted the MRI studies using a previously validated scoring system.26 The MRI was classified as normal, abnormal with a predominant watershed pattern of injury, or abnormal with predominant basal ganglia and/or thalamic injury. Severity of injury was dichotomized as being either moderate and/or severe or mild and/or normal as previously described.27 The study received institutional review board's approval at each of five participating hospitals.
After hospital discharge, patients were evaluated in the high-risk infant follow-up programs of each of the five study sites, as part of routine clinical care. During these visits, patients were evaluated for neurodevelopmental abnormalities: cerebral palsy, tone abnormalities, motor delay, language delay, and presence of seizures. The Bayley Scales of Infant Development (Bayley) II or III was performed in 16 patients at median age 24.4 months (range, 13-34 months). The eight patients who did not receive Bayley testing were either enrolled at a site where Bayley testing is not performed routinely (n = 5) or did not receive Bayley testing as part of their follow-up assessment (n = 3). We defined moderate-to-severe disability as either a clinical diagnosis of cerebral palsy with Gross Motor Function Classification System (GMFCS) III-V or moderate-to-severe cognitive delay based on Bayley II MDI of <70 or Bayley III cognitive composite score of <80. Mild impairment was defined as cognitive or language delays requiring referral to early intervention services, epilepsy, or abnormal neurological examination without a diagnosis of cerebral palsy or functional impairment.
Section snippets
Results
Twenty-four of 26 infants consented to the study. Hypotonia, lethargy, and poor suck were the most common signs of encephalopathy (Table 1). Fifteen infants (63%) had a 10-minute Apgar score of ≤5, and mean arterial or venous cord pH was 6.87 (S.D. = 0.14). Almost half of infants (45.8%) were delivered via emergent cesarean section. A sentinel event occurred in seven patients (29%), including placental abruption (four), uterine rupture (two), and prolapsed cord (one). Over half (n = 13) had
Discussion
In this small, open-label, phase I trial of combined Epo and hypothermia therapy for HIE, we report no deaths and a relatively low rate (4.5%) of moderate-to-severe neurodevelopmental disability at median age 22 months. This study lacked controls and was not designed to test efficacy. However, our data provide evidence extending beyond the neonatal period that high-dose Epo given in conjunction with hypothermia does not worsen outcomes when given to newborns with HIE.
This study is subject to a
Conclusions
High-dose Epo does not appear to worsen neurodevelopmental outcomes when administered in conjunction with therapeutic hypothermia for HIE. In addition to the neonatal safety data we previously reported, the neurodevelopmental outcome data presented here provide additional reassurance that this new potential therapy has no adverse long-term consequences and therefore appears safe. We eagerly await the results of future trials that will provide additional data regarding whether this promising
References (46)
- et al.
Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy
Early Hum Dev
(2010) - et al.
A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy
Am J Obstet Gynecol
(2008) - et al.
Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial
Lancet
(2005) Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models
Clin Perinatol
(2004)- et al.
Perinatal events and early magnetic resonance imaging in therapeutic hypothermia
J Pediatr
(2011) - et al.
Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats
Behav Brain Res
(2004) - et al.
Effect of erythropoietin on oxygen-induced brain injury in the newborn rat
Neurosci Lett
(2008) - et al.
Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis
Brain Res
(2002) - et al.
White matter and cortical injury in hypoxic-ischemic encephalopathy: antecedent factors and 2-year outcome
J Pediatr
(2012) - et al.
Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial
Lancet Neurol
(2010)
Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy
N Engl J Med
Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial
Arch Pediatr Adolesc Med
Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT
Pediatrics
Moderate hypothermia to treat perinatal asphyxial encephalopathy
N Engl J Med
Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage
Acta Paediatr Suppl
Recombinant erythropoietin is neuroprotective in a novel mouse oxidative injury model
Dev Neurosci
Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia
Pediatr Res
The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential
Biol Neonate
Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity
Brain
Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats
Stroke
A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats
Pediatr Res
Erythropoietin improves functional and histological outcome in neonatal stroke
Pediatr Res
Erythropoietin sustains cognitive function and brain volume after neonatal stroke
Dev Neurosci
Cited by (0)
Clinical Trial Registration: This trial is registered at www.clinicaltrials.gov (NCT00719407).