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Year : 2015  |  Volume : 4  |  Issue : 4  |  Page : 244-249

Erythropoietin with hypothermia improves outcomes in neonatal hypoxic ischemic encephalopathy

1 Department of Pediatrics, Neonatal Unit, Reina Sofía University Hospital, Andalusian Health Service, Menéndez Pidal Avenue, 14004 Cordoba, Spain
2 Department of IMIBIC, Maimonides Institute of Biomedical Research of Córdoba, Menendez Pidal Avenue, 14004 Córdoba, Spain

Date of Web Publication16-Oct-2015

Correspondence Address:
Inés Tofé Valera
Avda. República Argentina 30, Esc B, 5º -2, 14004 Córdoba
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2249-4847.167413

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Aims: To know the effects of recombinant human erythropoietin (rhEPO) concurrent with hypothermia (HT) on neuron-specific enolase (NSE) and S100B protein levels in cerebrospinal fluid (CSF) in newbons with hypoxia-ischemia encephalopathy (HIE) and to evaluate the presence of EPO in CSF as well as the safety of repeated low doses of rhEPO. Subjects and Methods: This prospective study enrolled 15 infants with HIE. All infants received rhEPO (NeoRecormon®) intravenously in the first 3 h of life, at a dose-rate of 400 IU/kg/48 h, 2 weeks concurrent with total body HT. NSE and PS100B in CSF were collected after rewarming. Magnetic resonance imaging was undertaken by a single neuroradiologist between 7 and 15 days of life in surviving infants. Developmental assessments were performed at the age of 18 months. The Bayley Scales of Infant Development was performed. Results: There were two deaths in the first 72 h of life (13.3%). Moderate to severe disability occurred in one child (6.6%). 80% survived with no neurodevelopmental handicaps at 18 months of life. NSE and PS100B values in CSF were 25.1 ± 14.23 μg/L and 9.27 ± 16.19 μg/L respectively. EPO values in CSF were 45.6 ± 12.23 mU/mL.Time to reach normal background pattern in infants with no severe disability at 18 months of age was before 48 h of life. No complications were recorded.
Conclusion: EPO is an affordable cytokine with the potential neuroprotective effect that can be used in combination with HT and crosses blood brain barrier. Further research is required to define the optimum treatment.

Keywords: Biomarker, cerebrospinal fluid, erythropoietin, hypothermia, hypoxic ischemic encephalopathy, newborn

How to cite this article:
Valera IT, Vázquez MD, González MD, Jaraba MP, Benítez MV, Moraño Cd, Laso EL, Cabañas JM, Quiles MJ. Erythropoietin with hypothermia improves outcomes in neonatal hypoxic ischemic encephalopathy. J Clin Neonatol 2015;4:244-9

How to cite this URL:
Valera IT, Vázquez MD, González MD, Jaraba MP, Benítez MV, Moraño Cd, Laso EL, Cabañas JM, Quiles MJ. Erythropoietin with hypothermia improves outcomes in neonatal hypoxic ischemic encephalopathy. J Clin Neonatol [serial online] 2015 [cited 2022 Jan 16];4:244-9. Available from: https://www.jcnonweb.com/text.asp?2015/4/4/244/167413

  Introduction Top

Neonatal brain injury remains a great challenge due to increasing survival in neonatal units. Brain injury results in poor neurodevelopmental outcomes including cerebral palsy, mental retardation, and motor disorders.

Hypoxic/ischemic brain injury is the cause of encephalopathy and occurs in 1–3 per 1000 term births.[1],[2],[3] Therapies for hypoxia-ischemia encephalopathy (HIE) remain limited. Hypothermia (HT) initiated within 6 h of life provides improvements in term of disability or death.[4],[5],[6] Therefore, given the high incidence of survival with neurodevelopmental sequelae, physicians have been searching for effective strategies to minimize the long-term consequences of neonatal brain injury. Fortunately, promising neuroprotective strategies are emerging.[7]

Erythropoietin (EPO) was originally identified for its role in erythropoiesis is widely used as a preventive treatment for anemia in premature infants and was found to play a variety of roles in modulation of the inflammatory response and has vasogenic effects.[4] EPO is a potentially supplemental therapy to augment brain repair and improve neurodevelopmental outcomes. As a result of that, some reports have demonstrated the safety and efficacy of recombinant human erythropoietin (rhEPO) and two clinical trials suggest that infants with HIE treated with 5–7 doses of rhEPO experience improved neurologic outcomes.[8],[9] Finally, EPO could be a neuroprotective treatment that is promising as adjunctive therapy to decrease HIE induced injury because decreases apoptosis, inflammation and oxidative injury and promotes glial cell survival and angiogenesis.[10],[11],[12]

Few studies have been published about concurrent EPO plus HT in asphyxiated newborn with HIE and no standard of dose or route of administration has been established. Thus, one objective of this study is to determine the influence of early rhEPO administration on brain injury cerebrospinal fluid (CSF) biomarkers.

  Subjects and Methods Top


The prospective descriptive study made at Neonatology-Unit (NU), Pediatric-Service, Reina-Sofía-University-Hospital (RSUH) of Córdoba, Spain. CSF samples, as well as monitor brain function, were performed in our unit. Neonates admitted to NU were considered as eligible population.

The study was performed with a favorable report of the RSUH Ethics and Research Committee. In all cases, a written informed consent was obtained.

Patients selection

We enrolled 15 newborns 36 weeks' gestation and 1800 g with HIE defined by 2 items (1) Altered consciousness: Lethargy, stupor or coma; hyper alert state, hypotonia; abnormal reflexes including oculomotor or pupillary abnormalities; clinical seizures or weak suck. (2) Perinatal depression based on at least one of the following: Acidosis (pH 7.1) or base deficit (BD 12), Apgar score at 5 min 5, or ongoing resuscitation at 10 min. Brain monitoring function was recorded but was not used as an entry criteria for hypothermia plus epo. Neonates with a known congenital infection or genetic abnormalities were excluded.

Active total body cooling was used and began to achieve a rectal temperature of 33.5°C and continued for 72 h (servo-controlled Tecotherm-Neo). EPO was administered intravenously (NeoRecorm ®) 400 U/kg every 48 h for 2 weeks starting <3 h after birth.

Biomarkers of brain injury

Neuron-specific enolase (NSE) is a neuronal form of the glycolytic enzyme enolase, which is only expressed in neurons. Protein S100B are mainly expressed in glial cells and neurons in the central nervous system (CNS). CSF was collected after rewarming. Samples were centrifuged at 1000 g for 10 min and refrigerated immediately at 4°C. The resulting serum was distributed in aliquots and frozen at −80°C until their subsequent analysis. EPO, NSE and S100B levels were determined by radioimmunoassay.

Brain function monitoring

Amplitude integrated electroencephalogram (aEEG) (Olympic-CFM 6000) was performed in all patients during at least 72 h. Background activity was classified according to published backgrounds patterns considering good prognosis pattern continuous normal voltage and discontinuous.[13],[14]

Pulsed Doppler sonography

It was registered in thefirst 2 h of life by a single neonatologist. The Porcelot's cerebrovascular resistance index (RI) in the medium cerebral artery (MCA) was determined.

Brain magnetic resonance imaging

Magnetic-resonance imaging (MRI) scans were performed between 7 and 15 days of life. Images were revised by a single neuroradiologist using a validated scoring system.[15] Severity of injury was classified as being either moderate and/or severe of mild and/or normal.

Developmental scoring system

Surviving infants were evaluated in the high-risk infants follow-up programs. Neuromotor development was assessed with Bayley Scales of Infant (BSI) Psychomotor Development Index in survivors. The cognitive outcome was assessed with the use of the BSI Development II at 18 months. Severe disability was defined as a Bayley Mental Development Index score more than 2 standard deviation below mean score (below 70).

Statistical analysis

This was performed using MicroStat (Ecosoft, Indianapolis, IN, USA) or GraphPad InStat (GraphPad Software, San Diego, CA, USA) software packages. Abnormal values (outliers) were excluded. Results were expressed as mean ± standard error of mean with a 95% confidence interval (95% CI). Correlation between variables was evaluated using Pearson's correlation coefficient and regression analysis.

  Results Top

1/15 infant was born outside. Two males newborns died in thefirst 96 h of life, one due to multiorgan failure and one limitation of therapeutic effort was made.

Baseline characteristics

[Table 1] shows clinical infants characteristics. 60% of enrolled infants were male, emergent caesarean section was the most frequent mode of delivery (80%), sentinel event was present in 100%. All required chest compressions. The medium central temperature on admission was 33.92.1 ± 1.17. One male patient needed gavage feedings at discharge.
Table 1: Baseline characteristics of the patients with hypoxic ischemic encephalopathy treated with hypothermia plus erythropoietin

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Biomarkers of brain injury and cerebrospinal fluid levels of EPO

72 h after treatment, CSF NSE and PS100B were detected. Those values were 25.1 ± 14.23 µg/L and 9.37 ± 16.19 µg/L respectively. Those values were compared with those published by Sun et al.[26] (normothermic and hypothermic asphyxiated infants). NSE were lower (P = 0.015) and PS100B were higher (P = 0.001) [Figure 1]. EPO was found on CSF at a range of 45.6 ± 12.23 mU/mL.
Figure  1: Effects of HT  +  EPO on brain injury biomarkers. (a) Neuronal specific enolase concentrations in cerebrospinal fluid  (CSF). There is a significant difference between HT  + EPO group and the rest of group *P  < 0.05. (b) PS100B concentrations in CSF. There is a significant difference between HT group and the rest of group *P  < 0.05 Values shown are the mean and standard deviation and were compared by H-Kruskal–Wallis test b

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Brain function monitoring

Electroencephalographic findings

53.3% had a bad background pattern on aEEG on admission, being burst suppression the most frequent. 20% still had a bad prognosis pattern after rewarming. Patients who reached a good prognosis pattern on aEEG before 48 h of life had no disability at 18 months [Figure 2]. 66.6% presented clinical/electrical seizures in thefirst 24 h of life.
Figure  2: Time to regain normal background pattern on aEEG and neurodevelopmental outcome

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Doppler ultrasound

Medium RI in MCA was 0.65 ± 0.14. There was an inverse correlation between RI and time to reach a normal background pattern (P < 0.01; 95% CI).

After 12 days of life: Radiologic findings

Brain MRI performed in 13 patients at a median of 12 days of life. Two patients had died before MRI was made. No intracranial hemorrhages or sinovenous thrombosis were revealed. In terms of severity of the injury, 1 surviving patient had severe damage, and 2 had mild. 10 remaining newborns was classified as normal.

At 18 months of life: Clinical findings

There were 2 deaths (13.3%) in thefirst 96 h of life. Surviving infants were evaluated in the high-risk infant follow-up program. Patients were reviewed, and neurodevelopmental assessment was made at 18 months of age. One male of the 13 surviving newborns had a severe cognitive disability (7.6%). None surviving infants had blindness nor sensorineural deafness requiring amplification.

Finally, there were no serious adverse events such as major venous thrombosis, polycythemia (hematocrit >60%) or retinopathy. Nor negative hematopoietic side-effects were observed.

  Discussion Top

Hypothermia has become a standard of care in developed countries for babies suffering from HIE. However, induced moderate HT does not completely protect an injured brain. As neonatal intensive care has evolved, the focus has a shift from improving survival alone to the prevention of morbidity.

Erythropoietin, a glycoprotein widely used in neonates, has neuroprotective effects demonstrated in preclinical studies.[16],[17],[18],[19] Furthermore, erythropoietin doses used in animal neuroprotection studies (1000–30,000 U/kg) are much higher than doses for anemia treatment (250–500 U/kg) and are not considered suitable for human neonates because of potential side-effects. Two trials suggest that multiple doses of EPO, 300–500 U/kg per dose, administered in thefirst 1–2 weeks after birth resulted in the improved neurodevelopmental outcome.[5],[6] In addition, multiple doses of EPO reduce infarct volume in a dose-dependent manner.[20],[21]

Similarly to Zhu et al., who used a dose of 300–500 U/kg of rhEPO, we used low doses of EPO (400 U/kg) in thefirst 3 h of age every 48 h during 2 weeks. Levels of EPO in CSF show that this dosage regimen is able to achieve CSF. EPO is larger than the molecular weight threshold for lipid-mediated transport across the blood-brain barrier (BBB) but it should be able to enter the brain barrier, presumably, due to increased permeability. In addition, HT may reduce EPO clearance. Previous studies showed that the neuroprotective effect of EPO is related to its effect within the CNS.[22] In the current study, levels of EPO in CSF after rewarming were much higher than those reported by others in babies with perinatal asphyxia (32.6 mU/mL vs. 23.75 mU/mL Zhu et al.)[8] We chose a dose that was in the range of the approved dose for anemia treatment. Accordance with Gonzalez et al.[23] who showed reduced tissue loss after neonatal stroke, multiple doses of EPO could result in a sustained neuroprotection because babies were reviewed at 18 months of age and the rate of death or severe disability was 20%, lower than that reported in asphyxiated infants treated with HT (44–51%).[2],[4] In contrast, Juul et al. (2004) reported that erythropoietic doses of EPO (200–400 U/kg) used to treat anemia do not raise CSF EPO concentrations.[24] Further investigations are required to define the optimal dose for neuroprotection.

PS100B are a group of calcium binding modulator proteins involved in cell cycle progression, cell differentiation, and cytoskeletal membrane interactions. Astroglial cells have a high concentration of PS100B, but other cells can release it. NSE is a glycolyticiso enzyme specific for neurons and neuroectodermal cells. Previous studies showed that PS100B and NSE levels in CSF after perinatal asphyxia are demonstrated to be good biomarkers of brain injury, and higher levels are present with unfavorable outcomes.[25]

Likewise, higher PS100B and NSE CSF levels in normothermic asphyxiated infants with HIE and hypothermic ones have been described and might be useful to identify brain injury and predict long-term outcomes.[25],[26],[27] The small number of patients is a limitation of this study but because our entry criteria are similar to that used in Sun et al. HT trial and since it has become a standard of care, we are able to compare our outcomes to those published before. Otherwise, it is no ethical to have a normothermic control group of asphyxiated newborn so we compared our protein biomarker of brain injury levels with data in the literature.

Cerebrospinal fluid levels of NSE were lower than those reported by Sun et al. in asphyxiated infants treated just with HT or normothermia [Figure 1].[26] Thus, EPO treatment could have an additive effect in concordance with HT and counteract brain damage decreasing NSE levels. On the other hand, PS100B levels were higher than published data but remained within normal range. It is important to note that there was a "outlier" infant with the highest NSE level. Interestingly, this neonate had an epileptic status on day 4th. Notice that this baby was male and Johnston et al., reported that male neurons in culture are more sensitive to death from exposure to NMDA and nitric oxide and female neurons were preferentially sensitive to caspase 3 inhibitions. EPO has been reported to be more protective in females.[28],[29] Evidence suggests that sex is an important determinant of which cell death pathways are activated during HIE and it could also influence effects of neuroprotective drugs. In our group of patients, there were 60% of males.

Moreover, different doses have been described with a range of 300–30,000 U/kg. It is of interest that EPO levels in CSF were high so low repeated doses of rhEPO administered in thefirst 3 h of life are enough to cross BBB.

It is widely known that a new bedside prognostic tool in perinatal asphyxiated infants is aEEG and time to recovery a normal background pattern seems to be a predictor of outcome in infants treated with HT.[30],[31],[32],[33],[34] [Figure 2] shows that those infants who recovered before a normal background pattern did have a normal outcome in terms of death or severe disability at 18 months. In terms of prognosis, we found an inverse relation between RI in MCA and time to reach normal background pattern. Although HT makes cerebral RI a poor prognostic tool in HIE,[35] this index was calculated in thefirst 2 h of life.

In keeping with results observed by Elmahdy et al. in humans and recently Traudt et al.[36] in a primate model and Rogers et al. in a newborn model [19] neurodevelopmental outcomes according to neurologic examinations at 18 months of age reached a 20% in terms of death of severe disability, lower than that reported previous studies.[4],[6] A recent trial demonstrated a neuroprotective role for human EPO only in moderate and not severe HIE.[37] Nonetheless, we enrolled patients with moderate/severe HIE.

Similar to previous neonatal studies,[38],[39] we found that EPO is well tolerated. Adverse events reported in adults after EPO treatment such as hypertension, polycythemia, and thrombosis has not been reported. Although some authors described a high risk of retinopathy after EPO treatment in premature infants, we did not find this complication in term asphyxiated infants.

After all, these findings suggest that exogenous administration of rhEPO may be a potential therapeutic tool for CNS brain injury. Limitations of this study include lack of patients, and more studies are warranted.

  Conclusion Top

Although this is a prospective study with no control group, rhEPO concurrent with HT for HIE did not worsen outcomes and could influence in downs levels of brain injury biomarkers on CSF. Nonetheless, further investigations are required to elucidate the dose-response relationship. No adverse reactions have been described.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1]


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