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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 2  |  Page : 45-52

Effect of erythropoietin as adjunctive therapy with whole-body cooling for treatment of hypoxic-ischemic encephalopathy in newborns


1 Pediatric Department, Division of Neonatology, Alexandria University Children’s Hospital, Alexandria, Egypt
2 Radiodiagnosis Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission20-May-2017
Date of Acceptance27-Aug-2017
Date of Web Publication17-Jan-2018

Correspondence Address:
Khalid M Saad
Pediatric Department, Division of Neonatology, University Children’s Hospital, Faculty of Medicine, Alexandria University, Alexandria, 21615
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJOP.AJOP_14_17

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  Abstract 


Background Hypothermia induced by whole-body cooling (WBC) and/or selective head cooling reduces brain injury after hypoxia-ischemia in newborns. Despite differences in approach (head cooling vs. total body cooling), there is a general agreement that hypothermia improves outcomes of moderately asphyxiated infants, decreasing the combined outcome of death and neurologic dysfunction from 60 to 45%. Subsequently, the search for adjuvant therapies that may provide long-lasting neuroprotection was mandatory.
Aim of the present work The present study aimed to evaluate the short-term effects of erythropoietin (Epo) as a neuroprotective agent in adjunction with WBC to treat newborn infants with hypoxic-ischemic encephalopathy (HIE).
Participants and methods This is a true interventional randomized controlled hospital-based study. A total of 33 full-term and late preterm newborn infants, delivered at El-Shatby Alexandria University Maternity Hospital, Egypt, were enrolled in the study. They fulfilled the criteria of HIE and received WBC during the first 6 h of life, in addition to the standard intensive care measures. Of the 33 studied babies, 11 received 500 IU/kg Epo every other day for 2 weeks as adjunctive therapy to WBC.
Results The Epo plus WBC group (group I) had a significantly shorter period of hospital stay in comparison with the other group managed by WBC solely (group II), [mean hospital stay in days±SD: 6.20±2.39 and 8.40±3.94, respectively (P=0.039)]. The incidence of seizures was insignificantly lower among babies in group I. Extensive white and gray matter brain lesions were observed more among group II neonates, although the difference was statistically insignificant. Clinical and neurological improvements, as guided by Thomson score, were better achieved among group I babies, despite the difference being statistically insignificant.
Conclusion Epo as an adjunctive therapy with WBC for treating asphyxiated neonates is a safe mode of therapy, which significantly shortens the period of hospital stay as well as it (marginally) improves their short-term outcome, both radiologically and clinically. WBC plus Epo lowers the rate of occurrence of clinically detectable seizures in the 1st week of life among asphyxiated neonates.

Keywords: erythropoietin, hypoxic-ischemic encephalopathy, neuroprotective, whole-body cooling


How to cite this article:
Badr-El Din MM, Abougabal AM, Saad KM, Abdel-Salam HR. Effect of erythropoietin as adjunctive therapy with whole-body cooling for treatment of hypoxic-ischemic encephalopathy in newborns. Alex J Pediatr 2017;30:45-52

How to cite this URL:
Badr-El Din MM, Abougabal AM, Saad KM, Abdel-Salam HR. Effect of erythropoietin as adjunctive therapy with whole-body cooling for treatment of hypoxic-ischemic encephalopathy in newborns. Alex J Pediatr [serial online] 2017 [cited 2018 Feb 23];30:45-52. Available from: http://www.ajp.eg.net/text.asp?2017/30/2/45/223451




  Introduction Top


Despite major advances in monitoring technology and knowledge of fetal and neonatal pathologies, hypoxic-ischemic encephalopathy (HIE) contributes significantly to neonatal mortality and long-term morbidity [1].

In the developed countries, HIE occurs in 3–5 in 1000 live births, with moderate or severe HIE affecting 0.5–1 per 1000 live births [2]. In developing countries, the reported incidence is approximately 10 times greater [3]. Despite advances in newborn intensive care, ∼10–60% of HIE-affected infants die, and at least 25% of those who survive experience lifelong neurological impairment, with common outcomes of epilepsy, cerebral palsy, and mental retardation [2]. Therapies for HIE remain limited. Although there are no established interventions that fully treat neonatal HIE, many potential therapies that may prevent injury progression and enhance repair are currently under investigation [4].

Accumulating evidence supports the neuroprotective benefit of therapeutic hypothermia (HT) in term newborns with HIE [5]. Therapeutic HT significantly reduced the risk of death or major sensorineural disability at 2 years of age [6]. Possible mechanisms of action of HT include reduced neuronal metabolic demand, diminished release of excitotoxic neurotransmitters and reactive oxygen species, and prevention of apoptosis during secondary energy failure [7].

Despite the remarkable beneficial effects of HT, improvement in the subsequent outcome of asphyxiated babies is only achieved by ∼30%, and it is likely that other neuroprotective therapies may add incrementally to the proven benefits of HT [8]. So, novel neuroprotective therapy to minimize neonatal brain injury is greatly needed [9]. Animal studies support the efficacy and safety of Epo as a preventive and therapeutic intervention for a variety of brain insults [10].

Although Epo was originally identified for its role in erythropoiesis, it has since been shown to have wide range of functions that may account for its neuroprotective effects, including cell death inhibition, immune response modulation, initiation of angiogenesis, and promotion of neurogenesis, thereby enhancing repair [11]. Epo receptors are expressed by multiple cell types in the central nervous system. Epo is expressed in the brain primarily by astrocytes. In the setting of hypoxia-ischemia, Epo receptor (Epo-R) expression is upregulated rapidly, with Epo production increasing only if significant hypoxia is prolonged. If Epo is available to bind to the upregulated receptor, cell survival is promoted, and in the absence of Epo, the pathway of programed cell death predominates [12].

The first trial of Epo therapy for neuroprotection in term infants with moderate-to-severe HIE revealed that repeated low-dose Epo (300 or 500 U/kg every other day for 2 weeks) was safe and resulted in improved neurological outcome for patients with moderate HIE at 18 months of age. Epo was only effective for infants with moderate injury and did not improve outcome for severely affected infants. Clinical studies are ongoing to confirm the safety and efficacy of Epo [13],[14]. McPherson and colleges reported that systemic effects of Epo, such as stabilizing oxygen availability, decreasing free iron, and reducing inflammation, complement the direct neuroprotective effects of Epo and may explain why lower dosing strategies also improve outcome. Combination therapies such as Epo plus HT are being considered to further improve outcomes [9].

Aim of the study

The aim of the present work was to evaluate the neuroprotective effects of erythropoietin in combination with therapeutic HT in treating neonates with HIE.

Participants and methods

The study was carried out on 33 babies delivered at El-Shatby Maternity Hospital of Alexandria University experiencing moderate HIE and admitted to its Newborn Intensive Care Unit (NICU).

The inclusion criteria for both groups were full-term and late preterm newborn infants older than or equal to 36 completed weeks of gestation admitted to the NICU with all of the following:
  1. Apgar score of up to 5 at 5 min after birth [15].
  2. Signs of fetal distress before delivery (including fetal bradycardia of less than 100/bpm or tachycardia of more than 160/bpm or meconium-stained amniotic fluid) [15].
  3. Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth [5].
  4. Acidosis within 60 min of birth (defined as umbilical cord, arterial or capillary pH <7.00 or base deficit ≥16 mmol/l) [5].
  5. Clinical evidence of encephalopathy, consisting of altered state of consciousness (lethargy, stupor, or coma) and at least one of the following [5]:
    1. Hypotonia.
    2. Abnormal reflexes including oculomotor or pupillary abnormalities.
    3. Absent or weak suckling.
    4. Clinical seizures.


All studied infants were closely monitored and treated in a standard manner with attention to maintenance of normal blood gases, blood pressure, fluid balance and renal function, hypoglycemia, jaundice, bleeding tendencies, and seizure management [16]. The studied babies were randomly allocated to WBC plus Epo group (group I, n=11) or WBC only group (group II, n=22). Allocation concealment and randomization were done using web-based software to assign patients to either group I or group II in an unequal manner. The two groups were unequal because erythropoietin is an expensive drug with limited research resources. Cooling was commenced within 6 h after birth and continued for 72 h.

In group I neonates, 500 IU/kg Epo was administered subcutaneously initially and then the same dose intravenously every other day for 2 weeks [13],[14] (Alpha Recombinant Human Erythropoietin-Epoetin 4000 IU/1 ml; South Egypt Drug Industries Co., 6th of October City, Egypt). Because the therapeutic window of Epo appears to be longer than for HT, Epo treatment is initiated at any time up to 24 h of life.

During cooling, a rectal temperature of 33–34°C is targeted [17]. Throughout hypothermic treatment and rewarming, rectal temperature was monitored continuously using a rectal probe placed 3 cm from the anus, and temperature was recorded hourly. The aim was to achieve the target temperature by 60 min of commencing cooling. HT had been targeted initially with passive cooling, but if that did not reduce the rectal temperature below 35°C within 30 min, then active cooling was resorted to. Passive cooling was applied by switch off radiant heater and keeping the baby naked in an open incubator in room temperature, whereas active cooling was applied using cool mattress with a temperature around 10°C. In case the baby’s temperature dropped below 33°C, the cooled packs or mattress is removed. If that was not sufficient, the radiant heater is switched on at minimal power until the temperature increased more than 33°C [17].

After 72 h of WBC, rewarming to a temperature of 37°C was conducted slowly. This was achieved by adjusting the temperature of the radiant heater so that the patient’s temperature increased by no more than 0.5°C/h [18].

Clinical assessment was done using neurological classification systems: Sarnat and Sarnat score [19] and Thompson score, which was recorded on day of life (DOL) 1, 3, and 7 [20].

Evaluation of cases was accomplished both clinically and radiologically:
  1. Clinical: using Thompson (recorded on DOL 1, 3, and 7) and Sarnat and Sarnat scoring systems [19],[20].
  2. MRI scan: The newborns were imaged as soon as they were stable enough to be transported safely to the MRI scanner. Images were obtained with closed superconducting magnets (Gyroscan; Philips Medical Systems, Eindhoven, the Netherlands) operating at a field-strength of 1.5 T. All scans were done within 2 weeks of birth after the initiation of Epo treatment, in all surviving babies. One case from group I and two cases from group II died before performing MRI, so n of 10 and 20 for group I and II, respectively.


The examination duration was around 20 min for each case. Sedation was resorted to using phenobarbital IV in sedative dose (3 mg/kg/dose) or midazolam IV (dormicum 5 mg/ml amp. − Roche company − made for Roche ltd., Basel, Switzerland by Cenexi SAS, Fontenay-Sous, Bois, France) in dose of 0.05 mg/kg/dose. The babies were closely observed and monitored during the procedure by a pulse-oximeter and counting the respiratory rate by an experienced neonatologist.

Statistical analysis

Data were fed to the computer using the Predictive Analytics Software (PASW Statistics 18). Categorical data, expressed as frequency, were analyzed using χ2 test. Fisher’s exact test or Monte Carlo correction was used when appropriate. The distribution of the quantitative data was expressed as median (range), or mean±SD. Parametric and nonparametric tests were applied if the results were normally or abnormally distributed, respectively. For normally distributed data, comparisons between two independent populations were done using independent t-test. For abnormally distributed data, Mann–Whitney test was used to analyze two independent populations. Significance of the obtained results was judged at the 5% level.

Ethical consideration

The study was ethically approved by the Alexandria Faculty of Medicine Ethical Review Committee, and NICU authority − taking permission to apply the intervention and follow-up the studied neonates in the NICU. Moreover, an informed consent was obtained from all parents.


  Results Top


The results are shown in [Table 1],[Table 2],[Table 3],[Table 4],[Table 5],[Table 6] and [Figure 1],[Figure 2],[Figure 3].
Table 1 Demographic data of the two studied groups

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Table 2 Comparison between the two studied groups according to Thompson score on day of life 1, 3, and 7

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Table 3 Comparison between the two studied groups according to the incidence of clinical seizures at day of life 1, 3, 5, and 7

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Table 4 Comparison between the two studied groups according to MRI finding

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Table 5 Comparison between the two studied groups according to outcome arranged in relation to hypoxic-ischemic encephalopathy grading (Sarnat and Sarnat)

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Table 6 Comparison between the two studied groups according to days of hospital stay

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Figure 1 Axial MRI of a neonate from group I on day of life 7 (case no. 1). Arrows showing multiple small ischemic lesions in the left high frontal lobe, showing hyperintense signal in both T1 (c) and T2 FLAIR (a) sequences, in addition to hyperintense signal in T2 diffusion (b) denoting restricted diffusion.

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Figure 2 Axial MRI from group II on day of life 7 (case no. 2) including T2 DW (diffusion weighted) (a) and T1-weighted sequence (b). Images show multiple acute ischemic lesions involving bilateral deep periventricular white matter (arrows). They show hyperintense signal in T2-weighted diffusion sequence (a) as well as hyperintense signals in T1-weighted sequence (b). Absence of hemorrhage was confirmed by T2 gradient sequence.

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Figure 3 Axial MRI of neonate from group II on day of life 14 (case no. 3). Arrows whether in T1-weighted (a) or T2-weighted (b) axial images show sizable bilateral cortical and subcortical T1 hypointense and T2 hyperintense lesions seen along bilateral cerebral hemispheres exhibiting near cerebrospinal fluid signal intensity. This is associated with dilatation of third and lateral ventricles and relative thinning of the deep white matter bilaterally. Such features are likely attributed to bilateral sizable encephalomalacic changes as a sequel of extensive perinatal hypoxic insult.

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  Discussion Top


HT has become a standard of care for babies experiencing HIE. Yet, clinical trials suggest that 44–53% of infants who receive HT will die or experience moderate-to-severe neurological disability. As HT does not provide complete neuroprotection, urgent investigation into additional pharmacological agents may further improve outcomes [21]. Epo is a good example of these agents. It is a glycoprotein widely used in neonates, possessing neuroprotective effects as demonstrated in preclinical studies [22]. In both animals and humans, Epo-R is expressed in the brain during early development, which gradually decreases after birth [23]. Hypoxia-ischemia in the brain leads to an increase in Epo expression, mediated by hypoxia-inducible factor-1 [24]. This upregulation of Epo and its receptors appears to represent an endogenous neuroprotective mechanism [23]. This created an important rationale for Epo administration, given that upregulation of this latter may take several hours, whereas brain injury can occur after brief but catastrophic insults that are insufficient to stimulate an increase in endogenous Epo synthesis [25].

In our study, there was no significant statistical difference regarding the demographic data ([Table 1]) − including the sex distribution − between the two study groups. However, the total number of males exceeded that of females, representing 72.7% of both study groups. Nearly similar results were reported by Seyal and Hanif. Approximately 69% of the cases were males. These workers reported that male sex adversely affects the outcome of neonates with perinatal asphyxia [26]. It is increasingly recognized that the mechanisms underlying ischemic cell death are sexually dimorphic. Stroke-induced cell death in males is initiated by the mitochondrial release of apoptosis-inducing factor, resulting in caspase-independent cell death. In contrast, ischemic cell death in females is primarily triggered by mitochondrial cytochrome c release with subsequent caspase activation. Because X-linked inhibitor of apoptosis (XIAP) is the primary endogenous inhibitor of caspases, its regulation may play a unique role in the response to injury in females. Chad Siegel et al. [27] reported that XIAP mRNA levels were higher in females at baseline.

The current study revealed improvement in the neurological evaluation in both groups on DOL 3 and 7, as evidenced by improving Thomson score. Although the difference was not statistically significant, it was more pronounced in group I. This can be explained by the beneficial clinical effect of cooling therapy. In accordance, in 2015, Valera and colleagues concluded from their study that Epo concurrent with HT for HIE has a potential neuroprotective effect. Epo crosses the blood–brain barrier and could influence in downregulation levels of brain injury biomarkers on cerebrospinal fluid [22]. In 2016, Dr. Wu reported a significant less frequency of the following items: deaths, lower global brain injury scores, and moderate/severe injury as well as subcortical and cerebellar injury among Epo plus HT group compared with the control group (HT only) [28].

In this study, a single case in group I had clinical convulsions comparable to nine cases in group II by DOL 5. However, no statistical significant difference between both groups was detected. By DOL 7, none of the babies in group I experienced convulsions in contrast to four in group II. Therefore, the control of seizures was much earlier among cases of group I. A meta-analysis of five trials of neonates with HIE failed to show a significant effect of therapeutic HT on the incidence of clinically recognized seizures [2]. In our study, the lower percentage in group I may be because of the use of Epo in combination with therapeutic HT. Recent experimental studies performed in adult rodents have indicated that Epo and its peptide derivative exerted antiepileptogenic effect and decreased seizure-induced neural cell death [13]. In addition, a recent clinical pilot study on infants with mild/moderate HIE showed that significantly less seizures has been observed in Epo-treated group [13],[29]. However, Valera and colleagues studied the efficacy and safety of Epo concurrent with HT among 15 newborns with HIE. They reported that no intergroup differences were recorded for incidence of clinical and electrical seizures over the first 24 h [30].

Of 33 studied neonates, only 30 had MRI scan of the brain. No significant statistical difference regarding MRI findings was detected between the two studied groups ([Table 4]). In group I, only one case (case no. 1) showed multiple small ischemic cortical lesions in the left high frontal lobe, and hyperintense signal in both T1 and T2 FLAIR sequences, in addition to hyperintense signal in T2 diffusion denoting restricted diffusion ([Figure 1]). However, in group II, two cases (cases no. 2 and 3) had MRI findings in the form of extensive white and gray matter lesions with mild ventricular dilatation (mild encephalomalacic changes) ([Figure 2] and [Figure 3]).

The absence of basal ganglia lesions in the current study was in agreement with the results of Rogers and colleagues, who reported a reduction in lesions of the basal ganglia among neonates with HIE after cooling plus Epo. In their study, only one (9%) of 11 neonates with abnormal MRI pattern had basal ganglia predominant injury [31]. In contrast, several other studies of cooled infants with HIE had reported a higher rate of basal ganglia injury, ranging from 24 to 60% [32],[33]. Basal ganglia and thalamic injury occurs most commonly in infants who have experienced a sentinel event such as uterine rupture, placental abruption, or cord prolapsed [34]. HT effectively reduces the incidence of basal ganglia injury after HIE [33],[35]. Rogers and colleagues commented whether high-dose Epo can further reduce the incidence of basal ganglia injury is unknown. Several clinical trials of Epo and HT are currently going on. It is unknown whether Epo therapy provides optimal neuroprotection when given within the first 72 h as an add-on therapy to HT, or whether Epo enhances regenerative and repair mechanisms best when given days later [31].

In the present study, of 30 studied cases that had MRI scan (between DOL 5 and 14), 27 (90%) cases showed no abnormal MRI patterns despite they had fulfilled the criteria of hypoxic encephalopathy. This may enforce the hypothesis that cooling with or without Epo might have reduced the severity of hypoxic brain injury. In agreement with our hypothesis, Rutherford et al. [36], concluded that therapeutic HT was associated with a reduction in lesions in the basal ganglia or thalamus and white matter. In addition, Debillon et al. [15] had reported − in a prospective pilot study applying whole-body cooling after perinatal asphyxia − that 72% of the survived cases had normal cerebral signal by MRI. Moreover, Rogers et al. [31] study results showed that only 54% of their studied HIE neonates − who received cooling plus Epo − had a normal brain MRI finding.

Regarding the outcome of the studied neonates, there was no statistical difference between both groups regarding percentages of deaths (9.1%) ([Table 5]). However, it should be highlighted that only 25% of HIE grade III cases in group I died, whereas 66.7% died in group II. Moreover, no cases of HIE grade III in group II were discharged with normal MRI finding in contrast to 50% in group I. In addition, it was noted that all cases of HIE grade II in group I were discharged with normal MRI finding in comparison with only 93.8% of group II. Thus, the overall proposed effect of adding Epo to cooling therapy was to lessen the mortality and disability. In accordance, Wu et al. [37] reported that neonatal deaths did not significantly differ between EPO plus HT group of HIE neonates and the placebo plus HT HIE group (8 vs. 19%, respectively, P=0.42). No deaths were encountered in Rogers et al. [31] study on 22 hypoxic neonates that received EPO plus HT. However, Valera et al. [22] reported two (13.3%) deaths in the first 72 h of life, of 15 HIE studied neonates who received Epo plus HT.

In the present study, group I had a significant shorter duration of hospital stay ([Table 6]). This may be because of the fact that newborns undergoing combination therapy showed rapid improvement of their neurological states. Moreover, adding Epo to the cooling therapy shortens the hospital stay by the early control of posthypoxic seizures [13],[29].


  Conclusion Top


WBC must be a standard care therapy for neonates with HIE in low-resource settings because it is achievable, using simple and easily available cooling materials, effective, safe mode of intervention, and inexpensive. Epo is an affordable cytokine with the potential neuroprotective effect that can be used in combination with HT, and it crosses blood–brain barrier. Epo as adjunctive therapy with WBC could improve short-term outcome both radiologically and clinically. It may protect the brain from the deleterious effect of seizures and decreases the use of anticonvulsants that may have significant apoptotic effect.

We conclude that adding Epo to cooling therapy for HIE may result in less MRI brain injury and significantly shortens the period of hospital stay.

MRI (including conventional and diffusion-weighted imaging) is a sensitive, well-established diagnostic and prognostic imaging technique in the management of neonates with asphyxial injury.

Further studies with similar aim are warranted. These studies should ideally include a greater number of babies, properly classified according to the severity of HIE (i.e., grade 2 and grade 3), followed till the last dose of Epo and the MRI done on the same DOL in all babies. Moreover, different regimens and doses of Epo administration could be the subject of future thesis or research.

Financial support and sponsorship

Nil.

Limitations

The sample size of the studied neonates was small and divided into unequal groups, and MRI was done at different ages.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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