Single dose recombinant erythropoietin versus moderate hypothermia for neonatal hypoxic ischemic encephalopathy in low resource settings

Shimi, Mohamed; Awad, Hassan M.; Hassanein, Sahar M A; Gad, Ghada I.; Imam, Safaa S.; Shaaban, Hebatallah A; Maraghy, Mohamed O El

doi:10.3109/14767058.2013.855894

Cited by 38 publications

(32 citation statements)

References 27 publications

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“…The present observation that delayed treatment with moderate induced hypothermia was substantially more neuroprotective than rEpo infusion started at the same time and continued for the same duration is broadly comparable with the findings from a recent small cohort study in term neonates with acute HIE that whole‐body hypothermia was superior to a single subcutaneous injection of 1500 U kg −1 of rEpo administered within 24 h of birth (El Shimi et al . ).…”

Section: Discussionmentioning

confidence: 97%

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Wassink

Davidson

Fraser

et al. 2020

The Journal of Physiology

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Key points Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether the combination of high‐dose rEpo therapy with therapeutic hypothermia can further improve outcomes. Hypothermia and rEpo independently improved neuronal survival, with greater improvement with hypothermia, and similarly reduced numbers of caspase‐3 positive cells and reactive microglia after 7 days recovery. Hypothermia, but not rEpo, was associated with markedly improved EEG power, whereas both interventions improved recovery of EEG frequency. There was no significant improvement in any outcome after combined rEpo and hypothermia compared with hypothermia alone, and of concern, the combination was associated with increased numbers of cortical caspase‐3‐positive cells compared with ischaemia‐hypothermia. These data suggest that the mechanisms of neuroprotection with hypothermia and rEpo overlap and, thus, high‐dose rEpo infusion does not appear to be an effective adjunct therapy for therapeutic hypothermia. Abstract Therapeutic hypothermia for hypoxic‐ischaemic encephalopathy (HIE) provides incomplete neuroprotection. Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether adjunct rEpo therapy with therapeutic hypothermia can further improve outcomes. Near‐term fetal sheep received sham‐ischaemia (n = 9) or global cerebral ischaemia for 30 min (ischaemia‐vehicle, n = 8), followed by intravenous infusion of rEpo (ischaemia‐Epo, n = 8; 5000 U/kg loading dose, then 833.3 U/kg/h), cerebral hypothermia (ischaemia‐hypothermia, n = 8), or rEpo plus hypothermia (ischaemia‐Epo‐hypothermia, n = 8), from 3 to 72 h post ischaemia. Fetal brains were collected 7 days after cerebral ischaemia. Cerebral ischaemia was associated with severe neuronal loss and microglial induction in the parasagittal cortex and subcortical regions. Hypothermia reduced overall neuronal loss, cortical caspase‐3 and reactive microglia in the striatum and cortex, with greater recovery of electroencephalographic (EEG) power and spectral edge (SEF) from 48 h onwards. rEpo independently improved neuronal survival in the parasagittal cortex, hippocampal CA4 and thalamus, and reduced cortical caspase‐3 and activated microglia in striatal and cortical areas, with greater SEF from 120 h onwards. However, ischaemia‐Epo‐hypothermia did not further improve outcomes compared with ischaemia‐hypothermia and was associated with increased numbers of cortical caspase‐3‐positive cells. These findings suggest that although delayed, prolonged treatment with both hypothermia and rEpo are independently neuroprotective, they have overlapping anti‐inflammatory and anti‐apoptotic mechanisms, such that the delayed, high‐dose rEpo infusion for 3 days did not materially augment neuroprotection with therapeutic hypothermia.

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Section: Discussionmentioning

confidence: 97%

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Wassink

Davidson

Fraser

et al. 2020

The Journal of Physiology

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“…The neurodevelopmental delay at 18 months-of-age was lower in both of the treated groups compared with the control group, although the differences were not statistically analyzed. El Shimi et al 2014 [118] (Table 3) compared 30 term neonates with HIE with 15 healthy neonates. Ten HIE neonates were treated with a single dose of r-Hu-EPO on day 1, 10 were treated with therapeutic hypothermia for 72 h, and 10 with supportive care.…”

Section: Clinical Studies On Neonatal Hypoxic-ischemic Encephalopathymentioning

confidence: 99%

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Oorschot

Sizemore

Amer

2020

IJMS

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Perinatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of morbidity and mortality. Moderate hypothermia (33.5 °C) is currently the sole established standard treatment. However, there are a large number of infants for whom this therapy is ineffective. This inspired global research to find neuroprotectants to potentiate the effect of moderate hypothermia. Here we examine erythropoietin (EPO) as a prominent candidate. Neonatal animal studies show that immediate, as well as delayed, treatment with EPO post-injury, can be neuroprotective and/or neurorestorative. The observed improvements of EPO therapy were generally not to the level of control uninjured animals, however. This suggested that combining EPO treatment with an adjunct therapeutic strategy should be researched. Treatment with EPO plus hypothermia led to less cerebral palsy in a non-human primate model of perinatal asphyxia, leading to clinical trials. A recent Phase II clinical trial on neonatal infants with HIE reported better 12-month motor outcomes for treatment with EPO plus hypothermia compared to hypothermia alone. Hence, the effectiveness of combined treatment with moderate hypothermia and EPO for neonatal HIE currently looks promising. The outcomes of two current clinical trials on neurological outcomes at 18–24 months-of-age, and at older ages, are now required. Further research on the optimal dose, onset, and duration of treatment with EPO, and critical consideration of the effect of injury severity and of gender, are also required.

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“…Predicting the occurrence and short-term outcome in neonates with HIE is particularly important for initiating and monitoring appropriate management 3. This has become even more important with the current availability of effective neuroprotective strategies such as therapeutic hypothermia and the administration of nerve growth factor 456. This may prove even more valid with the envisioned use of other, mainly pharmacological neuroprotective agents and strategies 7.…”

Section: Introductionmentioning

confidence: 99%

Human Umbilical Cord Blood CD34-Positive Cells as Predictors of the Incidence and Short-Term Outcome of Neonatal Hypoxic-Ischemic Encephalopathy: A Pilot Study

et al. 2017

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Background and PurposeNeonatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neurological handicap in developing countries. Human umbilical cord blood (hUCB) CD34-positive (CD34+) stem cells exhibit the potential for neural repair. We tested the hypothesis that hUCB CD34+ stem cells and other cell types [leukocytes and nucleated red blood cells (NRBCs)] that are up-regulated during the acute stage of perinatal asphyxia (PA) could play a role in the early prediction of the occurrence, severity, and mortality of HIE.MethodsThis case-control pilot study investigated consecutive neonates exposed to PA. The hUCB CD34+ cell count in mononuclear layers was assayed using a flow cytometer. Twenty full-term neonates with PA and 25 healthy neonates were enrolled in the study.ResultsThe absolute CD34+ cell count (p=0.02) and the relative CD34+ cell count (CD34+%) (p<0.001) in hUCB were higher in the HIE patients (n=20) than the healthy controls. The hUCB absolute CD34+ cell count (p=0.04), CD34+% (p<0.01), and Hobel risk scores (p=0.04) were higher in patients with moderate-to-severe HIE (n=9) than in those with mild HIE (n=11). The absolute CD34+ cell count was strongly correlated with CD34+% (p<0.001), Hobel risk score (p=0.04), total leukocyte count (TLC) (p<0.001), and NRBC count (p=0.01). CD34+% was correlated with TLC (p=0.02).ConclusionshUCB CD34+ cells can be used to predict the occurrence, severity, and mortality of neonatal HIE after PA.

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Single dose recombinant erythropoietin versus moderate hypothermia for neonatal hypoxic ischemic encephalopathy in low resource settings

Abstract: Therapeutic hypothermia was superior to single dose rEpo for neuro-protection in HIE especially in patients with stage-II Sarnat scale. Therapeutic effect of combined rEPO multiple dosing and modest hypothermia therapy should be studied.

Cited by 38 publications

References 27 publications

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Human Umbilical Cord Blood CD34-Positive Cells as Predictors of the Incidence and Short-Term Outcome of Neonatal Hypoxic-Ischemic Encephalopathy: A Pilot Study

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