Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial

Clinical article

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Object

Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH.

Methods

Within 72 hours of aSAH, 80 patients (age range 24–82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months.

Results

Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p = 0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p = 0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p = 0.001), a shortened duration of impaired autoregulation (ipsilateral side, p < 0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p = 0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p = 0.008).

Conclusions

This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Abbreviations used in this paper: aSAH = aneurysmal subarachnoid hemorrhage; DID = delayed ischemic deficit; EPO = erythropoietin; eNOS = endothelium-derived nitric oxide synthase; GOS = Glasgow Outcome Scale; MABP = mean arterial blood pressure; MCA = middle cerebral artery; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; TCD = transcranial Doppler; THRT = transient hyperemic response test; triple-H = hypertension, hypervolemia, and hemodilution; WFNS = World Federation of Neurological Societies.

Article Information

Address correspondence to: Peter J. Kirkpatrick, F.R.C.S.(SN), F.Med.Sci., Department of Neurosurgery, Addenbrooke's Hospital, Box 167, Level 4, Block A, Cambridge CB2 2QQ, United Kingdom. email: pjk21@medschl.cam.ac.uk.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Flow chart of the progress through phases of the randomized controlled trial of EPO and placebo in patients with aSAH.

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    Bar graph showing comparison of absolute reticulocyte counts (upper) and hematocrit (lower) between the trial groups. Each box represents the median value. Each whisker represents the 75th (upper hinge) and the 25th (lower hinge) percentiles. Dots mean outliers (that is, 1.5-fold the interquartile range). Asterisks indicate p < 0.001 after repeated-measurement ANOVA and Dunnett adjustment.

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    Comparison of MABP between the trial groups. Each box represents the median value. Each whisker represents the 75th (upper hinge) and the 25th (lower hinge) percentiles. Dots mean outliers (that is, 1.5-fold the interquartile range). No significant difference was seen between the trial groups.

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