Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage.
OBJECTIVE
In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy.


METHODS
The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-beta or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or > or = 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements.


RESULTS
Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 x 10(9)/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO.


CONCLUSIONS
Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.
Tseng
Ming-Yuan
MY
Neurosurgical Unit, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, UK. myt22@cam.ac.uk
Hutchinson
Peter J
PJ
Kirkpatrick
Peter J
PJ
D000367:Age Factors; D017542:Aneurysm, Ruptured / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017322:Clinical Trials, Phase II as Topic; D004311:Double-Blind Method; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000627:therapeutic use*; D023261:Glasgow Outcome Scale; D006410:Hematopoiesis / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006940:Hyperemia / Q000000981:diagnostic imaging / Q000188:drug therapy; D002532:Intracranial Aneurysm / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins; D018805:Sepsis / Q000188:drug therapy*; D013345:Subarachnoid Hemorrhage / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017585:Ultrasonography, Doppler, Transcranial; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000188:drug therapy*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin