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Francesco Tomasello, M.D.

Chairman and Professor, Department of NeurosurgeryUniversity of Messina

Erythropoietin for Subarachnoid Hemorrhage: Is There a Reason for Hope?

Giovanni Grasso1 and Francesco Tomasello2

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S ubarachnoid hemorrhage (SAH) associated with a rupturedcerebral aneurysm remains a source of significant morbid-ity and mortality, not only from the initial hemorrhage but

lso from the delayed complications, such as cerebral vasospasmften severe enough to induce irreversible changes in cerebralerfusion. Several drugs have been developed that have theotential to limit cerebral vasospasm and delayed ischemiceurologic deficit, thus improving outcome for patients. How-ver, although numerous agents that can prevent arterial narrow-

ng and/or block the excitatory cascade of events leading toschemic neuronal death in experimental conditions, there is stillo pharmacologic agent that has been shown conclusively to

mprove the outcome in the clinical practice. Because the SAH-nduced cerebrovascular dysfunction is a multifactorial process,he available pharmacologic therapies are addressed to counter-ct the main causative processes. The main therapeutic interven-ions used are limited to manipulation of systemic blood pres-ure, alteration of blood volume or viscosity, and control ofrterial carbon dioxide tension.

europrotection may be an alternative strategy to limit the extentf irreversible damage that occurs to the neuronal cells afterneurysmal SAH. Neuroprotectants disrupt the cellular, biochem-cal, and metabolic processes that lead to brain injury andncompass a wide and continually expanding array of pharmaco-

ogic interventions. An ideal addition to the SAH treatmentrmamentarium would be a well-tolerated neuroprotective agenthat has the ability to reduce arterial vasospasm and delayedschemic neurologic deficit.

n this scenario, a large body of evidence point to recombinantuman erythropoietin (EPO). Human EPO is a glycoproteinrowth factor that acts as the main regulator of erythropoiesis.ince the human EPO gene was cloned in the early 1980s, the

Key words� Erythropoietin� Neuroprotection� Subarachnoid hemorrhage

Abbreviations and AcronymsEPO: ErythropoietinSAH: Subarachnoid hemorrhage

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PO recombinant form was rapidly developed and its use hasxpanded dramatically in the clinical practice. During the pasteveral years, recombinant human EPO has greatly enhanced theanagement of anemia of chronic renal failure and has substan-

ially improved quality of life in patients undergoing dialysis.

t has been more than 10 years since the discovery that EPO andts receptor are expressed by the nervous system. In that briefime, a remarkable acceleration in understanding the biology ofhis paracrine-autocrine system has occurred, radically changingur concept of the biological functions of EPO. The observationhat systemically administered recombinant human EPO caneach local sites within the brain (2) has suggested manyotential clinical indications. In vivo preclinical studies haveemonstrated that recombinant human EPO administration caneduce neuronal injury as produced by different models includingxperimental SAH (1, 2, 9). Furthermore, successful translationf preclinical data has been confirmed by the first clinical trial withecombinant human EPO in a small cohort of patients with acutetroke (5). The results have shown that recombinant human EPOdministration is safe in this setting and is associated with aetter functional recovery at 1-month follow-up.

urner and collaborators (18) have done an excellent job byeviewing the current literature on the neuroprotective propertiesf EPO in SAH, providing an expert view on its possible clinicalranslation.

n this regard, our research group was the first to suggest theeneficial effect exerted by EPO during experimental SAH (4).tarting from the pioneering results by Sakanaka (14) and Sad-moto (13) and their colleagues we hypothesized that EPO, in itsecombinant form, could counteract the pathophysiologic mech-nisms underlying cerebrovascular dysfunction after SAH and

From the 1Neurosurgical Clinic, Department of Experimental Biomedicine andClinical Neurosciences, University of Palermo, School of Medicine, Palermo and

2Neurosurgical Clinic, Department of Neurosciences, Psychiatry and Anaesthesiology,niversity of Messina, School of Medicine, Messina, Italy

o whom correspondence should be addressed: Giovanni Grasso, M.D., Ph.D.E-mail: ggrasso@unipa.it]

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itation: World Neurosurg. (2012) 77, 1:46-48.OI: 10.1016/j.wneu.2011.01.028

RLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.01.028

PERSPECTIVES

the results obtained by our studies have suggested an effectiveEPO-based therapy in such a pathology (7-10). Thereafter, Spring-borg and collaborators (15) reinforced our intuition and expandedthe available findings on this topic to producing clinical trials (16,17). In this regard the recent clinical use of EPO after SAH (17)has shown that EPO can have chance as a neuroprotectant afteraneurysmal SAH in humans. Although the study has somelimitations (i.e., small sample size, a single predefined dose ofEPO, a single trial center, lack of timed computed tomographicscan data), it demonstrates, also in humans, what we havealready observed in our experimental studies—EPO administra-tion can be effective in limiting cerebral vasospasm and ischemiaafter aneurysmal SAH.

Although the data coming from preclinical and clinical studiesopen new avenue in this field, some issues should be strictlyconsidered. First, the safety of recombinant human EPOadministration in the setting of SAH. It must be taken intoaccount that all the information available at present regardingthe safety of recombinant human EPO in humans come fromits non-neurologic use. The logical extension of these argu-ments is that translating such information from anemic recom-binant human EPO-treated to SAH-affected patients can bemisleading, as interaction and influence between recombinanthuman EPO and different physiologic variables, as well as withcommon drugs taken by patients with SAH, are unknown.Second, although recombinant human EPO is usually a well-tolerated drug, several lines of evidence have shown thattherapy with recombinant EPO can result in hypertension,hypertensive encephalopathy, accelerated atherosclerosis,seizures, and thrombotic/vascular events. In these pioneeringclinical studies, no adverse effects during the EPO treatmenthave been reported. These findings, however, should becautionary as these results are related to a short-term treat-ment and low EPO dosage. In this regard, in our studies wehave provided evidence that recombinant human EPO treat-

ment at a dose of 1000 IU/kg, administered every 8 hours, is

ing subarachnoid hemorrhage. Eur J Pharmacol392:31-34, 2000.

perimental subarachnoidRev 44:49-63, 2004.

WORLD NEUROSURGERY 77 [1]: 46-48, JANUARY 2012

effective in reducing cerebral vasospasm, ischemic braindamage, and significantly capable of improving neurologicoutcome. The dose used in the clinical setting is the lowestdose known to be effective after SAH. However, it can beargued that the unfavorable results from the first clinical trial(16) and the weak findings of the second clinical study (17) canbe related to the small dose used and frequency of adminis-tration. In this regard, it is well known that vasospasm andcerebral ischemia after aneurysmal SAH follow a time coursecompletely different when considering humans and animals.In preclinical studies, EPO has been considered effective at adose starting from 400 IU to 1000 IU/kg with a duration of 24to 72 hours (9). In humans, although evidence has shown thatthere may be an early, short-lived phase that occurs immedi-ately after SAH and a subsequent phase that is prolonged orchronic (11), the delayed vasospasm, seen on angiogram in40%–70% of patients with SAH in the second week afterhemorrhage, appears clinically to be most important. Conse-quently, there is a rationale for starting and continuing neuro-protection for at least 14 days after SAH onset to achievestronger effects.

It should be considered, at present, that all phase III trialsusing neuroprotective drugs have failed to demonstrate effi-cacy and the lesson learned suggests that great optimism canlead to very early clinical investigations mainly driven bywishful thinking, undertaken without much detailed informa-tion. For this reason additional studies must be carried out todetermine the safety of EPO in the setting of this new clinicalapplication, optimal tolerated dosages, therapeutic time win-dow, and duration of therapy. Furthermore, increased bloodviscosity and possible thrombotic events seem to be the majorcomplications after prolonged EPO treatment. Accordingly,the new EPO-derived drugs without erythropoietic effects (2,3, 6, 12), developed and experimentally tested with efficacy atpresent, should be further investigated to tailor successful

future clinical trials.

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