- Open Access
Pharmacological treatment of delayed cerebral ischemia and vasospasm in subarachnoid hemorrhage
© Castanares-Zapatero and Hantson; licensee Springer. 2011
- Received: 25 March 2011
- Accepted: 24 May 2011
- Published: 24 May 2011
Subarachnoid hemorrhage after the rupture of a cerebral aneurysm is the cause of 6% to 8% of all cerebrovascular accidents involving 10 of 100,000 people each year. Despite effective treatment of the aneurysm, delayed cerebral ischemia (DCI) is observed in 30% of patients, with a peak on the tenth day, resulting in significant infirmity and mortality. Cerebral vasospasm occurs in more than half of all patients and is recognized as the main cause of delayed cerebral ischemia after subarachnoid hemorrhage. Its treatment comprises hemodynamic management and endovascular procedures. To date, the only drug shown to be efficacious on both the incidence of vasospasm and poor outcome is nimodipine. Given its modest effects, new pharmacological treatments are being developed to prevent and treat DCI. We review the different drugs currently being tested.
- Nitric Oxide
- Cerebral Blood Flow
Delayed cerebral ischemia (DCI) is a common and serious complication following subarachnoid hemorrhage (SAH) after ruptured cerebral aneurismal [1, 2]. Although this complication is at times reversible, it may develop into a cerebral infarction . DCI occurs in approximately 20% to 40%  of patients and is associated with increased mortality and poor prognosis [5, 6]. It is usually caused by a vasospasm , which, although preventable, remains a major cause of poor neurological outcome and increased mortality in the course of SAH [4–6].
Vasospasm is defined as a reversible narrowing of the subarachnoid arteries occurring between the third to fifth and fifteenth day after the hemorrhage, with a peak at the tenth day. It is observed in 70% of patients on angiographic scans and causes symptoms in 50% [7–10]. Angiographic vasospasm is defined as evidence of arterial narrowing compared with the parent vessels . It preferentially involves the vessels of the cranial base but also may affect small-caliber vessels or diffusely the entire cerebral vascularization. The severity of vasospasm is variable. The subsequent decrease in cerebral blood flow (CBF) in the spastic arteries leads to DCI, which may develop into cerebral infarction [7, 12, 13].
The etiology of vasospasm is complex and still poorly understood. Several factors have been shown to be involved, such as endothelial dysfunction, loss of autoregulation, and a hypovolemic component leading to a decrease in CBF [14–16]. At the acute phase, the presence of oxyhemoglobin in the subarachnoid spaces causes a local and systemic inflammatory reaction  with activation of platelets and coagulation [8–10]. The products derived from red blood cells (bilirubin) and endothelium (endothelin-1, free radicals) are considered to be mediators of the vasospasm [18–22] Structural anomalies in endothelial and smooth muscle cells also have been reported .
Treatments of DCI consist of preventing or minimizing secondary injuries by means of hemodynamic managements, pharmacological agents, and endovascular procedures [12, 24, 25]. Although these measures result in a decrease in the incidence of vasospasm, the prognostic of DCI remain unchanged [5, 24].
Because SAH is frequently accompanied by cerebral autoregulation impairment, hypotension should be avoided. To achieve an adequate cerebral perfusion pressure, triple H therapy was designed to induce volume expansion, rheology improvement, and blood pressure increase. Hence, systolic arterial pressure is increased to approximatively 150-175 mmHg once aneurysm is secured . Before treating aneurysm, it is nevertheless mandatory to maintain systolic blood pressure at lower levels than 150 mmHg. However, there is now evidence suggesting that blood pressure increase is the most important part of those measures because hypervolemia does not have any benefit on cerebral blood flow and tissue oxygenation.
Although triple H therapy reverses deficits associated with vasospasm, it has not been shown to decrease DCI occurrence or mortality .
Besides hemodynamic treatment, various pharmacological treatments have been tested [28, 29]. Nimodipine is the currently recommended drug . Given its relatively modest effects, new treatments have been developed.
We review recent literature pertaining to the different drugs being used or under evaluation.
Nimodipine is a voltage-gated calcium channel antagonist that inhibits calcium entry into smooth muscle cells and neurons. Its lipophilic properties allow it to cross the hematoencephalic barrier. Prophylactic administration of nimodipine was shown to be efficacious in decreasing the risk of secondary ischemia and poor outcome [31, 32]. The latest guidelines of the American Stroke Association recommend the oral administration of nimodipine at the dose of 60 mg every 4 hours for 21 days starting from the admission into the intensive care unit (Class I, Level of evidence A) .
The proof of its efficacy is based on four randomized, placebo-controlled trials of 853 patients, showing an improvement in functional outcome [32–36]. None of the studies were able to demonstrate a reduction in angiographic vasospasm . Its benefits seem to derive from neuroprotective properties rather than its vasodilatory effects. The exact mechanism preventing and limiting the extension of ischemic lesions remains unknown. In experimental models, nimodipine has been shown to attenuate the neuronal calcium increase after cellular ischemia and causing cell death .
Whereas calcium is recognized to play a significant role in the occurrence of vasospasm, other elements, such as inflammatory mediators, blood rheology, or microcirculation disturbances, are to be considered. Oxyhemoglobin, for example, causes a decreased activity of potassium channels, which may lead to membrane depolarization and consecutive vasoconstriction .
Nimodipine has been shown to be safe  and cost-effective  without any effect on mortality. Hypotension is a rarely reported side-effect. The current recommendations are based on data pertaining to oral administration of nimodipine. A recent study attempted to show that nimodipine's intravenous use would be associated with similar beneficial effects , although this mode of administration is more often linked to hypotension .
Among the other tested calcium channel antagonists, nicardipine was shown to decrease symptomatic vasospasm [39, 42] but without having any effect on DCI and outcome. The prophylactic use of diltiazem was investigated in a single monocenter study . The rate of favorable outcome was 74.8%.
During endovascular procedures, intra-arterial infusion of nicardipine , nimodipine , and diltiazem  were shown to reduce vasospasm with favorable effects on DCI. However, randomized control studies are still needed (Class IIb, Level of evidence B).
Lastly, two studies showed that prolonged-release nicardipine-loaded polymers implanted upon aneurysmal clipping decreased vasospasm and DCI and improved outcome [38, 47]. This mode of administration is promising, although further investigations are necessary.
Tirilazad mesylate is a neuroprotective corticosteroid whose efficacy was demonstrated in animal stroke models . It has antioxidant properties that block free radical-induced peroxidation of membrane lipids, which has been shown to facilitate vasospasm. The compound was evaluated in combination with nimodipine in five randomized, double-blind, placebo-controlled trials on a total of 3,821 patients, but no benefit was noted on DCI or outcome [49–52]. Therefore, this drug is not recommended.
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A, responsible for cholesterol synthesis . In addition, statins display pleiotropic effects, such as anti-inflammatory effects, a stabilizing effect on atheromatous plaques, and anti-adhesive effects on endothelium. Neuroprotective activity also was reported [54, 55].
Animal experiments showed a lower incidence of vasospasm when simvastatin therapy was initiated at the time of SAH [56, 57]. This beneficial effect is assumed to be due to increased nitric oxide (NO) production on account of NO synthesis induction , with subsequent vasodilatation likely to improve CBF.
Several retrospective studies demonstrated that patients treated with statins before SAH presented less DCI and fewer cerebral infarctions . Conversely, other retrospective investigations did not reveal any statin-induced benefits on vasospasm and outcome .
Two prospective phase II studies with 80 and 39 patients treated by simvastatin and pravastatin, respectively, revealed a reduction in vasospasm, a decrease in DCI, and an improvement in functional outcome [61, 62]. The use of statins deemed safe in both studies.
Nevertheless, the subsequent studies were not able to confirm the benefits of statin therapy. Two prospective, placebo-controlled trials using simvastatin on a small number of patients in addition [63, 64] to three observational studies with a historic control revealed no improvement in vasospasm incidence, DCI, or outcome [59, 60, 65].
Even if the most recent meta-analysis did not confirm the significant effect of statins , it should be noted that the trial results are difficult to interpret given the variable disease severity in the control groups and the differing methodologies used. Moreover, it is hazardous to draw conclusions on the basis of four placebo-controlled trials that included only 190 patients. The potential advantage of statins cannot be ruled out. In light of their potential benefits, the current recommendations  state that statins may be initiated in patients with SAH (Class IIb, Level of evidence B).
Presently ongoing is a multicenter phase III study on 1,600 SAH patients: STASH (Simvastatin in Aneurysmal Subarachnoid Hemorrhage). This investigation was designed to assess the effects of simvastatin given at a 40-mg dose for 21 days versus placebo. The primary evaluation criterion is functional outcome at 6 months using the modified Rankin disability score (mRS).
Magnesium exerts vasodilatory effects by blocking voltage-gated calcium channels. Hypomagnesemia occurs in 38% of SAH patients and is a predictor of DCI .
Based on animal experimental models supporting its neuroprotective activity , magnesium could be instrumental in improving vasospasm and limiting cerebral ischemia in humans. Although clinical studies have demonstrated that magnesium is safe, they were not able to confirm its efficacy clearly. The first clinical trials showed a trend toward reduced DCI and improved outcome . The randomized, double-blind, placebo-controlled MASH (Magnesium in Aneurysmal Subarachnoid Hemorrhage) study, including 283 patients revealed reduced DCI and improved outcome at 3 months, but the differences with placebo did not reach statistical significance . Another study using the same design and involving 60 patients showed a significant reduction in vasospasm duration assessed by ultrasounds, but no difference in outcome at 6 months .
Given that few studies obtained sufficient statistical strength, further clinical trials continue to be undertaken. The multicentre IMASH (Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Haemorrhage) study reevaluated the effect of magnesium on 327 patients using a prospective, double-blind, placebo-controlled design. No difference in outcome was observed at 6 months, nor was there any effect on clinical vasospasm . The results from another large multicenter study (MASH-II) are expected soon. Even though a few studies reported the occurrence of hypotension, data concerning its impact on DCI and outcome is still lacking .
Although magnesium cannot be explicitly recommended at present, it may exert neuroprotective activity, independently from the occurrence of vasospasm. In fact, the concept of predicting DCI in relation to the occurrence of vasospasm must be put into perspective. Given that endothelial dysfunction is the cause of cerebral perfusion problems, magnesium may play an important role, independently from its vasodilatory effects, although its mechanism is not yet understood. It has been shown to be protective in other types of brain injury, such as acute ischemic stroke .
Endothelin (ET) is a powerful vasoconstrictor . Its receptors are situated on smooth muscle cells (ET receptor ETA and ETB2) and endothelium (ET receptor ETB1). The isoform 1 (ET-1) displays a more significant effect on cerebral arteries, and elevated ET-1 levels were observed in plasma and CSF (cerebrospinal fluid) after SAH . ET-1 has been suggested to largely contribute to vasoconstriction-vasodilatation imbalance during SAH [77, 78].
ET-1 receptor blockers have been developed and successfully tested in animals . The first nonselective antagonist (TAK-044) was evaluated, showing a decrease in ischemic events at 3 months in 420 patients . A selective ETA antagonist (clazosentan) was shown to decrease the frequency and severity of vasospasm in a preliminary phase IIa study . Three doses of clazosentan were recently tested on 413 patients in a randomized, double-blind, placebo-controlled study (CONSCIOUS-1: Clazosentan to Overcome Neurological Ischemia and Infarction Occurring after Subarachnoid Haemorrhage) . The treatment was initiated within the first 56 hours and continued for 14 days. The aneurysmal treatment was conducted before or in the first 12 hours after administering clazosentan.
A dose-dependent decrease in angiographic vasospasm was observed. No benefit was noted on outcome, although this was not the primary evaluation criterion of the study. In post-hoc analyses, a trend toward improved clinical outcome was reported. Clazosentan was associated with an increased frequency of side-effects, such as hypotension, anaemia, and pulmonary infections. In addition, an increase in mortality was found in the active-treatment group. The majority of deaths were due to peroperative complications. Two phase III studies (CONSCIOUS-2 and CONSCIOUS-3) are currently ongoing in patients treated using clipping or coiling .
Fasudil is a rho-kinase inhibitor, an enzyme involved in the contraction of smooth muscle cells . The inhibition of the rho-kinase pathway causes cellular relaxation. Fasudil, initially investigated in Japan on 276 patients, was shown to reduce vasospasm but without any effect on outcome . However, when administered intra-arterially in combination with the drainage of intracisternal clots and intracisternal urokinase injection, fasudil appeared to reduce the incidence of vasospasm and improve outcome. A recent review of 90 cases seemed to indicate that this procedure was safe and effective on vasospasm and DCI . Further investigations are therefore necessary.
Due to the formation of microthrombi and secretion of thromboxane A2, platelet aggregation may play a role in DCI. Seven randomized and controlled trials involving 1,385 patients tested the effect of antiplatelet agents (acetylsalicylic acid or ticlopidine). However, none revealed any benefit on DCI or patient outcomes .
A single study tested the effect of low-molecular-weight heparin following SAH. In a randomized, double-blind, single-center trial of 170 patients, enoxaparin was administered 24 hours after aneurysm treatment and continued for 10 days. There was no benefit on outcome at 3 months . In addition, cerebral bleeding rate was increased with enoxaparin.
The neuroprotective activity of albumin was suggested in different types of brain injury, such as cranial trauma, cerebral ischemia, and SAH . Albumin demonstrated improved CBF in a dog model of SAH . Human data suggest that albumin has protective effects in ischemic stroke .
A retrospective study comparing albumin 25% and 0.9% NaCl administered for intravascular filling revealed improved outcome at 3 months in the albumin-treated group, whereas the incidence of vasospasm did not differ . A prospective, multicenter study, Albumin in Subarachnoid Haemorrhage (ALISAH), designed to demonstrate the tolerability and safety of four doses of albumin is currently in progress . This study has been designed to determine the maximally tolerated dose without provoking cardiac decompensation and pulmonary edema. An evaluation of neurological deteriorations is performed at 15 days and 3 months. The toxin-scavenging action of albumin has already been described in numerous diseases . It is possible that albumin acts by scavenging mediators of endothelial dysfunction, such as free radicals.
An alteration in NO production is an important mechanism in vasospasm etiology [95, 96]. A decrease in NO synthesis during SAH has been noted and is responsible for deficient vessel relaxation and a subsequent decline in CBF . The concept of NO donors was proposed as treatment for refractory vasospasm. Different modes of administration were tested: intravenous, intra-arterial, and intrathecal [2, 98]. Intraventricular administration of sodium nitroprusside was shown to improve vasospasm and CBF, although side-effects were common . One study suggested an improvement in outcome , whereas another involving a small number of patients did not reveal any effect of transdermal nitroglycerin . Currently, NO donors have a limited place in DCI treatment, and further investigations are needed.
Erythropoietin (EPO) is an amino acid sialoglycoprotein secreted by the kidney and known to play a role in hematopoiesis . EPO receptors have been found in a large number of tissues other than bone marrow, and its neuroprotective role has been suggested . In vitro experiments and animal studies showed that EPO enhances neuronal survival under stress situations, such as excitotoxicity  and ischemia [105, 106]. EPO doses must be sufficiently high due to its weak capacity to cross the blood-brain barrier . The proposed mechanisms are diverse, including anti-inflammatory and anti-apoptotic roles, and modulating NO production .
Two double-blind placebo-controlled trials were conducted involving 73 and 80 patients, respectively [109, 110]. Tseng et al. showed that patients treated with EPO had a lower incidence of severe vasospasm (27.5 vs. 7.5%), reduced DCI (40 vs. 7.5%), and improved outcome . Even if the number of investigated patients is still low, EPO is considered to be a promising molecule given its beneficial effects at the acute SAH phase and its protective effects at the ischemic phase.
An etiological role was attributed to spasmogenic substances released from clots in the subarachnoid spaces. Of note is that the quantity of blood is considered to be a predictor of vasospasm . The intraventricular injection of thrombolytic agents was proposed as treatment. To date, two types of thrombolytics have been tested: urokinase and t-PA (tissue plasminogen activator). The analysis of reported cases suggests a beneficial effect, although it is limited due to the small number of randomized studies . Only one double-blind, placebo-controlled trial assessed the peroperative administration of t-PA on 100 patients . No clear benefit was found with respect to vasospasm and DCI; only patients showing large clots experienced a decrease in vasospasm. The use of this technique requires further prospective studies to define optimal timing, mode of administration, and the type of patients likely to benefit the most. The low incidence of reported complications encourages the undertaking of new studies.
The poor prognosis of patients with DCI following SAH remains a major issue responsible for death and infirmity. Although our understanding of the physiopathology of DCI and vasospasm has improved, patient outcome has not been significantly modified. Management currently focuses on CBF improvement along with hemodynamic manipulation and endovascular procedures. The only recommended pharmacological treatment is nimodipine.
Although the different compounds tested mostly show a decline in the incidence of radiographic vasospasm, they do not impact on outcome. New pharmacological treatments with neuroprotective effects, such as statins, magnesium, and endothelin inhibitors, revealed promising results. However, the lack of randomized designs and insufficient statistical power of these studies do not allow us to recommend these medications in SAH management at the present time.
The disassociation of vasospasm and clinical outcome also is linked to the fact that DCI occurring after SAH is a multifactorial process without being restricted to arterial narrowing. Effectively, DCI may not only be predicted by cerebral vessels caliber alone; it also may occur in the absence of major vasospasm.
Future investigations should allow us to better understand the mechanisms of endothelial dysfunction, such as oxidative stress, inhibition of vasodilation, and the secretion of vasoconstrictors. The physiopathology of microcirculation dysfunction is all the more complex as unspecific phenomena, such as inflammation, platelet activation, and microthrombi formation. In addition, vasoconstrictors, such as norepinephrine, may have paradoxical effects, and their impact on cerebral microcirculation has not been determined yet.
There is evidence supporting the use of neuroprotective agents. The results of ongoing randomized studies will confirm or not the efficacy of these new treatments. While awaiting potential benefits from neuroprotective treatments, the standard management of intensive care patients using specifically metabolic and ionic control as well as temperature maintenance is still required to preserve the damaged brain. Fever is a common complication and is related to prognosis during the first 2 weeks after SAH . If hyperthermia should be avoided in a patient with increased intracranial pressure, early fever control after SAH could be associated with improved outcome. Recent retrospective data have shown that temperature maintenance above 37°C during the first 2 weeks may be associated with a better outcome .
- de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ: Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007, 78: 1365–1372. 10.1136/jnnp.2007.117655PubMed CentralPubMedGoogle Scholar
- Pluta RM, Hansen-Schwartz J, Dreier J, Vajkoczy P, Macdonald RL, Nishizawa S, Kasuya H, Wellman G, Keller E, Zauner A, Dorsch N, Clark J, Ono S, Kiris T, Leroux P, Zhang JH: Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res 2009, 31: 151–158. 10.1179/174313209X393564PubMed CentralPubMedGoogle Scholar
- Fergusen S, Macdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2007, 60: 658–667.PubMedGoogle Scholar
- Dorsch NW, King MT: A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part I: Incidence and effects. J Clin Neurosci 1994, 1: 19–26. 10.1016/0967-5868(94)90005-1PubMedGoogle Scholar
- Rabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM, Atkinson JL, Wijdicks EF: Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2004, 35: 1862–1866. 10.1161/01.STR.0000133132.76983.8ePubMedGoogle Scholar
- Macdonald RL, Pluta RM, Zhang JH: Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 2007, 3: 256–263.PubMedGoogle Scholar
- Vajkoczy P, Horn P, Thome C, Munch E, Schmiedek P: Regional cerebral blood flow monitoring in the diagnosis of delayed ischemia following aneurysmal subarachnoid hemorrhage. J Neurosurg 2003, 98: 1227–1234. 10.3171/jns.2003.98.6.1227PubMedGoogle Scholar
- Heros RC, Zervas NT, Varsos V: Cerebral vasospasm after subarachnoid hemorrhage: an update. Ann Neurol 1983, 14: 599–608. 10.1002/ana.410140602PubMedGoogle Scholar
- Fisher CM, Roberson GH, Ojemann RG: Cerebral vasospasm with ruptured saccular aneurysm-the clinical manifestations. Neurosurgery 1977, 1: 245–248. 10.1227/00006123-197711000-00004PubMedGoogle Scholar
- Kassell NF, Sasaki T, Colohan AR, Nazar G: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 1985, 16: 562–572.PubMedGoogle Scholar
- Greenberg ED, Gold R, Reichman M, John M, Ivanidze J, Edwards AM, Johnson CE, Comunale JP, Sanelli P: Diagnostic accuracy of CT angiography and CT perfusion for cerebral vasospasm: a meta-analysis. Am J Neuroradiol 2010, 31: 1853–1860. 10.3174/ajnr.A2246PubMed CentralPubMedGoogle Scholar
- 12.Weir B, Grace M, Hansen J, Rothberg C: Time course of vasospasm in man. J Neurosurg 1978, 48: 173–178. 10.3171/jns.1978.48.2.0173PubMedGoogle Scholar
- Suarez JI, Tarr RW, Selman WR: Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006, 354: 387–396. 10.1056/NEJMra052732PubMedGoogle Scholar
- Dhar R, Diringer MN: The burden of the systemic inflammatory response predicts vasospasm and outcome after subarachnoid hemorrhage. Neurocrit Care 2008, 8: 404–412. 10.1007/s12028-008-9054-2PubMed CentralPubMedGoogle Scholar
- Diringer MN: Subarachnoid hemorrhage: a multiple-organ system disease. Crit Care Med 2003, 31: 1884–1885. 10.1097/01.CCM.0000063528.09569.3APubMedGoogle Scholar
- Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, Kassell NF, Lee KS: Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 2003, 53: 123–133. 10.1227/01.NEU.0000068863.37133.9EPubMedGoogle Scholar
- Yoshimoto Y, Tanaka Y, Hoya K: Acute systemic inflammatory response syndrome in subarachnoid hemorrhage. Stroke 2001, 32: 1989–1993. 10.1161/hs0901.095646PubMedGoogle Scholar
- Liszczak TM, Varsos VG, Black PM, Kistler JP, Zervas NT: Cerebral arterial constriction after experimental subarachnoid hemorrhage is associated with blood components within the arterial wall. J Neurosurg 1983, 58: 18–26. 10.3171/jns.1983.58.1.0018PubMedGoogle Scholar
- Macdonald RL, Weir BK: A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke 1991, 22: 971–982.PubMedGoogle Scholar
- Mayberg MR, Okada T, Bark DH: The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage. J Neurosurg 1990, 72: 634–640. 10.3171/jns.1990.72.4.0634PubMedGoogle Scholar
- Rubanyi GM: Endothelium-derived relaxing and contracting factors. J Cell Biochem 1991, 46: 27–36. 10.1002/jcb.240460106PubMedGoogle Scholar
- Hendryk S, Jarzab B, Josko J: Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuro Endocrinol Lett 2004, 25: 141–147.PubMedGoogle Scholar
- Peterson JW, Kwun BD, Hackett JD, Zervas NT: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 1990, 72: 767–774. 10.3171/jns.1990.72.5.0767PubMedGoogle Scholar
- Weyer GW, Nolan CP, Macdonald RL: Evidence-based cerebral vasospasm management. Neurosurg Focus 2006, 21: E8.PubMedGoogle Scholar
- Kassell NF, Torner JC, Haley EC, Jane JA, Adams HP, Kongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 1990, 73: 18–36. 10.3171/jns.1990.73.1.0018PubMedGoogle Scholar
- Origitano TC, Wascher TM, Reichman OH, Anderson DE: Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution ("triple-H" therapy) after subarachnoid hemorrhage. Neurosurgery 1990, 27: 729–739. 10.1227/00006123-199011000-00010PubMedGoogle Scholar
- Treggiari MM, Walder B, Suter PM, Romand JA: Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage. J Neurosurg 2003, 98: 978–984. 10.3171/jns.2003.98.5.0978PubMedGoogle Scholar
- Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL: Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab, in press.Google Scholar
- Rabinstein AA, Lanzino G, Wijdicks EF: Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol 2010, 9: 504–519. 10.1016/S1474-4422(10)70087-9PubMedGoogle Scholar
- Bederson JB, Connolly ES, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE, Harbaugh RE, Patel AB, Rosenwasser RH, American Heart Association: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009, 40: 994–1025. 10.1161/STROKEAHA.108.191395PubMedGoogle Scholar
- Feigin VL, Rinkel GJ, Algra A, Vermeulen M, van Gijn J: Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology 1998, 50: 876–883.PubMedGoogle Scholar
- Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, Mellits DE, Bertsch LA, Boisvert DP, Hundley MB, Johnson RK, Strom JA, Transou CR: Cerebral arterial spasm-a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983, 308: 619–624. 10.1056/NEJM198303173081103PubMedGoogle Scholar
- Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P: Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine. Acta Neurochir 1986, 82: 110–4. 10.1007/BF01456369PubMedGoogle Scholar
- Mee E, Dorrance D, Lowe D, Neil-Dwyer G: Controlled study of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage. Neurosurgery 1988, 22: 484–491. 10.1227/00006123-198803000-00006PubMedGoogle Scholar
- Petruk KC, West M, Mohr G, Weir BK, Benoit BG, Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron GS, Tucker WS, Purves GB, Miller JD, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A: Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg 1988, 68: 505–517. 10.3171/jns.1988.68.4.0505PubMedGoogle Scholar
- Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989, 298: 636–642. 10.1136/bmj.298.6674.636PubMed CentralPubMedGoogle Scholar
- Zornow MH, Prough DS: Neuroprotective properties of calcium-channel blockers. New Horiz 1996, 4: 107–114.PubMedGoogle Scholar
- Kasuya H, Onda H, Takeshita M, Okada Y, Hori T: Efficacy and safety of nicardipine prolonged-release implants for preventing vasospasm in humans. Stroke 2002, 33: 1011–1015. 10.1161/01.STR.0000014563.75483.22PubMedGoogle Scholar
- Karinen P, Koivukangas P, Ohinmaa A, Koivukangas J, Ohman J: Cost-effectiveness analysis of nimodipine treatment after aneurysmal subarachnoid hemorrhage and surgery. Neurosurgery 1999, 45: 780–784.PubMedGoogle Scholar
- Kronvall E, Undren P, Romner B, Saveland H, Cronqvist M, Nilsson OG: Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration. J Neurosurg 2009, 110: 58–63. 10.3171/2008.7.JNS08178PubMedGoogle Scholar
- Haley EC, Kassell NF, Torner JC: A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg 1993, 78: 537–547. 10.3171/jns.1993.78.4.0537PubMedGoogle Scholar
- Abe K, Iwanaga H, Inada E: Effect of nicardipine and diltiazem on internal carotid artery blood flow velocity and local cerebral blood flow during cerebral aneurysm surgery for subarachnoid hemorrhage. J Clinl Anesth 1994, 6: 99–105. 10.1016/0952-8180(94)90004-3Google Scholar
- Papavasiliou AK, Harbaugh KS, Birkmeyer NJ, Feeney JM, Martin PB, Faccio C, Harbaugh RE: Clinical outcomes of aneurysmal subarachnoid hemorrhage patients treated with oral diltiazem and limited intensive care management. Surg Neurol 2001, 55: 138–146. 10.1016/S0090-3019(01)00364-0PubMedGoogle Scholar
- Schmidt U, Bittner E, Pivi S, Marota JJ: Hemodynamic management and outcome of patients treated for cerebral vasospasm with intraarterial nicardipine and/or milrinone. Anesth Analg 2010, 110: 895–902. 10.1213/ANE.0b013e3181cc9ed8PubMedGoogle Scholar
- Hui C, Lau KP: Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol 2005, 60: 1030–1036. 10.1016/j.crad.2005.04.004PubMedGoogle Scholar
- Saunders FW, Marshall WJ: Diltiazem: dose it affect vasospasm? Surg Neurol 1986, 26: 155–158. 10.1016/0090-3019(86)90368-XPubMedGoogle Scholar
- Kasuya H, Onda H, Sasahara A, Takeshita M, Hori T: Application of nicardipine prolonged-release implants: analysis of 97 consecutive patients with acute subarachnoid hemorrhage. Neurosurgery 2005, 56: 895–902.PubMedGoogle Scholar
- Kanamaru K, Weir BK, Findlay JM, Grace M, Macdonald RL: A dosage study of the effect of the 21-aminosteroid U74006F on chronic cerebral vasospasm in a primate model. Neurosurgery 1990, 27: 29–38. 10.1227/00006123-199007000-00004PubMedGoogle Scholar
- Kassell NF, Haley EC, Apperson-Hansen C, Alves WM: Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996, 84: 221–228. 10.3171/jns.1996.84.2.0221PubMedGoogle Scholar
- Haley EC, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM: A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 1997, 86: 467–474. 10.3171/jns.1997.86.3.0467PubMedGoogle Scholar
- Lanzino G, Kassell NF: Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 1999, 90: 1018–1024. 10.3171/jns.19126.96.36.1998PubMedGoogle Scholar
- Lanzino G, Kassell NF, Dorsch NW, Pasqualin A, Brandt L, Schmiedek P, Truskowski LL, Alves WM: Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg 1999, 90: 1011–1017. 10.3171/jns.19188.8.131.521PubMedGoogle Scholar
- Endo A: The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992, 33: 1569–1582.PubMedGoogle Scholar
- Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005, 45: 89–118. 10.1146/annurev.pharmtox.45.120403.095748PubMed CentralPubMedGoogle Scholar
- van der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL: Statins: mechanisms of neuroprotection. Prog Neurobiol 2009, 88: 64–75. 10.1016/j.pneurobio.2009.02.002PubMedGoogle Scholar
- Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N: Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 2008, 39: 1276–1285. 10.1161/STROKEAHA.107.503086PubMedGoogle Scholar
- Bulsara KR, Coates JR, Agrawal VK, Eifler DM, Wagner-Mann CC, Durham HE, Fine DM, Toft K: Effect of combined simvastatin and cyclosporine compared with simvastatin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model. Neurosurg Focus 2006, 21: E11.PubMedGoogle Scholar
- Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 1998, 95: 8880–8885. 10.1073/pnas.95.15.8880PubMed CentralPubMedGoogle Scholar
- McGirt MJ, Blessing R, Alexander MJ, Nimjee SM, Woodworth GF, Friedman AH, Graffagnino C, Laskowitz DT, Lynch JR: Risk of cerebral vasopasm after subarachnoid hemorrhage reduced by statin therapy: A multivariate analysis of an institutional experience. J Neurosurg 2006, 105: 671–674. 10.3171/jns.2006.105.5.671PubMedGoogle Scholar
- Kern M, Lam MM, Knuckey NW, Lind CR: Statins may not protect against vasospasm in subarachnoid haemorrhage. J Clin Neurosci 2009, 16: 527–530. 10.1016/j.jocn.2008.08.001PubMedGoogle Scholar
- Lynch JR, Wang H, McGirt MJ, Floyd J, Friedman AH, Coon AL, Blessing R, Alexander MJ, Graffagnino C, Warner DS, Laskowitz DT: Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke 2005, 36: 2024–2026. 10.1161/01.STR.0000177879.11607.10PubMedGoogle Scholar
- Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ: Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke 2005, 36: 1627–1632. 10.1161/01.STR.0000176743.67564.5dPubMedGoogle Scholar
- Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, van der Poll T, Vermeulen M, Roos YB: Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab 2009, 29: 1444–1453. 10.1038/jcbfm.2009.59PubMedGoogle Scholar
- Chou SH, Smith EE, Badjatia N, Nogueira RG, Sims JR, Ogilvy CS, Rordorf GA, Ayata C: A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke 2008, 39: 2891–2893. 10.1161/STROKEAHA.107.505875PubMedGoogle Scholar
- Kramer AH, Gurka MJ, Nathan B, Dumont AS, Kassell NF, Bleck TP: Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage. Neurosurgery 2008, 62: 422–427. 10.1227/01.neu.0000316009.19012.e3PubMedGoogle Scholar
- Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB: Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke 2010, 41: e47-e52. 10.1161/STROKEAHA.109.556332PubMedGoogle Scholar
- van den Bergh WM, Algra A, van der Sprenkel JW, Tulleken CA, Rinkel GJ: Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery 2003, 52: 276–281. 10.1227/01.NEU.0000043984.42487.0EPubMedGoogle Scholar
- Marinov MB, Harbaugh KS, Hoopes PJ, Pikus HJ, Harbaugh RE: Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. J Neurosurg 1996, 85: 117–124. 10.3171/jns.1996.85.1.0117PubMedGoogle Scholar
- Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, Marrocco A, Thomas AJ, Mitsias PD, Malik GM: Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg 2002, 96: 510–514. 10.3171/jns.2002.96.3.0510PubMedGoogle Scholar
- van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Marrocco A, Thomas AJ, Mitsias PD, Malik GM: Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 2005, 36: 1011–1015. 10.1161/01.STR.0000160801.96998.57PubMedGoogle Scholar
- Wong GK, Chan MT, Boet R, Poon WS, Gin T: Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study. J Neurosurgi Anesthesiol 2006, 18: 142–148. 10.1097/00008506-200604000-00009Google Scholar
- Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, Zee BC, IMASH Investigators: Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke 2010, 41: 921–926. 10.1161/STROKEAHA.109.571125PubMedGoogle Scholar
- Wong GK, Chan MT, Gin T, Poon WS: Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: current status. Acta Neurochir 2011,110(Suppl):169–173.Google Scholar
- Saver JL: Target brain: neuroprotection and neurorestoration in ischemic stroke. Rev Neurol Dis 2010,7(Suppl 1):14–21.Google Scholar
- Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988, 332: 411–415. 10.1038/332411a0PubMedGoogle Scholar
- Pluta RM, Boock RJ, Afshar JK, Clouse K, Bacic M, Ehrenreich H, Oldfield EH: Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage. J Neurosurg 1997, 87: 287–293. 10.3171/jns.1997.87.2.0287PubMedGoogle Scholar
- Zimmermann M, Seifert V: Endothelin and subarachnoid hemorrhage: an overview. Neurosurgery 1998, 43: 863–75. 10.1097/00006123-199810000-00083PubMedGoogle Scholar
- Zimmermann M, Seifert V: Endothelin receptor antagonists and cerebral vasospasm. Clin Auton Res 2004, 14: 143–145.PubMedGoogle Scholar
- Hansen-Schwartz J, Hoel NL, Zhou M, Xu CB, Svendgaard NA, Edvinsson L: Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 2003, 52: 1188–1194. 10.1227/01.NEU.0000058467.82442.64PubMedGoogle Scholar
- Shaw MD, Vermeulen M, Murray GD, Pickard JD, Bell BA, Teasdale GM: Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group. J Neurosurg 2000, 93: 992–997. 10.3171/jns.2000.93.6.0992PubMedGoogle Scholar
- Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thome C, Ringel F, Breu V, Schmiedek P: Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 2005, 103: 9–17. 10.3171/jns.2005.103.1.0009PubMedGoogle Scholar
- Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A, CONSCIOUS-1 Investigators: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 2008, 39: 3015–3021. 10.1161/STROKEAHA.108.519942PubMedGoogle Scholar
- Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Frey A, Marr A, Roux S, Kassell NF: Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care 2010, 13: 416–424. 10.1007/s12028-010-9433-3PubMedGoogle Scholar
- Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, Chardin P, Pacaud P, Loirand G: Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 2000, 275: 21722–21729. 10.1074/jbc.M000753200PubMedGoogle Scholar
- Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka H, Mitsuyoshi Nakashima: Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg 1992, 76: 571–577. 10.3171/jns.1992.76.4.0571PubMedGoogle Scholar
- Iwabuchi S, Yokouchi T, Hayashi M, Sato K, Saito N, Hirata Y, Harashina J, Nakayama H, Akahata M, Ito K, Kimura H, Aoki K: Intra-arterial Administration of Fasudil Hydrochloride for Vasospasm Following Subarachnoid Haemorrhage: Experience of 90 Cases. Acta Neurochir 2011,110(Suppl):179–181.Google Scholar
- Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ: Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane database of systematic reviews 2007, 4: CD006184.PubMedGoogle Scholar
- Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S, Hernesniemi J, Lassila R: No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. J Neurosurg 2003, 99: 953–959. 10.3171/jns.2003.99.6.0953PubMedGoogle Scholar
- Belayev L, Saul I, Huh PW, Finotti N, Zhao W, Busto R, Ginsberg MD: Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats. Brain Res 1999, 845: 107–111. 10.1016/S0006-8993(99)01952-6PubMedGoogle Scholar
- Matsui T, Asano T: The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 1993, 32: 79–83. 10.1227/00006123-199301000-00012PubMedGoogle Scholar
- Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D: The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke--I: Physiological responses and safety results. Stroke 2006, 37: 2100–2106. 10.1161/01.STR.0000231388.72646.05PubMedGoogle Scholar
- Suarez JI, Shannon L, Zaidat OO, Suri MF, Singh G, Lynch G, Selman WR: Effect of human albumin administration on clinical outcome and hospital cost in patients with subarachnoid hemorrhage. J Neurosurg 2004, 100: 585–590. 10.3171/jns.2004.100.4.0585PubMedGoogle Scholar
- Suarez JI, Martin RH: Treatment of subarachnoid hemorrhage with human albumin: ALISAH study. Rationale and design. Neurocrit Care 2010, 13: 263–277. 10.1007/s12028-010-9392-8PubMedGoogle Scholar
- Boldt J: Use of albumin: an update. Br J Anaesth 2010, 104: 276–84. 10.1093/bja/aep393PubMedGoogle Scholar
- Faraci FM: Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 1991, 261: H1038–1042.PubMedGoogle Scholar
- Pluta RM, Thompson BG, Afshar JK, Boock RJ, Iuliano B, Oldfield EH: Nitric oxide and vasospasm. Acta Neurochir 2001,77(Suppl):67–72.Google Scholar
- Pluta RM: Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther 2005, 105: 23–56. 10.1016/j.pharmthera.2004.10.002PubMedGoogle Scholar
- Keyrouz SG, Diringer MN: Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage. Critical care 2007, 11: 220. 10.1186/cc5958PubMed CentralPubMedGoogle Scholar
- Thomas JE, Rosenwasser RH: Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intraventricular sodium nitroprusside in humans. Neurosurgery 1999, 44: 48–57. 10.1097/00006123-199901000-00026PubMedGoogle Scholar
- Agrawal A, Patir R, Kato Y, Chopra S, Sano H, Kanno T: Role of intraventricular sodium nitroprusside in vasospasm secondary to aneurysmal subarachnoid haemorrhage: a 5-year prospective study with review of the literature. Minim Invasive Neurosurg 2009, 52: 5–8. 10.1055/s-0028-1085454PubMedGoogle Scholar
- Reinert M, Wiest R, Barth L, Andres R, Ozdoba C, Seiler R: Transdermal nitroglycerin in patients with subarachnoid hemorrhage. Neurol Res 2004, 26: 435–439. 10.1179/016164104225015976PubMedGoogle Scholar
- Fisher JW: Erythropoietin: physiology and pharmacology update. Exp Biol Med 2003, 228: 1–14.Google Scholar
- Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR, Brines M, Ghezzi P: Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 2003, 198: 971–975. 10.1084/jem.20021067PubMed CentralPubMedGoogle Scholar
- Koshimura K, Murakami Y, Sohmiya M, Tanaka J, Kato Y: Effects of erythropoietin on neuronal activity. J Neurochem 1999, 72: 2565–2572.PubMedGoogle Scholar
- Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Genc S, Genc K, Sagiroglu E, Cerami A, Brines M: Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 2002, 99: 2258–2263. 10.1073/pnas.042693799PubMed CentralPubMedGoogle Scholar
- Kumral A, Ozer E, Yilmaz O, Akhisaroglu M, Gokmen N, Duman N, Ulukus C, Genc S, Ozkan H: Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol neonate 2003, 83: 224–228. 10.1159/000068926PubMedGoogle Scholar
- Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000, 97: 10526–10531.PubMed CentralPubMedGoogle Scholar
- Arcasoy MO: The non-haematopoietic biological effects of erythropoietin. Br J Haematol 2008, 141: 14–31. 10.1111/j.1365-2141.2008.07014.xPubMedGoogle Scholar
- Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. J Neurosurg 2009, 111: 171–180. 10.3171/2009.3.JNS081332PubMedGoogle Scholar
- Springborg JB, Moller C, Gideon P, Jorgensen OS, Juhler M, Olsen NV: Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir 2007, 149: 1089–1101. 10.1007/s00701-007-1284-zPubMedGoogle Scholar
- Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980, 6: 1–9. 10.1227/00006123-198001000-00001PubMedGoogle Scholar
- Amin-Hanjani S, Ogilvy CS, Barker FG: Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis. Neurosurgery 2004, 54: 326–334. 10.1227/01.NEU.0000103488.94855.4FPubMedGoogle Scholar
- Findlay JM, Kassell NF, Weir BK, Haley EC, Kongable G, Germanson T, Truskowski L, Alves WM, Holness RO, Knuckey NW, Yonas H, Steinberg G, West M, Winn HR, Ferguson G: A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 1995, 37: 168–176. 10.1227/00006123-199507000-00041PubMedGoogle Scholar
- Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS, Chang Y, Ogilvy CS, Rordorf G, Schwamm LH, Koroshetz WJ, McDonald CT: Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology 2001, 56: 1299–1304.PubMedGoogle Scholar
- Badjatia N, Fernandez L, Schmidt JM, Lee K, Claassen J, Connolly ES, Mayer SA: Impact of induced normothermia on outcome after subarachnoid hemorrhage: a case-control study. Neurosurgery 2010, 66: 696–700. 10.1227/01.NEU.0000367618.42794.AAPubMedGoogle Scholar
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