Cerebral vasospasm is a major source of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Evidence suggests a multifactorial etiology and this concept remains supported by the assortment of therapeutic modalities under investigation. The authors provide an updated review of the literature for previous and recent clinical trials evaluating medical treatments in patients with cerebral vasospasm secondary to aSAH. Currently, the strongest evidence supports use of prophylactic oral nimodipine and initiation of triple-H therapy for patients in cerebral vasospasm. Other agents presented in this report include magnesium, statins, endothelin receptor antagonists, nitric oxide promoters, free radical scavengers, thromboxane inhibitors, thrombolysis, anti-inflammatory agents and neuroprotectants. Although promising data is beginning to emerge for several treatments, few prospective randomized clinical trials are presently available. Additionally, future investigational efforts will need to resolve discrepant definitions and outcome measures for cerebral vasospasm in order to permit adequate study comparisons. Until then, definitive recommendations cannot be made regarding the safety and efficacy for each of these therapeutic strategies and medical management practices will continue to be implemented in a wide-ranging manner. 1. Introduction Aneurysmal subarachnoid hemorrhage (aSAH) occurs in approximately 30,000 patients in the United States each year [1]. Cerebral vasospasm is estimated to occur in up to 70% of all aSAH patients and remains a major cause of morbidity and mortality [2]. The complex cascade of factors and events that result in arterial narrowing has been subject to extensive research, leading to a vast array of proposed treatment methods. A large number of these experimental therapies have been evaluated at the basic and translational levels with fewer reported prospective randomized clinical trials. Despite these efforts, no single treatment modality has proven efficacious and trial results have been frequently mixed or conflicting. Therefore medical management practices are often wide-ranging with an assortment of strategies implemented in various permutations. In this report, we review the literature and provide a concise, updated summary of recent clinical trials and current medical treatments evaluated in patients with cerebral vasospasm secondary to aSAH. 2. Triple-H Therapy The current mainstay for medical management of vasospasm secondary to aSAH remains triple-H therapy. The protocol is defined by
References
[1]
N. K. De Rooij, F. H. H. Linn, J. A. van der Plas, A. Algra, and G. J. E. Rinkel, “Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 12, pp. 1365–1372, 2007.
[2]
J. Biller, J. C. Godersky, and H. P. Adams, “Management of aneurysmal subarachnoid hemorrhage,” Stroke, vol. 19, no. 10, pp. 1300–1305, 1988.
[3]
M. M. Treggiari, B. Walder, P. M. Suter, and J. A. Romand, “Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 98, no. 5, pp. 978–984, 2003.
[4]
J. Sen, A. Belli, H. Albon, L. Morgan, A. Petzold, and N. Kitchen, “Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage,” The Lancet Neurology, vol. 2, no. 10, pp. 614–620, 2003.
[5]
A. Egge, K. Waterloo, H. Sj?holm, T. Solberg, T. Ingebrigtsen, and B. Romner, “Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study,” Neurosurgery, vol. 49, no. 3, pp. 593–606, 2001.
[6]
K. E. Wartenberg, J. M. Schmidt, J. Claassen, et al., “Impact of medical complications on outcome after subarachnoid hemorrhage,” Critical Care Medicine, vol. 34, pp. 617–623, 2006.
[7]
N. J. Solenski, E. C. Haley, N. F. Kassell et al., “Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study,” Critical Care Medicine, vol. 23, no. 6, pp. 1007–1017, 1995.
[8]
R. H. Rosenwasser, T. E. Delgado, W. A. Buchheit, and M. H. Freed, “Control of hypertension and prophylaxis against vasospasm in cases of subarachnoid hemorrhage: a preliminary report,” Neurosurgery, vol. 12, no. 6, pp. 658–661, 1983.
[9]
L. Lennihan, S. A. Mayer, M. E. Fink et al., “Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial,” Stroke, vol. 31, no. 2, pp. 383–391, 2000.
[10]
J. W. Dankbaar, A. J. C. Slooter, G. J. E. Rinkel, and I. C. V. D. Schaaf, “Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review,” Critical Care, vol. 14, no. 1, article R23, 2010.
[11]
E. S. Connolly, A. A. Rabinstein, J. R. Carhuapoma et al., “Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the american heart association/american stroke association,” Stroke, vol. 43, no. 6, pp. 1711–1737, 2012.
[12]
M. M. Treggiari, “Participants in the International Multi-disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Hemodynamic management of subarachnoid hemorrhage,” Neurocritical Care, vol. 15, no. 2, pp. 329–335, 2011.
[13]
D. H. Kim, M. Joseph, S. Ziadi et al., “Increases in cardiac output can reverse flow deficits from vasospasm independent of blood pressure: a study using xenon computed tomographic measurement of cerebral blood flow,” Neurosurgery, vol. 53, no. 5, pp. 1044–1052, 2003.
[14]
M. L. Levy, C. H. Rabb, V. Zelman, and S. L. Giannotta, “Cardiac performance enhancement from dobutamine in patients refractory to hypervolemic therapy for cerebral vasospasm,” Journal of Neurosurgery, vol. 79, no. 4, pp. 494–499, 1993.
[15]
Y. Arakawa, K. I. Kikuta, M. Hojo, Y. Goto, A. Ishii, and S. Yamagata, “Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: report of seven cases,” Neurosurgery, vol. 48, no. 4, pp. 723–730, 2001.
[16]
A. T. Fraticelli, B. P. Cholley, M. R. Losser, J. P. S. Maurice, and D. Payen, “Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage,” Stroke, vol. 39, no. 3, pp. 893–898, 2008.
[17]
S. M. Dorhout Mees, G. J. Rinkel, V. L. Feigin et al., “Calcium antagonists for aneurysmal subarachnoid haemorrhage,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD000277, 2007.
[18]
G. S. Allen, H. S. Ahn, T. J. Preziosi, et al., “Cerebral arterial spasm: a controlled trial of nimodipine in patients with subarachnoid hemorrhage,” New England Journal of Medicine, vol. 308, no. 11, pp. 619–624, 1983.
[19]
J. D. Pickard, G. D. Murray, R. Illingworth et al., “Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial,” British Medical Journal, vol. 298, no. 6674, pp. 636–642, 1989.
[20]
P. Karinen, P. Koivukangas, A. Ohinmaa, J. Koivukangas, and J. ?hman, “Cost-effectiveness analysis of nimodipine treatment after aneurysmal subarachnoid hemorrhage and surgery,” Neurosurgery, vol. 45, no. 4, pp. 780–785, 1999.
[21]
J. Philippon, R. Grob, and F. Dagreou, “Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine,” Acta Neurochirurgica, vol. 82, no. 3-4, pp. 110–114, 1986.
[22]
K. C. Petruk, M. West, G. Mohr et al., “Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial,” Journal of Neurosurgery, vol. 68, no. 4, pp. 505–517, 1988.
[23]
E. Mee, D. Dorrance, D. Lowe, and G. Neil-Dwyer, “Controlled study of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage,” Neurosurgery, vol. 22, no. 3, pp. 484–491, 1988.
[24]
J. Ohman and O. Heiskanen, “Effect of nimodipine on the outcome of patients after aneurysmal subarachnoid hemorrhage and surgery,” Journal of Neurosurgery, vol. 69, no. 5, pp. 683–686, 1988.
[25]
A. Harders, A. Kakarieka, and R. Braakman, “Traumatic subarachnoid hemorrhage and its treatment with nimodipine,” Journal of Neurosurgery, vol. 85, no. 1, pp. 82–89, 1996.
[26]
M. Jan, F. Buchheit, and M. Tremoulet, “Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms,” Neurosurgery, vol. 23, no. 2, pp. 154–157, 1988.
[27]
J. Ohman, A. Servo, and O. Heiskanen, “Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery,” Journal of Neurosurgery, vol. 74, no. 1, pp. 8–13, 1991.
[28]
K. Messeter, L. Brandt, B. Ljunggren, et al., “Prediction and prevention of delayed ischemic dysfunction after aneurysmal subarachnoid hemorrhage and early operation,” Neurosurgery, vol. 20, no. 4, pp. 548–553, 1987.
[29]
V. L. Feigin, G. J. E. Rinkel, A. Algra, M. Vermeulen, and J. Van Gijn, “Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review,” Neurology, vol. 50, no. 4, pp. 876–883, 1998.
[30]
G. J. Liu, J. Luo, L. P. Zhang et al., “Meta-analysis of the effectiveness and safety of prophylactic use of nimodipine in patients with an aneurysmal subarachnoid haemorrhage,” CNS and Neurological Disorders, vol. 10, no. 7, pp. 834–844, 2011.
[31]
E. S. Flamm, H. P. Adams, D. W. Beck et al., “Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 68, no. 3, pp. 393–400, 1988.
[32]
E. C. Haley, N. F. Kassell, and J. C. Torner, “A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study,” Journal of Neurosurgery, vol. 78, no. 4, pp. 537–547, 1993.
[33]
M. Barth, H. H. Capelle, S. Weidauer et al., “Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study,” Stroke, vol. 38, no. 2, pp. 330–336, 2007.
[34]
N. Lu, D. Jackson, S. Luke, E. Festic, R. A. Hanel, and W. D. Freeman, “Intraventricular nicardipine for aneurysmal subarachnoid hemorrhage related vasospasm: assessment of 90 days outcome,” Neurocritical Care, vol. 16, no. 3, pp. 368–375, 2012.
[35]
J. Zhao, D. Zhou, J. Guo et al., “Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage: results of a randomized trial of fasudil hydrochloride versus nimodipine,” Neurologia Medico-Chirurgica, vol. 46, no. 9, pp. 421–428, 2006.
[36]
M. Shibuya, Y. Suzuki, K. Sugita et al., “Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: results of a prospective placebo-controlled double-blind trial,” Journal of Neurosurgery, vol. 76, no. 4, pp. 571–577, 1992.
[37]
J. Zhao, D. Zhou, J. Guo et al., “Efficacy and safety of fasudil in patients with subarachnoid hemorrhage: final results of a randomized trial of fasudil versus nimodipine,” Neurologia Medico-Chirurgica, vol. 51, no. 10, pp. 679–683, 2011.
[38]
G. J. Liu, Z. J. Wang, Y. F. Wang et al., “Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage,” European Journal of Clinical Pharmacology, vol. 68, no. 2, pp. 131–139, 2012.
[39]
R. S. Veyna, D. Seyfried, D. G. Burke et al., “Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 96, no. 3, pp. 510–514, 2002.
[40]
G. K. C. Wong, W. S. Poon, M. T. V. Chan et al., “Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial,” Stroke, vol. 41, no. 5, pp. 921–926, 2010.
[41]
C. Muroi, A. Terzic, M. Fortunati, Y. Yonekawa, and E. Keller, “Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial,” Surgical Neurology, vol. 69, no. 1, pp. 33–39, 2008.
[42]
W. M. van den Bergh, A. Algra, F. van Kooten et al., “Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial,” Stroke, vol. 36, no. 5, pp. 1011–1015, 2005.
[43]
G. K. C. Wong, M. T. V. Chan, R. Boet, W. S. Poon, and T. Gin, “Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study,” Journal of Neurosurgical Anesthesiology, vol. 18, no. 2, pp. 142–148, 2006.
[44]
S. M. D. Mees, A. Algra, W. P. Vandertop et al., “Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial,” The Lancet, vol. 380, no. 9836, pp. 44–49, 2012.
[45]
M. Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick, “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, vol. 36, no. 8, pp. 1627–1632, 2005.
[46]
J. R. Lynch, H. Wang, M. J. McGirt et al., “Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial,” Stroke, vol. 36, no. 9, pp. 2024–2026, 2005.
[47]
V. A. H. Sillberg, G. A. Wells, and J. J. Perry, “Do statins improve outcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage: a meta-analysis,” Stroke, vol. 39, no. 9, pp. 2622–2626, 2008.
[48]
S. H. Y. Chou, E. E. Smith, N. Badjatia et al., “A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage,” Stroke, vol. 39, no. 10, pp. 2891–2893, 2008.
[49]
M. D. Vergouwen, J. C. Meijers, R. B. Geskus et al., “Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 8, pp. 1444–1453, 2009.
[50]
A. H. Kramer and J. J. Fletcher, “Statins in the management of patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis,” Neurocritical Care, vol. 12, no. 2, pp. 285–296, 2010.
[51]
M. D. M. Shaw, M. Vermeulen, G. D. Murray, J. D. Pickard, B. A. Bell, and G. M. Teasdale, “Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treat- ing subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Nether- lands/Eire TAK-044 Subarachnoid Haemorrhage Study Group,” Journal of Neurosurgery, vol. 93, no. 6, pp. 992–997, 2000.
[52]
P. Vajkoczy, B. Meyer, S. Weidauer et al., “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,” Journal of Neurosurgery, vol. 103, no. 1, pp. 9–17, 2005.
[53]
R. L. MacDonald, R. T. Higashida, E. Keller et al., “Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling,” Stroke, vol. 43, no. 6, pp. 1463–1469, 2012, Erratum in: Stroke,vol. 43, no. 7, article e68, 2012.
[54]
R. L. Macdonald, R. T. Higashida, E. Keller et al., “Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2),” The Lancet Neurology, vol. 10, no. 7, pp. 618–625, 2011.
[55]
R. L. MacDonald, N. F. Kassell, S. Mayer et al., “Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial,” Stroke, vol. 39, no. 11, pp. 3015–3021, 2008.
[56]
M. D. I. Vergouwen, A. Algra, and G. J. E. Rinkel, “Endothelin receptor antagonists for aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update,” Stroke, vol. 43, no. 10, pp. 2671–2676, 2012.
[57]
J. E. Thomas, R. H. Rosenwasser, R. A. Armonda, J. Harrop, W. Mitchell, and I. Galaria, “Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans,” Stroke, vol. 30, no. 7, pp. 1409–1416, 1999.
[58]
A. Agrawal, R. Patir, Y. Kato, S. Chopra, H. Sano, and T. Kanno, “Role of intraventricular sodium nitroprusside in vasospasm secondary to aneurysmal subarachnoid haemorrhage: a 5-year prospective study with review of the literature,” Minimally Invasive Neurosurgery, vol. 52, no. 1, pp. 5–8, 2009.
[59]
A. Raabe, M. Zimmermann, M. Setzer et al., “Effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm,” Neurosurgery, vol. 50, no. 5, pp. 1006–1014, 2002.
[60]
R. M. Pluta, E. H. Oldfield, K. D. Bakhtian et al., “Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers,” PLoS ONE, vol. 6, no. 1, Article ID e14504, 2011.
[61]
R. M. Pluta, A. Dejam, G. Grimes, M. T. Gladwin, and E. H. Oldfield, “Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage,” Journal of the American Medical Association, vol. 293, no. 12, pp. 1477–1484, 2005.
[62]
K. K. Mukherjee, S. K. Singh, V. K. Khosla, S. Mohindra, and P. Salunke, “Safety and efficacy of sildenafil citrate in reversal of cerebral vasospasm: a feasibility study,” Surgical Neurology International, vol. 3, no. 1, Article ID 92164, 2012.
[63]
N. F. Kassell, E. C. Haley, C. Apperson-Hansen, and W. M. Alves, “Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand,” Journal of Neurosurgery, vol. 84, no. 2, pp. 221–228, 1996.
[64]
E. C. Haley, N. F. Kassell, C. Apperson-Hansen, M. H. Maile, and W. M. Alves, “A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America,” Journal of Neurosurgery, vol. 86, no. 3, pp. 467–474, 1997.
[65]
G. Lanzino, N. F. Kassell, N. W. C. Dorsch et al., “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,” Journal of Neurosurgery, vol. 90, no. 6, pp. 1011–1017, 1999.
[66]
G. Lanzino and N. F. Kassell, “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,” Journal of Neurosurgery, vol. 90, no. 6, pp. 1018–1024, 1999.
[67]
S. Zhang, L. Wang, M. Liu, and B. Wu, “Tirilazad for aneurysmal subarachnoid haemorrhage,” Cochrane Database of Systematic Reviews, vol. 2, Article ID CD006778, 2010.
[68]
T. Asano, K. Takakura, K. Sano et al., “Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial,” Journal of Neurosurgery, vol. 84, no. 5, pp. 792–803, 1996.
[69]
I. Saito, T. Asano, K. Sano et al., “Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage,” Neurosurgery, vol. 42, no. 2, pp. 269–278, 1998.
[70]
A. Munakata, H. Ohkuma, T. Nakano, N. Shimamura, K. Asano, and M. Naraoka, “Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage,” Neurosurgery, vol. 64, no. 3, pp. 423–428, 2009.
[71]
S. Suzuki, K. Sano, H. Handa et al., “Clinical study of OKY-046, a thromboxane synthetase inhibitor, in prevention of cerebral vasospasms and delayed cerebral ischaemic symptoms after subarachnoid haemorrhage due to aneurysmal rupture: a randomized double-blind study,” Neurological Research, vol. 11, no. 2, pp. 79–88, 1989.
[72]
Y. Suzuki, M. Shibuya, S. I. Satoh, H. Sugiyama, M. Seto, and K. Takakura, “Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study,” Neurologia Medico-Chirurgica, vol. 48, no. 6, pp. 241–247, 2008.
[73]
H. Yanamoto, H. Kikuchi, M. Sato, Y. Shimizu, S. Yoneda, and S. Okamoto, “Therapeutic trial of cerebral vasospasm with the serine protease inhibitor, FUT-175, administered in the acute stage after subarachnoid hemorrhage,” Neurosurgery, vol. 30, no. 3, pp. 358–363, 1992.
[74]
M. Kaminogo, M. Yonekura, M. Onizuka, A. Yasunaga, and S. Shibata, “Combination of serine protease inhibitor FUT-175 and thromboxane synthetase inhibitor OKY-046 decreases cerebral vasospasm in patients with subarachnoid hemorrhage,” Neurologia Medico-Chirurgica, vol. 38, no. 11, pp. 704–709, 1998.
[75]
E. M. Manno, D. R. Gress, C. S. Ogilvy, C. M. Stone, and N. T. Zervas, “The safety and efficacy of cyclosporine A in the prevention of vasospasm in patients with Fisher Grade 3 subarachnoid hemorrhages: a pilot study,” Neurosurgery, vol. 40, no. 2, pp. 289–293, 1997.
[76]
L. Fei and F. Golwa, “Topical application of dexamethasone to prevent cerebral vasospasm after aneurysmal subarachnoid haemorrhage: a pilot study,” Clinical Drug Investigation, vol. 27, no. 12, pp. 827–832, 2007.
[77]
D. Chyatte, N. C. Fode, D. A. Nichols, and T. M. Sundt, “Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage,” Neurosurgery, vol. 21, no. 2, pp. 157–160, 1987.
[78]
P. Gomis, J. P. Graftieaux, R. Sercombe, D. Hettler, B. Scherpereel, and P. Rousseaux, “Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 112, no. 3, pp. 681–688, 2010.
[79]
J. M. Findlay, N. F. Kassell, B. K. A. Weir et al., “A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm,” Neurosurgery, vol. 37, no. 1, pp. 168–178, 1995.
[80]
J. I. Hamada, Y. Kai, M. Morioka et al., “Effect on cerebral vasospasm of coil embolization followed by micro- catheter intrathecal urokinase infusion into the cisterna magna: a prospective randomized study,” Stroke, vol. 34, no. 11, pp. 2549–2554, 2003.
[81]
S. Amin-Hanjani, C. S. Ogilvy, F. G. Barker et al., “Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis,” Neurosurgery, vol. 54, no. 2, pp. 326–335, 2004.
[82]
S. Muehlschlegel, G. Rordorf, M. Bodock, and J. R. Sims, “Dantrolene mediates vasorelaxation in cerebral vasoconstriction: a case series,” Neurocritical Care, vol. 10, no. 1, pp. 116–121, 2009.
[83]
S. Muehlschlegel, G. Rordorf, and J. Sims, “Effects of a single dose of dantrolene in patients with cerebral vasospasm after subarachnoid hemorrhage: a prospective pilot study,” Stroke, vol. 42, no. 5, pp. 1301–1306, 2011.
[84]
J. B. Springborg, C. M?ller, P. Gideon, O. S. J?rgensen, M. Juhler, and N. V. Olsen, “Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial,” Acta Neurochirurgica, vol. 149, no. 11, pp. 1089–1100, 2007.
[85]
J. Siironen, S. Juvela, J. Varis et al., “No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial,” Journal of Neurosurgery, vol. 99, no. 6, pp. 953–959, 2003.
[86]
G. Wurm, B. Tomancok, K. Nussbaumer, C. Adelw?hrer, and K. Holl, “Reduction of ischemic sequelae following spontaneous subarachnoid hemorrhage: a double-blind, randomized comparison of enoxaparin versus placebo,” Clinical Neurology and Neurosurgery, vol. 106, no. 2, pp. 97–103, 2004.
[87]
J. I. Suarez, R. H. Martin, E. Calvillo et al., “The albumin in subarachnoid hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes,” Stroke, vol. 43, no. 3, pp. 683–690, 2012.
[88]
K. T. Kreiter, S. A. Mayer, G. Howard et al., “Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage,” Stroke, vol. 40, no. 7, pp. 2362–2367, 2009.
[89]
M. D. Vergouwen, M. Vermeulen, J. van Gijn et al., “Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group,” Stroke, vol. 41, no. 10, pp. 2391–2395, 2010.
[90]
D. T. Laskowitz and B. J. Kolls, “Neuroprotection in subarachnoid hemorrhage,” Stroke, vol. 41, no. 10, supplement, pp. S79–S84, 2010.