Advertisement

Current Treatment Options in Neurology

, Volume 14, Issue 2, pp 164–174 | Cite as

Statins and Anti-Inflammatory Therapies for Subarachnoid Hemorrhage

  • Rajat DharEmail author
  • Michael Diringer
Critical Care Neurology (K Sheth, Section Editor)

Opinion statement

Aneurysmal subarachnoid hemorrhage (SAH) induces a potent inflammatory cascade that contributes to endothelial dysfunction, imbalance of vasoactive substances (excess endothelin, depletion of nitric oxide), and arterial vasospasm. This process results in delayed cerebral ischemia, a major cause of neurologic disability in those surviving the initial hemorrhage. The only therapy shown to be effective in improving neurologic outcomes after SAH is a calcium-channel antagonist, nimodipine (although it achieved this result without reducing vasospasm). A number of novel therapies have been explored to inhibit the development of vasospasm and reduce the burden of ischemia and cerebral infarction. Statins are promising candidates, as they block multiple aspects of the inflammatory pathway that contributes to ischemic brain injury. Early clinical trials have produced conflicting results, however, and the adoption of statins in clinical practice should await the results of larger, more definitive studies. Though endothelin-receptor antagonists showed promise in significantly reducing vasospasm in preliminary trials, their failure to improve clinical outcomes in phase 3 studies has been disappointing, highlighting the complex link between vasospasm and ischemia. Future directions in the quest to improve outcomes of patients with SAH may need to approach ischemia as a multifactorial process with inflammatory, vasoactive, and ionic/metabolic components.

Keywords

Subarachnoid hemorrhage Intracranial aneurysm Statins Cerebral vasospasm Treatment Delayed cerebral ischemia Endothelin antagonists Pravastatin Simvastatin HMG-CoA reductase inhibitors Tirilazad Edaravone 

Notes

Disclosure

Conflicts of Interest: R. Dhar: none; M. Diringer: Board membership, Mid America Transplant Services.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Macdonald RL, Kassell NF, Mayer S, 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. 2008;39(11):3015–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38(8):2315–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Hijdra A, van Gijn J, Nagelkerke NJ, et al. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke. 1988;19(10):1250–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009;31(2):151–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Vergouwen MD, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42(4):924–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Provencio JJ, Vora N. Subarachnoid hemorrhage and inflammation: bench to bedside and back. Semin Neurol. 2005;25(4):435–44.PubMedCrossRefGoogle Scholar
  7. 7.•
    Chaichana KL, Pradilla G, Huang J, Tamargo RJ. Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage. World Neurosurg. 2010;73(1):22–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Gruber A, Rossler K, Graninger W, et al. Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2000;12(4):297–306.PubMedCrossRefGoogle Scholar
  9. 9.
    Fassbender K, Hodapp B, Rossol S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry. 2001;70(4):534–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Schoch B, Regel JP, Wichert M, et al. Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage. Neurosurgery. 2007;60(5):828–36.PubMedCrossRefGoogle Scholar
  11. 11.
    Gallia GL, Tamargo RJ. Leukocyte-endothelial cell interactions in chronic vasospasm after subarachnoid hemorrhage. Neurol Res. 2006;28(7):750–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Kubo Y, Ogasawara K, Kakino S, et al. Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage. Surg Neurol. 2008;69(6):592–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther. 2005;105(1):23–56.PubMedCrossRefGoogle Scholar
  14. 14.
    Clark JF, Sharp FR. Bilirubin oxidation products (BOXes) and their role in cerebral vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2006;26(10):1223–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Ryba M, Jarzabek-Chorzelska M, Chorzelski T, Pastuszko M. Is vascular angiopathy following intracranial aneurysm rupture immunologically mediated? Acta Neurochir (Wien ). 1992;117(1–2):34–7.CrossRefGoogle Scholar
  16. 16.
    Khurana VG, Sohni YR, Mangrum WI, et al. Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm. J Cereb Blood Flow Metab. 2004;24(3):291–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Bavbek M, Polin R, Kwan AL, et al. Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke. 1998;29(9):1930–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Clatterbuck RE, Gailloud P, Ogata L, et al. Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg. 2003;99(2):376–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshimoto Y, Tanaka Y, Hoya K. Acute systemic inflammatory response syndrome in subarachnoid hemorrhage. Stroke. 2001;32(9):1989–93.PubMedCrossRefGoogle Scholar
  20. 20.
    Rothoerl RD, Axmann C, Pina AL, et al. Possible role of the C-reactive protein and white blood cell count in the pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2006;18(1):68–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Dhar R, Diringer MN. The burden of the systemic inflammatory response predicts vasospasm and outcome after subarachnoid hemorrhage. Neurocrit Care. 2008;8(3):404–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Anderson CS, Feigin V, Bennett D, et al. Active and passive smoking and the risk of subarachnoid hemorrhage: an international population-based case-control study. Stroke. 2004;35(3):633–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg. 2008;108(5):1052–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Lasner TM, Weil RJ, Riina HA, et al. Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1997;87(3):381–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Weir BK, Kongable GL, Kassell NF, et al. Cigarette smoking as a cause of aneurysmal subarachnoid hemorrhage and risk for vasospasm: a report of the Cooperative Aneurysm Study. J Neurosurg. 1998;89(3):405–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Juvela S. Plasma endothelin concentrations after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2000;92(3):390–400.PubMedCrossRefGoogle Scholar
  27. 27.
    Krishnamurthy S, Kelleher JP, Lehman EB, Cockroft KM. Effects of tobacco dose and length of exposure on delayed neurological deterioration and overall clinical outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;61(3):475–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Gerzanich V, Zhang F, West GA, Simard JM. Chronic nicotine alters NO signaling of Ca(2+) channels in cerebral arterioles. Circ Res. 2001;88(3):359–65.PubMedGoogle Scholar
  29. 29.
    Seder DB, Schmidt JM, Badjatia N, et al. Transdermal nicotine replacement therapy in cigarette smokers with acute subarachnoid hemorrhage. Neurocrit Care. 2011;14(1):77–83.PubMedCrossRefGoogle Scholar
  30. 30.••
    Al Tamimi YZ, Orsi NM, Quinn AC, et al. A review of delayed ischemic neurologic deficit following aneurysmal subarachnoid hemorrhage: historical overview, current treatment, and pathophysiology. World Neurosurg. 2010;73(6):654–67.CrossRefGoogle Scholar
  31. 31.
    Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;(3):CD000277.Google Scholar
  32. 32.
    Sehba FA, Pluta RM, Zhang JH. Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol. 2011;43(1):27–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Feigin VL, Anderson N, Rinkel GJ, et al. Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage. Cochrane Database Syst Rev. 2005;(3):CD004583.Google Scholar
  34. 34.
    Hashi K, Takakura K, Sano K, et al. Intravenous hydrocortisone in large doses in the treatment of delayed ischemic neurological deficits following subarachnoid hemorrhage—results of a multi-center controlled double-blind clinical study. No To Shinkei. 1988;40(4):373–82.PubMedGoogle Scholar
  35. 35.
    Katayama Y, Haraoka J, Hirabayashi H, et al. A randomized controlled trial of hydrocortisone against hyponatremia in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38(8):2373–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Chyatte D, Fode NC, Nichols DA, Sundt Jr TM. Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 1987;21(2):157–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Gomis P, Graftieaux JP, Sercombe R, et al. Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2010;112(3):681–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Hall ED. Efficacy and mechanisms of action of the cytoprotective lipid peroxidation inhibitor tirilazad mesylate in subarachnoid haemorrhage. Eur J Anaesthesiol. 1996;13(3):279–89.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang S, Wang L, Liu M, Wu B. Tirilazad for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2010;(2):CD006778.Google Scholar
  40. 40.
    Munakata A, Ohkuma H, Nakano T, et al. Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2009;64(3):423–8.PubMedCrossRefGoogle Scholar
  41. 41.
    van den Bergh WM, Algra A, Dorhout Mees SM, et al. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study. Stroke. 2006;37(9):2326–30.PubMedCrossRefGoogle Scholar
  42. 42.
    Chyatte D, Rusch N, Sundt Jr TM. Prevention of chronic experimental cerebral vasospasm with ibuprofen and high-dose methylprednisolone. J Neurosurg. 1983;59(6):925–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Pradilla G, Thai QA, Legnani FG, et al. Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage. Neurosurgery. 2005;57(1 Suppl):184–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97(12):1129–35.PubMedGoogle Scholar
  45. 45.
    McGirt MJ, Lynch JR, Parra A, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33(12):2950–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci. 2002;23(10):482–6.PubMedCrossRefGoogle Scholar
  47. 47.
    McGirt MJ, Pradilla G, Legnani FG, et al. Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery. 2006;58(5):945–51.PubMedCrossRefGoogle Scholar
  48. 48.
    Rikitake Y, Kawashima S, Takeshita S, et al. Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 2001;154(1):87–96.PubMedCrossRefGoogle Scholar
  49. 49.
    Cheng G, Wei L, Zhi-Dan S, et al. Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci. 2009;10:7.PubMedCrossRefGoogle Scholar
  50. 50.
    Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke. 2005;36(9):2024–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Tseng MY, Czosnyka M, Richards H, et al. 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(8):1627–32.PubMedCrossRefGoogle Scholar
  52. 52.
    Chou SH, Smith EE, Badjatia N, et al. A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 2008;39(10):2891–3.PubMedCrossRefGoogle Scholar
  53. 53.
    Vergouwen MD, Meijers JC, Geskus RB, et al. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab. 2009;29(8):1444–53.PubMedCrossRefGoogle Scholar
  54. 54.•
    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(1):e47–52.PubMedCrossRefGoogle Scholar
  55. 55.
    Tseng MY. Participants in the International Multidisciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Summary of evidence on immediate statins therapy following aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;15(2):298–301.PubMedCrossRefGoogle Scholar
  56. 56.
    Bederson JB, Connolly Jr ES, Batjer HH, et al. 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(3):994–1025.PubMedCrossRefGoogle Scholar
  57. 57.
    Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658–69.PubMedCrossRefGoogle Scholar
  58. 58.
    Singhal AB, Topcuoglu MA, Dorer DJ, et al. SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage. Neurology. 2005;64(6):1008–13.PubMedCrossRefGoogle Scholar
  59. 59.
    Risselada R, Straatman H, van Kooten F, et al. Withdrawal of statins and risk of subarachnoid hemorrhage. Stroke. 2009;40(8):2887–92.PubMedCrossRefGoogle Scholar
  60. 60.
    Seifert V, Loffler BM, Zimmermann M, et al. Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage. Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma. J Neurosurg. 1995;82(1):55–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Kastner S, Oertel MF, Scharbrodt W, et al. Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH. Acta Neurochir (Wien ). 2005;147(12):1271–9.CrossRefGoogle Scholar
  62. 62.
    Fassbender K, Hodapp B, Rossol S, et al. Endothelin-1 in subarachnoid hemorrhage: an acute-phase reactant produced by cerebrospinal fluid leukocytes. Stroke. 2000;31(12):2971–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Macdonald RL, Higashida RT, Keller E, 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). Lancet Neurol. 2011;10(7):618–25.PubMedCrossRefGoogle Scholar
  64. 64.
    Macdonald RL, Higashida RT, Keller E, et al. Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care. 2010;13(3):416–24.PubMedCrossRefGoogle Scholar
  65. 65.
    Santhanam AV, Smith LA, Akiyama M, et al. Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 2005;36(12):2731–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Jerndal M, Forsberg K, Sena ES, et al. A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab. 2010;30(5):961–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40(12):e647–56.PubMedCrossRefGoogle Scholar
  68. 68.
    Tseng MY, Hutchinson PJ, Richards HK, et al. 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.Google Scholar
  69. 69.
    Hoh BL, Ogilvy CS. Endovascular treatment of cerebral vasospasm: transluminal balloon angioplasty, intra-arterial papaverine, and intra-arterial nicardipine. Neurosurg Clin N Am. 2005;16(3):501–16. vi.PubMedCrossRefGoogle Scholar
  70. 70.
    Rosenwasser RH, Armonda RA, Thomas JE, et al. Therapeutic modalities for the management of cerebral vasospasm: timing of endovascular options. Neurosurgery. 1999;44(5):975–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Zwienenberg-Lee M, Hartman J, Rudisill N, et al. Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with Fisher grade III subarachnoid hemorrhage: results of a phase II multicenter, randomized, clinical trial. Stroke. 2008;39(6):1759–65.PubMedCrossRefGoogle Scholar
  72. 72.
    McAuliffe W, Townsend M, Eskridge JM, et al. Intracranial pressure changes induced during papaverine infusion for treatment of vasospasm. J Neurosurg. 1995;83(3):430–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Carhuapoma JR, Qureshi AI, Tamargo RJ, et al. Intra-arterial papaverine-induced seizures: case report and review of the literature. Surg Neurol. 2001;56(3):159–63.PubMedCrossRefGoogle Scholar
  74. 74.
    Clyde BL, Firlik AD, Kaufmann AM, et al. Paradoxical aggravation of vasospasm with papaverine infusion following aneurysmal subarachnoid hemorrhage. Case report J Neurosurg. 1996;84(4):690–5.Google Scholar
  75. 75.
    Dreier JP, Major S, Manning A, et al. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain. 2009;132(Pt 7):1866–81.PubMedCrossRefGoogle Scholar
  76. 76.•
    Sabri M, Macdonald RL. Statins: a potential therapeutic addition to treatment for aneurysmal subarachnoid hemorrhage? World Neurosurg. 2010;73(6):646–53.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of NeurologyWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Neurology and Neurological SurgeryWashington University School of MedicineSt. LouisUSA

Personalised recommendations