Skip to main content

Advertisement

SpringerLink
Log in

A Propensity Score-Matched Study of the Use of Non-steroidal Anti-inflammatory Agents Following Aneurysmal Subarachnoid Hemorrhage

  • Original Article
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Background

Inflammation may contribute to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Here, we compared outcomes among propensity score-matched cohorts who did and did not receive non-steroidal anti-inflammatory drug (NSAID) use after aSAH.

Methods

Propensity score-matched analysis of 413 subjects enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUring after Subarachnoid hemorrhage (CONSCIOUS-1) study. Propensity score matching was performed on the basis of age, sex, baseline National Institutes of Health Stroke Scale score, World Federation of Neurological Societies grade on admission, procedure used for securing aneurysm, and SAH clot burden.

Results

178 patients were matched (89 received NSAIDs, 89 did not). Propensity score matching was considered acceptable. Patients who had received NSAIDs during their hospital stay had significantly lower mortality rate, and reduced duration of intensive care unit stay and total length of hospital stay (P = 0.035, P = 0.009, and P = 0.053, respectively). At 6 weeks, 80.9 % of patients treated with NSAIDs had good functional outcome compared to 68.5 % of matched controls (P = 0.083). There was no significant difference in the proportions of patients who developed delayed ischemic neurological deficits, angiographic vasospasm, or required rescue therapy.

Conclusions

Inflammation may play a crucial role in the poor outcomes after SAH, and that NSAIDs may be a useful therapeutic option, once validated by larger prospective studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8(4):355–69.

    Article  PubMed  Google Scholar 

  2. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27(9):1459–66.

    Article  CAS  PubMed  Google Scholar 

  3. Ayling OG, Ibrahim GM, Drake B, Torner JC, Macdonald RL. Operative complications and differences in outcome after clipping and coiling of ruptured intracranial aneurysms. J Neurosurg. 2015;123(3):621–8.

    Article  PubMed  Google Scholar 

  4. Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, van Oostenbrugge RJ, Al-Shahi Salman R, Lavados PM, Rinkel GJ, van den Bergh WM, Group M-S. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380(9836):44–9.

    Article  PubMed  Google Scholar 

  5. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir Suppl. 2013;115:27–31.

    PubMed  Google Scholar 

  6. Zhang S, Wang L, Liu M, Wu B. Tirilazad for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2010;17(2):CD006778.

    Google Scholar 

  7. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br Med J. 1989;298(6674):636–42.

    Article  CAS  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Muroi C, Hugelshofer M, Seule M, Tastan I, Fujioka M, Mishima K, Keller E. Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2013;72(3):367–75 discussion 375.

    Article  PubMed  Google Scholar 

  10. Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS. Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg. 1998;89(4):559–67.

    Article  CAS  PubMed  Google Scholar 

  11. Tam AK, Ilodigwe D, Mocco J, Mayer S, Kassell N, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL. Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database. Neurocrit Care. 2010;13(2):182–9.

    Article  PubMed  Google Scholar 

  12. Ibrahim GM, Morgan BR, Macdonald RL. Patient phenotypes associated with outcomes after aneurysmal subarachnoid hemorrhage: a principal component analysis. Stroke. 2014;45(3):670–6.

    Article  PubMed  Google Scholar 

  13. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A, Investigators C. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, De Villiers JC. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry. 1988;51(11):1457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21(8):1156–61.

    Article  CAS  PubMed  Google Scholar 

  16. Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and prognosis. Radiology. 1982;143(1):91–6.

    Article  CAS  PubMed  Google Scholar 

  17. Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10(2):150–61.

    Article  PubMed  Google Scholar 

  18. Spallone A, Acqui M, Pastore FS, Guidetti B. Relationship between leukocytosis and ischemic complications following aneurysmal subarachnoid hemorrhage. Surg Neurol. 1987;27(3):253–8.

    Article  CAS  PubMed  Google Scholar 

  19. Rousseaux P, Scherpereel B, Bernard MH, Graftieaux JP, Guyot JF. Fever and cerebral vasospasm in ruptured intracranial aneurysms. Surg Neurol. 1980;14(6):459–65.

    CAS  PubMed  Google Scholar 

  20. Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E, Beringhelli T, Fasano M. Hemoglobin and heme scavenging. IUBMB Life. 2005;57(11):749–59.

    Article  CAS  PubMed  Google Scholar 

  21. Clatterbuck RE, Oshiro EM, Hoffman PA, Dietsch GN, Pardoll DM, Tamargo RJ. Inhibition of vasospasm with lymphocyte function-associated antigen-1 monoclonal antibody in a femoral artery model in rats. J Neurosurg. 2002;97(3):676–82.

    Article  CAS  PubMed  Google Scholar 

  22. Sabri M, Ai J, Lakovic K, D’Abbondanza J, Ilodigwe D, Macdonald RL. Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience. 2012;224:26–37.

    Article  CAS  PubMed  Google Scholar 

  23. Gallia GL, Tamargo RJ. Leukocyte-endothelial cell interactions in chronic vasospasm after subarachnoid hemorrhage. Neurol Res. 2006;28(7):750–8.

    Article  CAS  PubMed  Google Scholar 

  24. Ayer R, Jadhav V, Sugawara T, Zhang JH. The neuroprotective effects of cyclooxygenase-2 inhibition in a mouse model of aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;111:145–9.

    Article  CAS  PubMed  Google Scholar 

  25. Chyatte D. Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone. Stroke. 1989;20(8):1021–6.

    Article  CAS  PubMed  Google Scholar 

  26. Frazier JL, Pradilla G, Wang PP, Tamargo RJ. Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage. J Neurosurg. 2004;101(1):93–8.

    Article  CAS  PubMed  Google Scholar 

  27. Hakan T, Berkman MZ, Ersoy T, Karatas I, San T, Arbak S. Anti-inflammatory effect of meloxicam on experimental vasospasm in the rat femoral artery. J Clin Neurosci. 2008;15(1):55–9.

    Article  CAS  PubMed  Google Scholar 

  28. Chyatte D, Fode NC, Nichols DA, Sundt TM Jr. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P. Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2010;112(3):681–8.

    Article  CAS  PubMed  Google Scholar 

  30. Manno EM, Gress DR, Ogilvy CS, Stone CM, Zervas NT. The safety and efficacy of cyclosporine A in the prevention of vasospasm in patients with Fisher grade 3 subarachnoid hemorrhages: a pilot study. Neurosurgery. 1997;40(2):289–93.

    Article  CAS  PubMed  Google Scholar 

  31. Ascer E, Bertolami MC, Venturinelli ML, Buccheri V, Souza J, Nicolau JC, Ramires JA, Serrano CV Jr. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis. 2004;177(1):161–6.

    Article  CAS  PubMed  Google Scholar 

  32. Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD, Collaborators S. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666–75.

    Article  CAS  PubMed  Google Scholar 

  33. Green GA. Understanding NSAIDs: from aspirin to COX-2. Clin Cornerstone. 2001;3(5):50–60.

    Article  CAS  PubMed  Google Scholar 

  34. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232–5.

    Article  CAS  PubMed  Google Scholar 

  35. Diaz-Gonzalez F, Sanchez-Madrid F. Inhibition of leukocyte adhesion: an alternative mechanism of action for anti-inflammatory drugs. Immunol Today. 1998;19(4):169–72.

    Article  CAS  PubMed  Google Scholar 

  36. Hamza M, Dionne RA. Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition. Curr Mol Pharmacol. 2009;2(1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kapiotis S, Sengoelge G, Sperr WR, Baghestanian M, Quehenberger P, Bevec D, Li SR, Menzel EJ, Muhl A, Zapolska D, Virgolini I, Valent P, Speiser W. Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells. Life Sci. 1996;58(23):2167–81.

    Article  CAS  PubMed  Google Scholar 

  38. Muroi C, Hugelshofer M, Seule M, Keller E. The impact of nonsteroidal anti-inflammatory drugs on inflammatory response after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2014;20(2):240–6.

    Article  CAS  PubMed  Google Scholar 

  39. Hop JW, Rinkel GJ, Algra A, Berkelbach van der Sprenkel JW, van Gijn J. Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Neurology. 2000;54(4):872–8.

    Article  CAS  PubMed  Google Scholar 

  40. van den Bergh WM, Group MS, Algra A, Dorhout Mees SM, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Rinkel GJ. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH study. Stroke. 2006;37(9):2326–30.

    Article  CAS  PubMed  Google Scholar 

  41. Mendelow AD, Stockdill G, Steers AJ, Hayes J, Gillingham FJ. Double-blind trial of aspirin in patient receiving tranexamic acid for subarachnoid hemorrhage. Acta Neurochir (Wien). 1982;62(3–4):195–202.

    Article  CAS  Google Scholar 

  42. Ghodsi SM, Mohebbi N, Naderi S, Anbarloie M, Aoude A, Habibi Pasdar SS. Comparative efficacy of meloxicam and placebo in vasospasm of patients with subarachnoid hemorrhage. Iran J Pharm Res. 2015;14(1):125–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Broessner G, Beer R, Lackner P, Helbok R, Fischer M, Pfausler B, Rhorer J, Kuppers-Tiedt L, Schneider D, Schmutzhard E. Prophylactic, endovascularly based, long-term normothermia in ICU patients with severe cerebrovascular disease: bicenter prospective, randomized trial. Stroke. 2009;40(12):e657–65.

    Article  PubMed  Google Scholar 

  44. Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(11):1761–70.

    Article  PubMed  Google Scholar 

  45. Tso MK, Macdonald RL. Subarachnoid hemorrhage: a review of experimental studies on the microcirculation and the neurovascular unit. Transl Stroke Res. 2014;5(2):174–89.

    Article  PubMed  Google Scholar 

  46. Claassen J, Albers D, Schmidt JM, De Marchis GM, Pugin D, Falo CM, Mayer SA, Cremers S, Agarwal S, Elkind MS, Connolly ES, Dukic V, Hripcsak G, Badjatia N. Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann Neurol. 2014;75(5):771–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Legras A, Giraudeau B, Jonville-Bera AP, Camus C, Francois B, Runge I, Kouatchet A, Veinstein A, Tayoro J, Villers D, Autret-Leca E. A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock. Crit Care. 2009;13(2):R43.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Aronoff DM, Bloch KC. Assessing the relationship between the use of nonsteroidal antiinflammatory drugs and necrotizing fasciitis caused by group A streptococcus. Medicine. 2003;82(4):225–35.

    CAS  PubMed  Google Scholar 

  49. Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis. Intensive Care Med. 2012;38(8):1249–57.

    Article  CAS  PubMed  Google Scholar 

  50. Czymek R, Grossmann A, Roblick U, Schmidt A, Fischer F, Bruch HP, Hildebrand P. Surgical management of acute upper gastrointestinal bleeding: still a major challenge. Hepatogastroenterology. 2012;59(115):768–73.

    PubMed  Google Scholar 

  51. Chua SK, Liao CS, Hung HF, Cheng JJ, Chiu CZ, Chang CM, Lee SH, Lin SC, Liou JY, Lo HM, Kuan P, Shyu KG. Gastrointestinal bleeding and outcomes after percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Crit Care. 2011;20(3):218–25.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neurosurgery, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Farshad Nassiri, George M. Ibrahim, Jetan H. Badhiwala, Christopher D. Witiw, Alireza Mansouri, Naif M. Alotaibi & R. Loch Macdonald

  2. Labatt Family Centre of Excellence in Brain Injury and Trauma Research, St. Michael’s Hospital, Toronto, Canada

    Farshad Nassiri, George M. Ibrahim, Jetan H. Badhiwala, Christopher D. Witiw, Alireza Mansouri, Naif M. Alotaibi & R. Loch Macdonald

  3. Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada

    Farshad Nassiri, George M. Ibrahim, Jetan H. Badhiwala, Christopher D. Witiw, Alireza Mansouri, Naif M. Alotaibi & R. Loch Macdonald

  4. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Farshad Nassiri, George M. Ibrahim, Jetan H. Badhiwala, Christopher D. Witiw, Alireza Mansouri, Naif M. Alotaibi & R. Loch Macdonald

Authors
  1. Farshad Nassiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George M. Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jetan H. Badhiwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher D. Witiw
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alireza Mansouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naif M. Alotaibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Loch Macdonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Loch Macdonald.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Disclosure

Actelion Pharmaceuticals was the sponsor of the CONSCIOUS-1 trial; the company provided the authors with the anonymized trial data set but had no role in this exploratory analysis nor the development of this article. R.L.M is the chief scientific officer for Edge Therapeutics Inc. R.L.M received grant support from the Physicians Services Incorporated Foundation, Brain Aneurysm Foundation, Canadian Institutes for Health Research, and the Heart and Stroke Foundation of Canada.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individuals included in this study.

Additional information

Clinical Trial Registration: URL - www.clinicaltrials.gov; Unique Identifier - NCT00111085.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nassiri, F., Ibrahim, G.M., Badhiwala, J.H. et al. A Propensity Score-Matched Study of the Use of Non-steroidal Anti-inflammatory Agents Following Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 25, 351–358 (2016). https://doi.org/10.1007/s12028-016-0266-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-016-0266-6

Keywords

Search

Navigation