Skip to main content

Advertisement

SpringerLink
Log in

Locally-administered Intrathecal Thrombolytics Following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis

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

Abstract

Background

The volume and clearance rate of blood in the basal cisterns and ventricles are important predictors of complications following aneurysmal subarachnoid hemorrhage (SAH). Thus, there is a strong rationale for interventions aimed at accelerating the clearance of blood.

Methods

We systematically searched MEDLINE, EMBASE, Cochrane databases, references of review articles and gray literature sources to identify randomized controlled trials (RCTs) assessing the efficacy of locally-administered, intrathecal thrombolytics in patients with SAH. Primary outcomes included the occurrence of poor neurologic recovery and delayed neurologic deficits (DNDs). Secondary outcomes included angiographic vasospasm, chronic hydrocephalus and treatment-related complications. Data were extracted and appraised independently and in duplicate, using standardized forms. Fixed or random effects models, as appropriate based on the degree of study heterogeneity were applied to calculate summary measures.

Results

Five RCTs, enrolling 465 patients, met eligibility criteria. The methodology, results and risk of bias varied considerably across individual studies. Overall, use of intrathecal thrombolytics was associated with significant reductions in the development of poor outcomes (OR 0.52, 0.34–0.78, P < 0.01), DNDs (OR 0.54, 0.34–0.87, P = 0.01), angiographic vasospasm (OR 0.32, 0.15–0.70, P < 0.01) and chronic hydrocephalus (OR 0.33, 0.15–0.74, P < 0.01), without any increment in hemorrhagic or infectious complications. These findings were dampened by the exclusion of a study which concomitantly administered intrathecal vasodilators and thrombolytics.

Conclusions

Current data suggests that intrathecal thrombolytics improve outcomes following SAH. However, there are important limitations to existing RCTs, with considerable risk of bias. Further standardization of techniques and evaluation in larger, more rigorous RCTs is required.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

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

    Article  PubMed  Google Scholar 

  2. Mayer SA, Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, Du YE, Connolly ES Jr. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8.

    PubMed  CAS  Google Scholar 

  3. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21.

    Article  PubMed  Google Scholar 

  4. Sheehan JP, Polin RS, Sheehan JM, Baskaya MK, Kassell NF. Factors associated with hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery. 1999;45:1120–7.

    Article  PubMed  CAS  Google Scholar 

  5. Macdonald RL, Rosengart A, Huo D, Karrison T. Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage. J Neurosurg. 2003;99:644–52.

    Article  PubMed  Google Scholar 

  6. Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2004;101:255–61.

    Article  PubMed  Google Scholar 

  7. Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther. 2005;105:23–56.

    Article  PubMed  CAS  Google Scholar 

  8. Findlay JM, Weir BK, Steinke D, Tanabe T, Gordon P, Grace M. Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg. 1988;69:723–35.

    Article  PubMed  CAS  Google Scholar 

  9. Amin-Hanjini S, Ogilvy CS, Barker FG 2nd. Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis. Neurosurgery. 2004;54:326–34.

    Article  Google Scholar 

  10. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke. 2009;40:1533–8.

    Article  PubMed  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9.

    PubMed  Google Scholar 

  12. Berlin JA. Does blinding of readers affect the results of meta-analyses? Lancet. 1997;350:185–6.

    Article  PubMed  CAS  Google Scholar 

  13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trial. 1996;17:1–12.

    Article  CAS  Google Scholar 

  14. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.

    Article  PubMed  CAS  Google Scholar 

  15. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  16. Egger M, Smith GD. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    PubMed  CAS  Google Scholar 

  17. Kanamura K, Waga S, Sakakura M, Morikawa A, Yamamoto Y, Morooka Y, Okada M. Comparative study of cisternal lavage methods for the treatment of cerebral vasospasm. In: Cerebral Vasospasm. Proceedings of the 5th international conference, Findlay JM, editor. Amsterdam: Elsevier;1993. p 471–473.

  18. Findlay JM, Kassell NF, Weir BK, Haley EC Jr, Kongable G, Germanson T, Truskowski L, Alves WM, Holness RO, Knuckey NW. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995;37:168–76.

    Article  PubMed  CAS  Google Scholar 

  19. Hamada J, Kai Y, Morioka M, Yano S, Mizuno T, Hirano T, Kazekawa K, Ushio Y. Effect on cerebral vasospasm of coil embolization followed by microcatheter intrathecal urokinase infusion into the cistern magna: a prospective randomized study. Stroke. 2003;34:2549–54.

    Article  PubMed  Google Scholar 

  20. Li YH, Guo K, Zi XH, Song Z. Combining exchange of cerebrospinal fluid with small dose of urokinase injection for subarachnoid hemorrhage. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005;30:217–20.

    PubMed  Google Scholar 

  21. Hanggi D, Eicker S, Beseoglu K, Behr J, Turowski B, Steiger HJ. A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single centre prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cen Eur Neurosurg. 2009;70:61–7.

    Article  PubMed  CAS  Google Scholar 

  22. Klimo P, Kestle JR, MacDonald JD, Schmidt RH. Marked reduction of cerebral vasospasm with lumbar drainage of cerebrospinal fluid after subarachnoid hemorrhage. J Neurosurg. 2004;100:215–24.

    Article  PubMed  Google Scholar 

  23. Hariton GB, Findlay JM, Weir BK, Kasuya H, Grace MG, Mielke BW. Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. Neurosurgery. 1993;33:691–6.

    Article  PubMed  CAS  Google Scholar 

  24. Findlay JM, Weir BKA, Kanamuru K, Grace M, Baughman R. The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage. Neurosurgery. 1990;26:201–6.

    Article  PubMed  CAS  Google Scholar 

  25. Zabramski JM, Spetzler RF, Lee KS, Papadopoulos SM, Bovill E, Zimmerman RS, Bederson JB. Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patietns with aneurysmal subarachnoid hemorrhage. Neurosurgery. 1991;75(2):189–96.

    Article  CAS  Google Scholar 

  26. Sasaki T, Ohta T, Kikuchi H, Takakura K, Usui M, Ohnishi H, Kondo A, Tanabe H, Nakamura J, Yamada K. A phase II clinical trial of recombinant human tissue-type plasminogen activator against cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 1994;35:597–604.

    Article  PubMed  CAS  Google Scholar 

  27. Findlay JM, Jacka MJ. Cohort study of intraventricular thrombolysis with recombinant tissue plasminogen activator for aneurysmal intraventricular hemorrhage. Neurosurgery. 2004;55:532–7.

    Article  PubMed  Google Scholar 

  28. Varelas PN, Rickert KL, Cusick J, Hacein-Bey L, Sinson G, Torbey M, Spanaki M, Gennarelli TA. Intraventricular hemorrhage after aneurysmal subarachnoid hemorrhage: pilot study of treatment with intraventricular tissue plasminogen activator. Neurosurgery. 2005;56:205–13.

    Article  PubMed  Google Scholar 

  29. Ramakrishna R, Sekhar LN, Ramanathan D, Temkin N, Hallam D, Ghodke BV, Kim LJ. Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurismal subarachnoid hemorrhage. Neurosurgery. 2010;67:110–7.

    Article  PubMed  Google Scholar 

  30. http://european-stroke-conference.com/2008/Nice/webcast/1_clinical_trial_I06_hanley/index.html; accessed August1, 2008.

Download references

Acknowledgments

Dr. Andreas Kramer has received funding from the University of Calgary and the Hotchkiss Brain Institute in order to perform a pilot/feasibility randomized controlled trial of intraventricular tissue plasminogen activator in the management of patients with concomitant subarachnoid and intraventricular hemorrhage. The investigators have corresponded with the authors of three of the randomized controlled trials included in this meta-analysis (Drs. Findlay, Hanggi and Kanamura), and have been provided with additional information.

Author information

Authors and Affiliations

  1. Departments of Critical Care Medicine & Clinical Neurosciences, University of Calgary, Room EG23 J, Foothills Medical Center, 403 29th St. N.W, Calgary, AB, T2N 2T9, Canada

    Andreas H. Kramer

  2. Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA

    Jeffrey J. Fletcher

Authors
  1. Andreas H. Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey J. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas H. Kramer.

Appendix

Appendix

Search strategy to identify randomized controlled trials involving the use of intrathecal thrombolytics among patients with subarachnoid hemorrhage.

Database: CCTR, CDSR, EMBASE, Ovid MEDLINE(R).

Search Strategy.

  1. 1

    exp Thrombolytic therapy/(26130)

  2. 2

    exp Fibrinolytic agents/(199241)

  3. 3

    exp Streptokinase/(22776)

  4. 4

    exp Tissue plasminogen activator/(27729)

  5. 5

    streptase.mp. (592)

  6. 6

    kabikinase.mp. (281)

  7. 7

    exp Urokinase-type plasminogen activator/(22589)

  8. 8

    urokinase.mp. (31031)

  9. 9

    abbokinase.mp. (371)

  10. 10

    activase.mp. (966)

  11. 11

    alteplase.mp. (10511)

  12. 12

    cathflo.mp. (30)

  13. 13

    retavase.mp. (153)

  14. 14

    tenecteplase.mp. (1531)

  15. 15

    TNKase.mp. (72)

  16. 16

    Eminase.mp. (278)

  17. 17

    1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 (220500)

  18. 18

    exp Intracranial aneurysm/(30413)

  19. 19

    exp Subarachnoid hemorrhage/(28197)

  20. 20

    exp Vasospasm, intracranial/(4601)

  21. 21

    exp Ultrasonography, Doppler, transcranial/(23523)

  22. 22

    exp Cerebral angiography/(35964)

  23. 23

    SAH.mp. (9318)

  24. 24

    delayed ischemic neurologic deficit$.mp. (41)

  25. 25

    delayed ischemic neurological deficit$.mp. (228)

  26. 26

    delayed neurologic deficit$.mp. (61)

  27. 27

    delayed neurological deficit$.mp. (140)

  28. 28

    delayed infarct$.mp. (85)

  29. 29

    vasospasm$.mp. (19955)

  30. 30

    delayed cerebral ischemia.mp. (314)

  31. 31

    18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 (110874)

  32. 32

    17 and 31 (3266)

  33. 33

    limit 32 to (abstracts and human) [Limit not valid in CCTR,CDSR; records were retained] (2372)

  34. 34

    remove duplicates from 33 (2042)

  35. 35

    from 34 keep 1–2042 (2042)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kramer, A.H., Fletcher, J.J. Locally-administered Intrathecal Thrombolytics Following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis. Neurocrit Care 14, 489–499 (2011). https://doi.org/10.1007/s12028-010-9429-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-010-9429-z

Keywords

Search

Navigation