Neurocritical Care

, Volume 2, Issue 2, pp 124–132 | Cite as

Intra-arterial papaverine infusions for the treatment of cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage

  • James K. Liu
  • William T. CouldwellEmail author
Review Article


Cerebral vasospasm secondary to aneurysmal subarachnoid hemorrhage that has become refractory to maximal medical management can be treated with selective intra-arterial papaverine infusions. Papaverine is a potent vasodilator of the proximal, intermediate, and distal cerebral arteries and can improve cerebral blood flow (CBF). When infused intra-arterially using endovascular microcatheter techniques, papaverine can effectively increase angiographic vessel diameter, decrease prolonged cerebral circulation time, and improve cerebral oxygenation. However, one of the major disadvantages of papaverine is its transient nature, which can result in recurrent and/or persistent angiographic and clinical vasospasm that may require multiple repeated infusions, despite a successful response to the initial treatment. Intra-arterial papaverine can be used alone or in combination with balloon angioplasty. This article reviews the mechanism of action, technique of administration, effects on CBF, clinical results, and complications of intra-arterial papaverine for the treatment of cerebral vasospasm.

Key Words

Cerebral vasospasm subarachnoid hemorrhage intra-arterial papaverine 


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  1. 1.
    Heros RC, Zervas NT, Varsos V. Cerebral vasospasm after subarachnoid hemorrhage: an update. Ann Neurol 1983;14(6):599–608.PubMedCrossRefGoogle Scholar
  2. 2.
    Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 1985;16(4):562–572.PubMedGoogle Scholar
  3. 3.
    Award IA, Carter LP, Spetzler RF, Medina M, Williams FC, Jr. Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke 1987;18(2):365–372.Google Scholar
  4. 4.
    Barker FG, 2nd, Ogilvy CS. Efficacy of prophylactin nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis. J Neurosurg 1996;84(3):405–414.PubMedGoogle Scholar
  5. 5.
    Handa Y, Weir BK, Nosko M, Mosewich R, Tsuji T, Grace M. The effect of timing of clot removal on chronic vasospasm in a primate model. J Neurosurg 1987;67(4):558–564.PubMedGoogle Scholar
  6. 6.
    Elliott JP, Newell DW, Lam DJ, et al. Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 1998;88(2):277–284.PubMedGoogle Scholar
  7. 7.
    Newell DW, Elliott JP, Eskridge JM, Winn HR. Endovascular therapy for aneurysmal vasospasm. Crit Care Clin 1999;15(4): 685–699, v.PubMedCrossRefGoogle Scholar
  8. 8.
    Newell DW, Eskridge JM, Aaslid R. Current indications and results of cerebral angioplasty. Acta Neurochir Suppl 2001;77:181–183.PubMedGoogle Scholar
  9. 9.
    Livingston K, Guterman LR, Hopkins LN. Interaarterial papaverine as an adjunct to transluminal angioplasty for vasospasm induced by subarachnoid hemorrhage. AJNR Am J Neuroradiol 1993;14(2):346–347.PubMedGoogle Scholar
  10. 10.
    Kaku Y, Yonekawa Y, Tsukahara T, Kazekawa K. Superselective intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 1992;77(6):842–847.PubMedGoogle Scholar
  11. 11.
    Kassell NF, Helm G, Simmons N, Phillips CD, Cail WS. Treatment of cerebral vasospasm withintra-arterial papaverine. J Neurosurg 1992;77(6):848–852.PubMedGoogle Scholar
  12. 12.
    Fandino J, Kaku Y, Schuknecht B, Valavanis A, Yonekawa Y. Improvement of cerebral oxygenation patterns and metabolic validation of superselective intraarterial infusion of papaverine for the treatment of cerebral vasospasm. J Neurosurg 1998;89(1):93–100.PubMedGoogle Scholar
  13. 13.
    Firlik KS, Kaufmann AM, Firlik AD, Jungreis CA, Yonas H. Intraarterial papaverine for the treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Surg Neurol 1999;51(1):66–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Liu JK, Tenner MS, Gottfried ON, et al. Efficacy of multiple intraarterial papaverine infusions for improvement in cerebral circulation time in patients with recurrent cerebral vasospasm. J Neurosurg 2004;100(3):414–421.PubMedGoogle Scholar
  15. 15.
    Liu JK, Tenner MS, Oestreich HM, Couldwell WT. Reversal of radiographically impending stroke with multiple intraarterial papaverine infusions in severe diffuse cerebral vasospasm induced by subarachnoid hemorrhage. Acta Neurochir (Wien) 2001;143(12):1249–1255; discussion 56.CrossRefGoogle Scholar
  16. 16.
    Milburn JM, Moran CJ, Cross DT, 3rd, Diringer MN, Pilgram TK, Dacey RG, Jr. Increase in diameters of vasospastic intracranial arteries by intraarterial papaverine administration. J Neurosurg 1998;88(1):38–42.PubMedGoogle Scholar
  17. 17.
    Milburn JM, Moran CJ, Cross DT, 3rd, Diringer MN, Pilgram TK, Dacey RG, Jr. Effect of intraarterial papaverine on cerebral circulation time. AJNR Am J Neuroradiol 1997;18(6):1081–1085.PubMedGoogle Scholar
  18. 18.
    Numaguchi Y, Zoarski GH. Intra-arterial papaverine treatment for cerebral vasospasm: our experience and review of the literature. Neurol Med Chir (Tokyo) 1998;38(4):189–195.CrossRefGoogle Scholar
  19. 19.
    Oskouian RJ, Jr., Martin NA, Lee JH, et al. Multimodal quantitation of the effects of endovascular therapy for vasospasm on cerebral blood flow, transcranial doppler ultrasonographic velocities, and cerebral artery diameters. Neurosurgery 2002;51(1):30–41; discussion, 41–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Sawada M, Hashimoto N, Tsukahara T, Nishi S, Kaku Y, Yoshimura S. Effectiveness of intra-arterially infused papaverine solutions of various concentrations for the treatment of cerebral vasospasm. Acta Neurochir (Wien) 1997;139(8):706–711.CrossRefGoogle Scholar
  21. 21.
    Numaguchi Y, Zoarski GH, Clouston JE, et al. Repeat intra-arterial papaverine for recurrent cerebral vasospasm after subarachnoid haemorrhage. Neuroradiology 1997;39(10):751–759.PubMedCrossRefGoogle Scholar
  22. 22.
    Lugnier C, Stoclet JC. Inhibition by papaverine of cGMP and cAMP phosphodiesterases from the rat heart. Biochem Pharmacol 1974;23(21):3071–3074.PubMedCrossRefGoogle Scholar
  23. 23.
    Varsos VG, Liszczak TM, Han DH, et al. Delayed cerebral vasospasm is not reversible by aminophylline, nifedipine, or papaverine in a “two-hemorrhage” canine model. J Neurosurg 1983;58(1):11–17.PubMedGoogle Scholar
  24. 24.
    Cook P, James I. Drug therapy: cerebral vasodilators (first of two parts). N Engl J Med 1981;305(25):1508–1513.PubMedCrossRefGoogle Scholar
  25. 25.
    Mathis JM, Jensen ME, Dion JE. Technical considerations on intraarterial papaverine hydrochloride for cerebral vasospasm. Neuroradiology 1997;39(2):90–98.PubMedCrossRefGoogle Scholar
  26. 26.
    Rosenwasser RH, Armonda RA, Thomas JE, Benitez RP, Gannon PM, Harrop J. Therapeutic modalities for the management of cerebral vasospasm: timing of endovascular options. Neurosurgery 1999;44(5):975–979; discussion, 979–980.PubMedCrossRefGoogle Scholar
  27. 27.
    Mathis JM, DeNardo AJ, Thibault L, Jensen ME, Savory J, Dion JE. In vitro evaluation of papaverine hydrochloride incompatibilities: a simulation of intraarterial infusion for cerebral vasospasm. AJNR Am J Neuroradiol 1994;15(9):1665–1670.PubMedGoogle Scholar
  28. 28.
    Clouston JE, Numaguchi Y, Zoarski GH, Aldrich EF, Simard JM, Zitnay KM. Intraarterial papaverine infusion for cerebral vasospasm after subarachnoid hemorrhage. AJNR Am J Neuroradiol 1995;16(1):27–38.PubMedGoogle Scholar
  29. 29.
    Cross DT, 3rd, Moran CJ, Angtuaco EE, Milburn JM, Diringer MN, Dacey RG, Jr. Intracranial pressure monitoring during intraarterial papaverine infusion for cerebral vasospasm. AJNR Am J Neuroradiol 1998;19(7):1319–1323.PubMedGoogle Scholar
  30. 30.
    McAuliffe W, Townsend M, Eskridge JM, Newell DW, Grady MS, Winn HR. Intracranial pressure changes induced during papaverine infusion for treatment of vasospasm. J Neurosurg 1995;83(3):430–434.PubMedCrossRefGoogle Scholar
  31. 31.
    Fandino J, Schuknecht B, Yuksel C, Wieser HG, Valavanis A, Yonekawa Y. Clinical, angiographic, and sonographic findings after structured treatment of cerebral vasospasm and their relation to final outcomes. Acta Neurochir (Wien) 1999;141(7):677–690.CrossRefGoogle Scholar
  32. 32.
    Bevan JA, Bevan RD. Arterial wall changes in chronic cerebrovasospasm: in vitro and in vivo pharmacological evidence. Annu Rev Pharmacol Toxicol 1988;28:311–329.PubMedCrossRefGoogle Scholar
  33. 33.
    Vorkapic P, Bevan RD, Bevan JA. Longitudinal time course of reversible and irreversible components of chronic cerebrovasospasm of the rabbit basilar artery. J Neurosurg 1991;74(6):951–955.PubMedGoogle Scholar
  34. 34.
    Yonas H. Cerebral blood measurements in vasospasm. Neurosurg Clin N Am 1990;1(2):307–318.PubMedGoogle Scholar
  35. 35.
    Gado M, Eichling J, Grubb R, Phelps M, Raichie M, Ter-Pogossian MM. Appraisal of the angiographic circulation time as an index of cerebral blood flow. Radiology 1975;115(1):107–112.PubMedGoogle Scholar
  36. 36.
    Cronqvist S, Greitz T. Cerebral circulation time and cerebral blood flow. Acta Radiol Diagn (Stockh) 1969;8(4):296–304.Google Scholar
  37. 37.
    Greitz T. Normal cerebral circulation time as determined by carotid angiography with sodium and methylglucamine diatrizoate (Urografin). Acta Radiol Diagn (Stockh) 1968;7(4):331–336.Google Scholar
  38. 38.
    Greitz T, Cronqvist S. Angiographic evaluation of cerebral circulation time and regional cerebral blood flow. A comparative study. Scand J Clin Lab Invest Suppl 1968;102:XI:A.PubMedGoogle Scholar
  39. 39.
    Minami H, Kuwamura K, Tamaki N. Intraarterial infusion of papaverine and change of cerebral hemodynamics in symptomatic cerebral vasospasm. Kobe J Med Sci 2001;47(4):169–179.PubMedGoogle Scholar
  40. 40.
    Ohkuma H, Ogane K, Tanaka M, Suzuki S. Assessment of cerebral microcirculatory changes during cerebral vasospasm by analyzing cerebral circulation time on DSA images. Acta Neurochir Suppl 2001;77:127–130.PubMedGoogle Scholar
  41. 41.
    Ohkuma H, Manabe H, Tanaka M, Suzuki S. Impact of cerebral microcirculatory changes on cerebral blood flow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2000;31(7):1621–1627.PubMedGoogle Scholar
  42. 42.
    Iseda T, Nakano S, Yoneyama T, et al. Angiographic cerebral circulation time before and after endovascular therapy for symptomatic vasospasm. Clin Radiol 2000;55(9):679–683.PubMedCrossRefGoogle Scholar
  43. 43.
    Marks MP, Steinberg GK, Lane B. Intraarterial papaverine for the treatment of vasospasm. AJNR Am J Neuroradiol 1993;14(4):822–826.PubMedGoogle Scholar
  44. 44.
    Terent A, Ronquist G, Bergstrom K, Hallgren R, Aberg H. Ischemic edema in stroke. A parallel study with computed tomography and cerebrospinal fluid markers of disturbed brain cell metabolism. Stroke 1981;12(1):33–40.PubMedGoogle Scholar
  45. 45.
    Todd NV, Picozzi P, Crockard HA, Russell RR. Reperfusion after cerebral ischemia: influence of duration of ischemia. Stroke 1986;17(3):460–466.PubMedGoogle Scholar
  46. 46.
    Polin RS, Hansen CA, German P, Chadduck JB, Kassell NF. Intraarterially administered papaverine for the treatment of symptomatic cerebral vasospasm. Neurosurgery 1998;42(6):1256–1264; discussion 64–67.PubMedCrossRefGoogle Scholar
  47. 47.
    Hendrix LE, Dion JE, Jensen ME, Phillips CD, Newman SA. Papaverine-induced mydriasis. AJNR Am J Neuroradiol 1994;15(4):716–718.PubMedGoogle Scholar
  48. 48.
    Barr JD, Mathis JM, Horton JA. Transient severe brain stem depression during intraarterial papaverine infusion for cerebral vasospasm. AJNR Am J Neuroradiol 1994;15(4):719–723.PubMedGoogle Scholar
  49. 49.
    Mathis JM, DeNardo A, Jensen ME, Scott J, Dion JE. Transient neurologic events associated with intraarterial papaverine infusion for subarachnoid hemorrhage-induced vasospasm. AJNR Am J Neuroradiol 1994;15(9):1671–1674.PubMedGoogle Scholar
  50. 50.
    Carhuapoma JR, Qureshi AI, Tamargo RJ, Mathis JM, Hanley DF. Intra-arterial papaverine-induced seizures: case report and review of the literature. Surg Neurol 2001;56(3):159–163.PubMedCrossRefGoogle Scholar
  51. 51.
    Miller JA, Cross DT, Moran CJ, Dacey RG, Jr., McFarland JG, Diringer MN. Severe thrombocytopenia following intraarterial papaverine administration for treatment of vasospasm. J Neurosurg 1995;83(3):435–437.PubMedGoogle Scholar
  52. 52.
    Clyde BL, Firlik AD, Kaufmann AM, Spearman MP, Yonas H. Paradoxical aggravation of vasospasm with papaverine infusion following aneurysmal subarachnoid hemorrhage. Case report. J Neurosurg 1996;84(4):690–695.PubMedGoogle Scholar
  53. 53.
    Polin RS, Coenen VA, Hansen CA, et al. Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 2000;92(2):284–290.PubMedGoogle Scholar
  54. 54.
    Eskridge JM, McAuliffe W, Song JK, et al. Balloon angioplasty for the treatment of vasospasm: results of first 50 cases. Neurosurgery 1998;42(3):510–516; discussion 6–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Eskridge JM, Newell DW, Pendleton GA. Transluminal angioplasty for treatment of vasospasm. Neurosurg Clin N Am 1990;1(2):387–399.PubMedGoogle Scholar
  56. 56.
    Le Roux PD, Newell DW, Eskridge J, Mayberg MR, Winn HR. Severe symptomatic vasospasm: the role of immediate postoperative angioplasty. J Neurosurg 1994;80(2):224–229.PubMedGoogle Scholar
  57. 57.
    Zubkov YN, Nikiforov BM, Shustin VA. Balloon catheter technique for dilatation of constricted cerebral arteries after aneurysmal SAH. Acta Neurochir (Wien) 1984;70(1–2):65–79.CrossRefGoogle Scholar
  58. 58.
    Newell DW, Eskridge JM, Mayberg MR, Grady MS, Winn HR. Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg 1989;71(5 Pt 1):654–660.PubMedGoogle Scholar
  59. 59.
    Arakawa Y, Kikuta K, Hojo M, Goto Y, Ishii A, Yamagata S. Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: report of seven cases. Neurosurgery 2001;48(4):723–728; discussion, 728–730.PubMedCrossRefGoogle Scholar
  60. 60.
    Badjatia N, Topcuoglu MA, Pryor JC, et al. Preliminary experience with intra-arterial nicardipine as a treatment for cerebral vasospasm. AJNR Am J Neuroradiol 2004;25(5):819–826.PubMedGoogle Scholar
  61. 61.
    Feng L, Fitzsimmons BF, Young WL, et al. Intraarterially administered verapamil as adjunct therapy for cerebral vasospasm: safety and 2-year experience. AJNR Am J Neuroradiol 2002;23(8):1284–1290.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  1. 1.Department of NeurosurgeryUniversity of Utah School of MedicineSalt Lake City

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