Firlik AD, Kaufmann AM, Jungreis CA, Yonas H. The effect of transluminal angioplasty on cerebral blood flow in the manage- ment of symptomatic vasospasm ...
Commentary Infusing Doubt into the Efficacy of Papaverine David F. Kallmes, Clinical Instructor, Radiology, Mary E. Jensen, Assistant Professor of Radiology and Neurosurgery, and Jacques E. Dion, Professor of Radiology and Neurosurgery, University of Virginia, Charlottesville
Since the first report, in 1984 by Zubkov (1), of the use of intracranial balloon angioplasty for subarachnoid hemorrhage–induced cerebral vasospasm, endovascular techniques have gained acceptance as valuable therapies in the treatment of vasospasm resistant to conventional therapies (2– 6). Although angioplasty and intraarterial papaverine infusion are both used by many practitioners, the role of angioplasty seems better defined than that of papaverine. This likely relates to a perception that the risk:benefit ratio of angioplasty is more favorable than that of papaverine. Granted, the risks of angioplasty, which include vessel perforation, can be serious. However, the benefit of angioplasty has been documented through clinical and angiographic response as well as by single-photon emission computed tomography and quantitative cerebral blood flow measurement (2, 6, 7). Furthermore, the effect of angioplasty on vessel diameter is usually permanent (2). The risk:benefit ratio of papaverine therapy has been difficult to establish; both the reliability and the durability of papaverine-induced vessel dilation appears less certain than that typically achieved with angioplasty. Indeed, the reported frequency of clinical response to papaverine has been as low as 25% (4). Improved understanding of the factors that govern a vessel’s response to papaverine infusion would allow better stratification of the expected utility of the treatment, which in turn would allow better definition of the drug’s risk:benefit ratio. Studies in multiple animal models have suggested that the response of a spastic vessel to the vasodilatory effects of papaverine depends on the duration of the spasm (8 –10). Using a rabbit model of cerebralvasospasm, Vorkapic et al (10) showed that the response to papaverine was excellent over the first 3 days after induction of vasospasm, but that a progressive de-
cline in responsiveness to papaverine was noted from day 3 until day 9 after spasm induction. Macdonald et al (8), using a canine model, showed diminished response to papaverine 10 to 14 days after induction of vasospasm, compared to 4 to 7 days after induction. These data suggest that the pathophysiology of arterial narrowing early in vasospasm consists of smooth muscle contraction; later, the vessel narrowing probably results from arterial wall fibrosis, edema, inflammation, or intimal proliferation (8). The study by Fujiwara et al (11) in this issue of AJNR adds further experimental evidence not only that the response of vasospasm to papaverine is transient but also that it declines with increasing duration of vasospasm. These authors present a well-conceived experiment to address both issues. Although the number of animals is small, there is little variation in results among the subjects. Furthermore, the histologic sections add further evidence that morphologic changes within the vessel wall increase with increasing duration of vasospasm. It is unfortunate, however, that repeat lumen measurements could not be carried out 24 hours after papaverine infusion, and that the transient effect of papaverine was shown only by transcranial Doppler. The major drawback of the study under consideration is that, like most previous animal studies, attention was focused on large, proximal arteries rather than smaller, distal arteries (11). In clinical practice proximal vasospasm is treated by balloon angioplasty. Papaverine therapy for proximal spasm is instituted only when angioplasty is not technically feasible. The primary role for papaverine is in treating distal vessels beyond the reach of angioplasty. These distal vessels were not evaluated with either angiography or histologic analysis in the study by Fujiwara et al (11). Morphologic changes noted
Address reprint requests to Jacques E. Dion, MD, Department of Radiology, Room 1815, Box 170, Lee Street, Charlottesville, VA 22908. Index terms: Drugs, intraarterial infusion; Papaverine; Animal studies; Commentaries AJNR 18:263–264, Feb 1997 0195-6108/97/1802–0263
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in large, proximal vessels do not necessarily reflect what is occurring in smaller, distal vessels. Indeed, Bevan et al (9) showed in monkeys that 6 days after spasm induction, proximal vessels were narrowed by an inflammatory response while distal vessels were narrowed by increased vascular tone, which may respond favorably to papaverine. Should one conclude, based on the animal data, that the benefits of papaverine therapy will be transient and limited only to spasm occurring early after subarachnoid hemorrhage? Probably not, because clinical data do not necessarily corroborate the experimental data. Granted, an early clinical report suggested that early vasospasm might be more responsive than late spasm to the effects of papaverine (5). However, that report was based on only two patients. Multiple subsequent series have shown no difference in the time after subarachnoid hemorrhage between groups of patients who did and did not respond to papaverine (3, 4, 7, 12). Also, Kassell et al (4) noted excellent responses to papaverine in two patients treated again 5 days after initial papaverine therapy. Furthermore, a recent series noted no evidence for recurrent spasm among early responders, suggesting that even though the pharmacologic duration of action of papaverine is relatively short, prolonged clinical response is achievable (12). Therefore, even though mounting experimental evidence suggests that changes occur within the spastic vessel walls that should be unresponsive to pharmacologic therapy, papaverine remains an acceptable therapy in selected patients. There is much yet to be understood about the mechanism of action of papaverine. For instance, it is not clear why the rate of clinical response to papaverine is only one half that of the angiographic response in most series (4, 12, 13). Also, the spectrum of potential adverse reaction is broad, including transient neurologic dysfunction, increased intracranial pressure, mydriasis, precipitation of the drug from solution, and, according to a recent report, paradoxical aggravation of vasospasm in response to papaverine (13–17). Even so, in our practice the routine use of papaverine remains an adjunct to balloon angioplasty in the treatment of refractory vasospasm.
AJNR: 18, February 1997
References 1. Zubkov YN, Nikiforov BM, Shustin VA. Balloon catheter technique for dilatation of constricted cerebral arteries after aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 1984;70:65–79 2. Newell DW, Eskridge JL, Mayberg MR, Grady MS, Winn HR. Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg 1989;71:654 – 660 3. 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; 77:842– 847 4. Kassell NF, Helm GA, Simmons N, Phillips CD, Cail WS. Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 1992;77:848 – 852 5. Marks MP, Steinberg GK, Lane B. Intraarterial papaverine for the treatment of vasospasm. AJNR Am J Neuroradiol 1993;14:822– 826 6. Lewis DH, Eskridge JM, Newell DW, et al. Brain SPECT and the effect of cerebral angioplasty in delayed ischemia due to vasospasm. J Nucl Med 1992;33:1789 –1796 7. Firlik AD, Kaufmann AM, Jungreis CA, Yonas H. The effect of transluminal angioplasty on cerebral blood flow in the management of symptomatic vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg (In press) 8. Macdonald RL, Zhang J, Siona B, Johns L. Papaverine sensitive vasospasm and arterial contractibility and compliance after subarachnoid hemorrhage in dogs. Neurosurgery 1995;37:962–967 9. Bevan JA, Bevan RD, Frazee JG. Functional arterial changes in chronic cerebrovasospasm in monkeys: an in vitro assessment of the contribution to arterial narrowing. Stroke 1987;18:472– 481 10. Vorkapic D, Beran RD, Bevan JA. Pharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits associated with functional damage. Stroke 1990;21:1478 –1484 11. Fujiwara N, Honjo Y, Ohkawa M, et al. Intraarterial infusion of papaverine in experimental cerebral vasospasm. AJNR Am J Neuroradiol 1997;18:255–262 12. 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;16:27–38 13. McAuliffe W, Townsend M, Eskridge JM, Newell DW, Grady SM, Winn HR. Intracranial pressure changes induced during papaverine infusion for treatment of vasospasm. J Neurosurg 1995;83: 430 – 434 14. Mathis JM, DeNardo AJ, Jensen ME, Scott J, Dion JE. Transient neurologic events associated with intraarterial papaverine infusion for subarachnoid hemorrhage-induced vasospasm. AJNR Am J Neuroradiol 1994;15:1671–1674 15. Hendrix LE, Dion JE, Jensen ME, Phillips CD, Newman SA. Papaverine-induced mydriasis. AJNR Am J Neuroradiol 1994;15: 716 –718 16. 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;15:1665–1670 17. 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;84:690 – 695
