J Neurosurg 77:848-852, 1992

Treatment of cerebral vasospasm with intra-arterial papaverine NEAL F. KASSELL,M.D., GREGORY HELM, M.D., NATHAN SIMMONS~B.S., C. DOUGLAS PHILLIPS, M.D., AND WAYNE S. CAIL, M.D.

Departments of Neurological Surgery and Radiology, University of Virginia Health Sciences Center, Charlottesville, Virginia ~" Cerebral vasospasm continues to be the leading treatable cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage. In this preliminary anecdotal series of 12 patients who were candidates for balloon angioplasty, vasospasm was treated instead with intra-arterial papaverine. Eight patients had marked angiographic reversal of the arterial narrowing following papaverine infusion, four of whom showed dramatic reversal of profound neurological deficits. Two patients deteriorated clinically 5 days after the initially successful papaverine infusions. In both, repeat angiography demonstrated severe recurrent vasospasm, which was partially reversed with a second intra-arterial papaverine treatment. Two patients developed focal neurological deficits during papaverine infusion, which resolved spontaneously over several hours after cessation of the intra-arterial infusion. Arterial narrowing in the posterior circulation and middle cerebral artery distribution appeared to be more responsive to papaverine infusion than was spasm in the anterior cerebral arteries. The infusion of 300 mg of papaverine over 1 hour seemed to be an adequate and safe dose to effect these angiographic and clinical improvements. KEY WORDS

9

cerebral vasospasm

LTHOUGH significant advances have been made in the treatment of cerebral vasospasm, the arterial narrowing that commonly occurs after subarachnoid hemorrhage (SAH) is still a leading cause of morbidity and mortality in patients with ruptured aneurysms? Hypertensive hypervolemic hemodilution therapy, 5 calcium channel blacking agents, ~~and early surgery with clot removal have all contributed to the decreased incidence and severity of vasospasm. 4 Balloon angioplasty has been used with dramatic success in certain patients with vasospasm in the larger cerebral vessels 23 but is not effective in dilating the distal arteries. In addition, there are significant risks associated with angioplasty, including occlusion or rupture of arteries and displacement of clips placed on aneurysm necks) 8 In an attempt to find a safer and more comprehensive method for dilating the narrowed vessels, we have infused papaverine into the cerebral arterial system. This technique was performed at the suggestion of T. Tsukahara (personal communication, 1990). We report our initial experience with intra-arterial infusion of papav-

A

848

9 papaverine

9 subarachnoid hemorrhage

erine in a small series of patients with profound angiographic vasospasm. Clinical Material and Methods

Patient Population Between December, 1990, and October, 1991, 12 patients with severe angiographic arterial narrowing secondary to aneurysmal SAH were treated at the University of Virginia with papaverine infused into the major cerebral arteries in an attempt to reverse the vasospasm. The characteristics of these patients are listed in Table 1. All were candidates for balloon angioplasty.

Treatment A Tracker-18 catheter and guidewire system* was advanced coaxially close to the involved vessels. Papav-

* Tracker- 18 catheter and guidewire system manufactured by Target Therapeutics, Inc., Los Angeles, California.

J. Neurosurg. / Volume 77/December, 1992

lntra-arterial papaverine for cerebral vasospasm TABLE 1

Characteristics of 12 patients before and after injection with papaverine* Modified GCS Scorer Case No.

I

2

3

Sex, Age (yrs)

Aneurysm Location

M, 66 ACoA rt PCoA, rt MCA, It PCoA F, 61 It ACoA car CA F, 40 ACoA

Days Vessels Post- in Spasm bleed

M, 48 vertebrobasilar (saccular)

After Papaverine

100/60

2T

5T

diffuse, severe diffuse, severe

none diffuse, severe

8 13

It MCA It MCA It ACA It ACA

It MCA It supraclinoid ICA II supraclinoid ICA rt supraclinoid ICA rt vertebral art

100/60 100/60

13 13

14 13

60/30

9T

9T

diffuse, severe diffuse, severe diffuse, severe diffuse, severe

diffuse, mild diffuse, mild focal, severe diffuse, severe

300/90

2T

5T

diffuse, severe

diffuse, mild

rt vertebral art It ICA

150/30 150/30

6T

10T

11

11

9T

9T

15

15

diffuse, moderate diffuse, moderate focal, mild focal, mild diffuse, severe

11 8T

11 8T

diffuse, moderate diffuse, moderate diffuse, severe diffuse, severe

14

14

diffuse, severe

6T

6T

9

10

diffuse, moderate none diffuse, moderate none diffuse, severe none

9

5

8

vertebrobasilar vertebrobasilar, It MCA It MCA It ACA rt MCA ACA MCA, It A~

7

8 9

F, 65 rt MCA F, 70 ACoA

10 6

It MCA It ACA rt ACA

10

F, 47 It PCoA

6

It MCA

11

F, 75 rt MCA, basilar tip F, 55 It PCoA, It AChA

5

rt MCA ACA It MCA

12

Before Papaverine

rt supraclinoid ICA

F, 46 It supraclinoid ICA F, 63 rt MCA, ACoA, basilar tip F, 43 It PCoA

6

Before After Papav- Papavefine erine

Angiographic Vasospasm

rt MCA rt ACA

10

5

Dose/Time (mg/min)

14

rt ACA 4

Vessel(s) Infused

5 5

7

70/30

It supraclinoid 300/60 ICA rt supraclinoid 300/42 ICA It supraclinoid 135/15 (infuICA sion terminated) It MCA 300/45 rt A~ atretic, It 0 art could not be catheterized It MCA 180/35 (infusion terminated) rt ICA 300/42 It supraclinoid carotid

300/45

diffuse, severe diffuse, mild diffuse, moderate diffuse, mild none diffuse, moderate none focal, mild none

diffuse, severe

* Abbreviations: ACoA = anterior communicating artery; PCoA = posterior communicating artery; MCA = middle cerebral artery; car CA = cavernous carotid artery; AChA = anterior choroidal artery; ICA = internal carotid artery; ACA = anterior cerebral artery; art = artery. t Glasgow Coma Scale score. T = intubated.

erine dissolved in normal saline was infused via a power injector through the microcatheter for a period of 30 to 60 minutes. The concentration of papaverine ranged from 100 to 300 mg/100 ml saline, and the total dose administered ranged from 100 to 300 mg. Eight patients had infusion into one vessel and two into two vessels; two others had the treatment repeated, both after an interval of 5 days (Table 1). The various doses and times of perliasion of papaverine reflect the evolution

TABLE 2

Grading scalefor cerebral vasospasm Grade

Definition

none mild

no change in vessel diameter < 50% reduction in vessel diameter

moderate severe

50% reduction in vessel diameter > 50% reduction in vessel diameter

of the protocol.

Evaluation of Vasospasm The pre- and postpapaverine infusion angiograms were graded by a blinded evaluator at the Central Registry of the Cooperative Aneurysm Study using the grading scale shown in Table 2. J. Neurosurg. / Volume 77/December, 1992

Results A ngiographic Arterial Narrowing P a p a v e r i n e w a s i n f u s e d i n t o a t o t a l o f 16 a r t e r i e s in 12 p a t i e n t s o n 14 o c c a s i o n s . I n e i g h t p a t i e n t s t h e r e w a s 849

N. F. Kassell, el al. following rupture of a vertebrobasilar junction aneurysm. Figure 2 demonstrates similar studies in a patient (Case 5) with diffuse vasospasm of the left anterior cerebral and middle cerebral arteries after rupture of a left supraclinoid internal carotid artery (ICA) aneurysm.

Clinical Condition Table 1 demonstrates the preinfusion neurological status of the 12 patients in comparison to their condition 1 hour after papaverine treatment, based on the modified Glasgow Coma Scale.l" Dramatic reversal of profound neurological deficits occurred in three patients and was associated with reversal of severe arterial narrowing in the appropriate vascular distribution.

Toxicity FI~. 1. Case 4. Left: Right vertebral angiogram, obtained before papaverine injection and 5 days following rupture of a vertebrobasilar aneurysm (arrow), demonstrating severe vasospasm of the vertebrobasilar system proximal and distal to the aneurysm (arrowheads). The left vertebral artery was hypoplastic. The patient showed clinical deterioration. Right. Right vertebral angiogram, obtained following infusion of 300 mg papaverine into the right vertebral artery, showing marked reduction in the arterial narrowing both proximal and distal to the aneurysm, which corresponded to a marked clinical improvement.

dramatic reversal of the angiographic vasospasm (Table 1). In several patients the maximum effect was not reached until 90 minutes postinfusion. Figure 1 demonstrates a pre- and postpapaverine angiogram in a patient (Case 4) with severe basilar artery vasospasm

No patient exhibited material reduction in systemic arterial pressure, nor were there any other adverse systemic events related to administration of papaverine. One patient (Case 7) developed decreased mental status and hemiparesis during treatment but returned to baseline after several hours. The etiology of this deterioration remains unclear. Another patient (Case 10) with mild preinfusion deficits had transient dilatation of the ipsilateral pupil during papaverine infusion. Papaverine treatment in both patients was discontinued as soon as these findings were noted.

Recurrence of Vasospasm In two patients (Cases 2 and 4) who had improvement in both clinical and angiographic vasospasm after papaverine infusion, there was recurrence of ischemie symptoms and arterial narrowing 5 days after the initial treatment. The vasospasm was confirmed angiographieally, and a further infusion of papaverine was given into the affected vessels. In each case there was marked improvement of the angiographic spasm after the second infusion.

Discussion

FIG. 2. Case 5. Left: Left carotid angiogram, obtained before papaverine injection and 8 days following rupture of a left supraclinoid internal carotid artery (ICA) aneurysm, demonstrating diffuse moderate vasospasm in the anterior and middle cerebral arteries. The patient developed dysphasia and right hemiparesis. Right: Left carotid angiogram, obtained after infusion of 300 mg papaverine into the left supraclinoid ICA, showing a marked reduction in the narrowing of the middle cerebral artery (arrowheads) and decreased filling in the anterior cerebral artery. The patient was clinically unchanged following papaverine infusion. 850

Papaverine is one of the strongest nonspecific vasodilator agents, 9 and was used as an early treatment for cerebral vasospasm following SAH. The low success rate in the early 1950's and 1960's was probably related to administration of the agent at the wrong time, and its use was generally abandoned. However, intracisternal administration of papaverine has been shown to reverse SAH-induced vasospasm in experimental animals': and in m a n / ' Intra-arterial administration of papaverine has also been shown to reverse experimental

t The modified Glasgow Coma Scale utilizes the worst motor score instead of the best motor score of the four extremities and is a better indicator of clinical deterioration or improvement in patients with cerebral vasospasm after SAH.

J. Neurosurg. / Volume 77 / December, 1992

Intra-arterial papaverine for cerebral vasospasm cerebral v a s o s p a s m / I n addition, papaverine has been used to reverse acute arterial spasm occurring in peripheral vessels during angiography. The package insert for papaverine~ states, "Papaverine relaxes the smooth musculature of the larger blood vessels, including the coronary, cerebral, peripheral, and pulmonary arteries. This action is particularly evident when such vessels are in spasm." This was the foundation for our attempts to use papaverine infusion as an alternative to balloon angioplasty. Papaverine was administered through a microcatheter as close as possible to the narrowed arteries. The close of papaverine was selected empirically. The initial attempt was with 100 mg diluted in 100 cc of saline and administered over a 30-minute period. The total dose and duration of administration were progressively increased when no response was seen initially and no adverse effects occurred. In several of the patients no appreciable change in arterial diameter was noted over the first 30 to 60 minutes of infusion, but then fairly dramatic dilatation occurred in the last 30 minutes. The optimum dose and duration of infusion remains to be determined, although 300 mg/100 cc infused over 60 minutes appears to be adequate and safe. In certain patients the papaverine treatment was dramatically effective, while in others it was totally ineffective. The reasons for this are unclear. One possibility is that, as suggested by Vorkapic, et al., ~3 vasospasm has a papaverine-sensitive phase, during which papaverine infusion quickly and completely reverses cerebral vasospasm, and a papaverine-resistant phase, when the arterial wall becomes stiff and unresponsive. However, this hypothesis is inconsistent with the natural history of vasospasm, in which the arterial narrowing resolves spontaneously in a relatively short time. In addition, two patients whose angiographic vasospasm was successfully treated with papaverine had recurrence of arterial narrowing 5 days after treatment, which in both cases responded to reinfusion of papaverine. A second possibility is that the patients who failed to respond to papaverine treatment received an inadequate dose and/or inadequate duration of administration. Obviously, papaverine can only work on vessels where it is delivered by flowing blood; it will not be as effective, for example, in a case of anterior cerebral artery spasm with a normal middle cerebral artery since the blood flow preferentially delivers papaverine infused into the ICA to the middle cerebral artery territory. This problem could be circumvented by transiently occluding the middle cerebral artery with a balloon and infusing papaverine in the more proximal ICA. Furthermore, uncertainty exists as to the duration of the dilatation resulting from papaverine infusion. In at least two patients, arterial narrowing recurred but was responsive to further papaverine administration. It is

Papaverine produced by Eli Lilly Co., Indianapolis, Indiana. J. Neurosurg. / Volume 77 / December, 1992

possible that multiple intermittent infusions or constant long-term infusion of papaverine can be utilized in patients with severe arterial narrowing when the effect of the initial treatment is transient. The papaverine treatment was intended to replace balloon angioplasty. Balloon angioplasty has achieved widespread use and is dramatically effective in certain patients. 2'3 In patients with recurrent vasospasm following balloon dilatation, angioplasty can be successfully repeated. However, balloon angioplasty is associated with significant risks. Occlusion of major cerebral arteries, bursting of arteries by the balloon, and displacement of clips off aneurysm necks have all been reported. 6'8 The overall safety and effectiveness of balloon angioplasty has never been rigorously documented. The anecdotal experience we present regarding the use of intra-arterial papaverine provides sufficient suggestive evidence about its effectiveness to warrant further investigation.

Conclusions

Intra-arterial papaverine is a theoretically attractive modality for treating severe vasospasm. The results of this preliminary anecdotal series suggest that this approach is at least partially effective. Although there is adequate suggestive evidence to warrant further investigation, we caution against the widespread adoption of this modality until the safety and efficacy of this approach have been conclusively demonstrated.

References

1. Bevan JA, Bevan RD: Arterial wall changes in chronic cerebrovasospasm: in vitro and in vivo pharmacological evidence. Annu Rev Pharmacol Toxicol 28:311-339, 1988 2. Brothers MF, Holgate RC: Intracranial angioplasty for treatment of vasospasm after subarachnoid hemorrhage: technique and modifications to improve branch access. AJNR 11:239-247, 1990 3. Dion JE, Duckwiler GR, Vifiuela F, et al: Pre-operative micro-angioplasty of refractory vasospasm secondary to subarachnoid hemorrhage. Neuroradiology 32:232-236, 1990 4. Handa Y, Weir BKA, Nosko M, et al: The effect of timing of clot removal on chronic vasospasm in a primate model. J Neurosurg 67:558-564, 1987 5. Kassell NF, Peerless SJ, Durward Q J, et al: Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Nearosurgery 11:337-343, 1982 6. Kassell NF, Shaffrey ME, Shaffrey CI: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage, in Apuzzo M (ed): Brain Surgery: Complication Avoidance and Management. New York: Churchill Livingstone (In press) 7. Kuwayama A, Zervas NT, Shintani A, et al: Papaverine hydrochloride and experimental hemorrhagic cerebral arterial spasm. Stroke 3:27-33, 1972 8. Newell DW, Eskridge JM, Mayberg MR, et al: Angioplasty for the treatment of symptomatic vasospasm 851

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following subarachnoid hemorrhage. J Neurosurg 71: 654-660, 1989 Pal J: Das papavefin als Gef~issmittelund An/istheticum. Dtsch Med Wochenschr 40:164-168, 19 l 4 Pickard JD, Murray GD, lllingworth R, et al: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British Aneurysm Nimodipine Trial. Br Med J 298:636-642, 1989 SegawaH, Saito I, Okada T, et al: Efficacyof intracisternal papaverine on symptomatic vasospasm. Neurol Surg 14: 847-854, 1986 Vollmer DG, Jane JS, Torner JC, et al: lntracisternal papaverine reverses experimental cerebral vasospasm in a rabbit model, in Wilkins RH (ed): Cerebral Vasospasm. New York: Raven Press, 1988, pp 425-433

13. Vorkapic P, Bevan RD, Bevan JA: Longitudinal time course of reversible and irreversible components of chronic cerebrovasospasm of the rabbit basilar artery. J Neurosurg 74:951-955, 1991

Manuscript received March 10, 1992. This paper was presented in part at the Annual Meetings of the Congress of Neurological Surgeons, Orlando, Florida, 1991, and the American Association of Neurological Surgeons, New Orleans, Louisiana, 1991. Address reprint requests to: Neal F. Kassell, M.D., Department of Neurosurgery, University of Virginia, Box 212, Charlottesville, Virginia 22908.

J. Neurosurg. / Volume 77/December, 1992

Treatment of cerebral vasospasm with intra-arterial papaverine.

Cerebral vasospasm continues to be the leading treatable cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage. In this prelim...
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