J Neurosurg 84:690–695, 1996

Paradoxical aggravation of vasospasm with papaverine
infusion following aneurysmal subarachnoid hemorrhage
Case report
BRENT L. CLYDE, M.D., ANDREW D. FIRLIK, M.D.,
ANTHONY M. KAUFMANN, B.SC.(MED), M.D., F.R.C.S.(C), MICHAEL P. SPEARMAN, M.D.,
AND HOWARD YONAS, M.D.
Departments of Neurological Surgery and Radiology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania
U Reports of intraarterial papaverine infusion as treatment for cerebral vasospasm are few and documented complications
are uncommon. The authors report the case of a patient with paradoxical aggravation of cerebral arterial narrowing during
selective intraarterial papaverine infusion intended to treat vasospasm following aneurysmal subarachnoid hemorrhage
(SAH). A 48-year-old man presented to the authors’ service with symptomatic vasospasm 10 days after experiencing an
SAH. The ruptured anterior communicating artery aneurysm was surgically obliterated the following day, and thereafter
maximum hypervolemic and hypertensive therapies were used. However, the patient remained lethargic, and a stable
xenon–computerized tomography (CT) cerebral blood flow (CBF) study revealed CBF to be 15 cc/100 g/minute in the left
anterior cerebral artery (ACA) and 25 cc/100 g/minute in the right ACA territories. Cerebral arteriography demonstrated
diffuse severe left ACA and mild left middle cerebral artery (MCA) vasospasm. In response intraarterial papaverine was
infused into the internal carotid artery just proximal to the ophthalmic artery. During the infusion the patient became aphasic and exhibited right hemiplegia. Arteriography performed immediately after the intraarterial papaverine infusion
revealed diffuse exacerbation of vasospasm in the distal ACA and MCA territories. A repeat xenon–CT CBF study showed
that CBF in the left ACA and the MCA had drastically decreased (2 cc/100 g/minute and 10 cc/100 g/minute, respectively). Despite aggressive management, infarction ultimately developed.
This is the first clinical case to illustrate a paradoxical effect of intraarterial papaverine treatment for vasospasm following aneurysmal SAH. The possible mechanisms of this paradoxical response and potential therapeutic reactions are
reviewed.

KEY WORDS • cerebral vasospasm • papaverine • subarachnoid hemorrhage •
drug reaction • angiography

C

EREBRAL vasospasm remains a leading cause of

morbidity and mortality following aneurysmal
subarachnoid hemorrhage (SAH). Recent advances, including early surgery,19,20,35,40 hypervolemic3,18,
31,38,45
and hypertensive therapies,3,7,18,21 and nimodipine
administration,1,12,43 have reduced the incidence of symptomatic vasospasm. More aggressive endovascular interventions have been reserved for refractory vasospasm.
Balloon angioplasty may be effective for larger proximal
arteries;4,9 however, it cannot be applied to small-caliber
distal cerebral vessels or severely narrowed spastic segments. Experimental use of intraarterial papaverine for
cerebral vasospasm was first reported in the 1970s.2,23
Since the initial reports of selective intraarterial cerebral
papaverine infusion in humans, published by Kassell,
et al.,17 and Kaku, et al.,16 a total of 67 patients have
reportedly been treated with this agent for cerebral
vasospasm following aneurysmal SAH.5,8,15–17,24–26,29,33,46
Only 10 complications have been recorded in these 67
patients: transient decreased mental status with hemipare690

sis (one patient),17 transient brainstem depression (four
patients),5,26 seizure,8 monocular blindness secondary to
orbital infarction,8 thrombocytopenia,33 bradycardia/heart
block,29 and parenchymal hemorrhage (one patient
each).29 None of these complications was attributed to aggravated vasospasm. In addition, two patients had ipsilateral pupillary dilation, which may represent a transient
direct action of papaverine on pupillary smooth muscle.37
Jin and colleagues14 recently reported a dose-dependent
aggravation of phorbol dibutyrate–induced microvascular
constriction in vitro in rat brain slices with papaverine.
Aggravated microvascular vasospasm following papaverine infusion may explain the common observation of a
lack of correlation between angiographic and clinical
benefit after intraarterial papaverine infusion.8,14,17 The
present case represents a possible clinical correlate to
those laboratory and clinical findings in which intraarterial papaverine treatment may lead to a paradoxical aggravation of vasospasm following SAH.
J. Neurosurg. / Volume 84 / April, 1996

Aggravation of vasospasm with papaverine

FIG. 1. Left: Coronal T1-weighted magnetic resonance (MR)
image on postbleed Day 9 displaying subacute interhemispheric
blood. Right: Coronal MR angiogram showing anterior communicating artery aneurysm and interhemispheric blood.

Case Report
This 48-year-old right-handed man with a history of
alcohol abuse presented to a community emergency department with a sudden severe headache, transient loss of
consciousness, and epileptiform movements. No computerized tomography (CT) scan or lumbar puncture was
performed on initial evaluation and the episode was attributed to alcohol intoxication. The patient was discharged
home and remained lethargic. Nine days after the initial
event he developed urinary incontinence and right leg
weakness. On return to the emergency department he
demonstrated right leg paresis and a right pronator drift
with no cranial nerve deficits. A CT scan was reported
to be normal and lumbar puncture was performed. Xanthochromia was present and the cerebrospinal fluid contained 4200 red blood cells and 92 white blood cells per
high-power field. The patient was admitted to a medical
service and magnetic resonance (MR) imaging was obtained, which demonstrated an anterior communicating
artery (ACoA) aneurysm surrounded by interhemispheric
blood (Fig. 1) and an established small medial left frontal
infarct. The following day, 10 days after the initial ictus,
cerebral angiography further delineated the ACoA aneurysm and demonstrated severe vasospasm involving both
A2 branches (Fig. 2).
Examination and Preliminary Treatment. The patient was
transferred to our neurosurgical service. He awoke easily
to voice, was oriented, and paretic on the right side with
4/5 motor strength. To facilitate aggressive vasospasm
management and protect the patient from further rebleeding, the decision was made to perform surgery, which
resulted in clip obliteration of the ACoA aneurysm 11
days after the initial event. After the operation the patient
remained intubated, but was awake, followed commands,
and had 4/5 right motor strength, unchanged from preoperative status. An immediate postoperative xenon–CT
cerebral blood flow (CBF) study was performed to assess
perfusion in light of the patient’s significant preoperative
vasospasm. This study showed greater hypoperfusion
in the left than in the right ACA territories (10 cc/100
g/minute and 18 cc/100 g/minute, respectively, calculated
by averaging all regions of interest in the ACA territory on
three CT slices). Hypervolemic and hypertensive therapies were maximally advanced and a repeat xenon–CT
CBF study made 4 hours later showed modest, though
inadequate, augmentation of CBF in the left (15 cc/100 g/
J. Neurosurg. / Volume 84 / April, 1996

FIG. 2. Anteroposterior (left) and lateral (right) preoperative angiograms obtained on postbleed Day 10 demonstrating anterior
communicating artery aneurysm and significant anterior cerebral
artery vasospasm, affecting primarily the A2 segments, with the left
segment affected more than the right.

minute) and right (25 cc/100 g/minute) distal ACA territories (Fig. 3 center).
The patient underwent angiography, which showed persistent vasospasm (Fig. 4 left). The patient’s ongoing neurological deficit, which was associated with quantitative
CBF reduction and corresponding cerebral vasospasm, led
to the decision to initiate endovascular treatment.
Papaverine Infusion. A Tracker 18 microcatheter was introduced through a base catheter and a guidewire was
advanced easily into the left A2 segment. However, multiple attempts at selective catheterization of the left ACA
with various wires and catheters were unsuccessful and,
therefore, papaverine was instilled by constant infusion
into the internal carotid artery (ICA) just proximal to the
ophthalmic artery. Although no systemic heparin administration was used, small amounts of 6000 U/L heparin flush
were slowly infused through the base catheter. No heparin
was infused through the Tracker microcatheter. After 25
minutes of constant infusion of 300 mg papaverine (0.3%)
and 100 cc normal saline at 4 cc/minute (300 mg total), the
patient became aphasic and exhibited right hemiplegia.
Postinfusion Examination. Papaverine infusion was
stopped and immediate repeat angiography showed that,
although vasodilation of the supraclinoid ICA, and A1 and
M1 segments was achieved, new severe distal left middle
cerebral artery (MCA) vasospasm had developed (Fig.
4 center and right). No alternative intraarterial dilating
agents were used, in part because they were not immediately available and also because in our experience nitroglycerin infusions for vasospasm had not been effective in
previously treated patients. An immediate xenon–CT CBF
study demonstrated severe hypoperfusion in the left ACA
(2 cc/100 g/minute) and MCA (10 cc/100 g/minute) distributions (Fig. 3 lower), although CT scans showed no
infarction (Fig. 3 upper). Despite aggressive medical therapies, a subsequent CT scan confirmed the development
of infarction in the left ACA and MCA territories (Fig. 5).
The patient made no recovery from his deficits and was
later transferred to a nursing care facility.
Discussion
Papaverine has long been known to relax smooth muscle in a nonspecific manner and has thus been used for
its vasodilating capabilities. It is thought to act by inhibit691

B. L. Clyde, et al.

FIG. 3. Plain computerized tomography (CT) scans obtained after papaverine infusion (upper), prepapaverine stable
xenon–CT cerebral blood flow map (center), and immediate postpapaverine blood flow map (lower). Scale is cc/100
g/minute. Average blood flow in a given vascular territory was calculated by averaging the flow values for all regions of
interest in a given vascular territory over all three scanning slices. Prepapaverine blood flow values are 15 cc/100
g/minute in the left and 25 cc/100 g/minute in the right anterior cerebral arteries (ACAs); postpapaverine blood flows are
2 cc/100 g/minute in the left ACA and 10 cc/100 g/minute in the middle cerebral artery.

ing phosphodiesterase and elevating intracellular levels
of cyclic adenosine monophosphate. Papaverine was first
used in neurological disease to treat ischemic occlusive
cerebrovascular conditions, including stroke and hypertensive encephalopathy.30,32,39 Subsequent work focused
on the potential benefits of using papaverine in treating
vasospasm following aneurysmal SAH. To obtain a more

692

potent local effect, early experimental studies utilized an
intrathecal route of papaverine administration,34 in some
cases using a sustained release preparation for longer
effect.13 Others have used postoperative intrathecal–
intracisternal papaverine.42 Recently, interest in papaverine has focused on selective intraarterial infusions in
the acute management of vasospasm after less aggressive

J. Neurosurg. / Volume 84 / April, 1996

Aggravation of vasospasm with papaverine

FIG. 4. Cerebral angiograms obtained on postbleed Day 12 and postoperative Day 1. Prepapaverine anteroposterior
projection (left) demonstrating aneurysm clip obliteration as well as mild A1 and M1 vasospasm and severe A2 narrowing
with the left A2 segment more affected than the right. After 300 mg of papaverine was infused into the distal left internal carotid artery, the patient became aphasic and hemiplegic. Immediate repeat anteroposterior (center) and lateral
(right) angiograms demonstrating some dilation of A1, M1, and M2 arteries with paradoxical aggravation of vasospasm
in the left A2 and M3 branches.

therapies have failed. To date, only four series with 10 or
more patients8,16,17,29 and several small series or case reports have been published.5,15,24–26,33,46 In total, 67 cases
have been reported with 10 complications (Table 1). This
excludes two patients with ipsilateral pupillary dilation,
which is probably a direct effect of papaverine on pupillary smooth muscle.
The present finding of paradoxical aggravation of vasospasm during intraarterial papaverine treatment has not
previously been reported. However, the complications
that have been reported—brainstem depression following
vertebrobasilar infusions, seizures, monocular blindness,
and hemiparesis with decreased mental status—may have
occurred as a result of aggravated vasospasm (Table 1).
Four of these patients underwent immediate arteriography
after exhibiting the complication (one patient with monocular blindness and three with brainstem depression); the
arteriograms showed no exacerbated vasospasm. Three
other patients did not have immediate follow-up arteriography, leaving the possibility of exacerbated vasospasm in
those cases unresolved. However, even if postpapaverine
arteriography is performed, the possibility of aggravated
vasospasm in small distal vessels below the resolution of
angiography cannot be excluded. Recent in vitro experiments indicate that paradoxical vasoconstriction as a response to papaverine infusion may occur in microvessels
after activation of protein kinase C. The activation of protein kinase C is thought to mediate vasoconstriction in
chronic vasospasm following aneurysmal SAH,28 and in
a study by Jin, et al.,14 papaverine was found to elicit a
dose-dependent exacerbation of protein kinase C–induced
vasospasm in the microvessels. The present case represents the first evidence that papaverine-induced vasoconstriction may also occur in larger distal vessels (Fig. 4 center and right).
Papaverine has also been used extensively in other systemic vascular beds for problems such as coronary spasm
and impotence. An exhaustive literature review yielded
no references to a paradoxical vasoconstrictive action of
papaverine in these or other vascular beds. However, the
cerebral circulation is unique in its reaction to drugs and
exposure to aneurysmal SAH. For example, it is difficult
to explain the lack of clinical benefit in patients with
cerebral vasospasm that responds angiographically with
J. Neurosurg. / Volume 84 / April, 1996

vasodilation following intraarterial papaverine treatment.
Kassell, et al.,17 reported that 60% of patients treated with
papaverine who had angiographic improvement in vasospasm had no clinical benefit, and Clouston, et al.,8 noted
that 50% of patients had no clinical benefit despite angiographic improvement. A more recent study demonstrated
that only 52% of patients had objective clinical improvement despite a 76% rate of angiographic improvement.29
Although some of the patients in these cases may have
sustained an irreversible ischemic injury prior to papaverine administration, these clinical and experimental findings indicate a possible paradoxical effect of papaverine
at the microvascular level, which may account for the lack
of ischemia reversal despite successful large vessel vasodilation.
Other potential etiologies of vasoconstriction during selective intraarterial papaverine treatment must also be
considered. Coronary vasospasm has been reported in two
patients following contrast infusion during cardiac angiography.41 This is an unusual finding and has been at least
partially attributed to an anaphylactoid reaction with release of histamine, because both patients demonstrated
systemic signs of anaphylaxis, including urticaria and hy-

FIG. 5. Computerized tomography scan obtained 24 hours after
left internal carotid artery papaverine infusion showing left anterior cerebral and middle cerebral arteries territory infarction.

693

B. L. Clyde, et al.
potension. Our patient did not exhibit allergic signs during
angiography and the onset of his symptoms occurred only
during the intraarterial papaverine treatment. It is also
unlikely that contrast material aggravated vasospasm in
our patient because he had undergone previous cerebral
angiography on two occasions without sequelae. Studies
of the effect of radiographic contrast material on peripheral and renal vessels indicate no arterial vasoconstrictive
action exists in these vascular beds,22,44 and no cases of
radiographic contrast–induced vasoconstriction in the
cerebrovascular system have been reported during angiography. Therefore, it is unlikely that the aggravated vasospasm in this case was contrast related. It may be possible
that preservatives mixed with the papaverine, rather than
the papaverine itself, caused the distal vessel narrowing
in our patient. Papaverine has one supplier (Eli Lilly and
Company, Indianapolis, IN) and has only one preservative
(edetate disodium, 0.005%) mixed with it. Because papaverine is only supplied in this form and because other
reports of exacerbated vasospasm with papaverine do not
exist, it is difficult to distinguish which substance may be
the causative agent.
Precipitation of papaverine in solution may also account for some of the reported complications. An early
report notes thrombotic occlusion of the subclavian artery
after angiography using Isovue 370 followed by papaverine infusion.36 This was thought to be related to concomitant heparin use as noted in a subsequent letter.10 An
indepth study of the compatibility of papaverine with various solutions showed that the drug at high concentrations
(3.0%) will crystallize with as little as 2000 U/L heparin,
but at lower concentrations, such as those used in the cerebrovascular system (0.3%), does not crystallize even in
10,000 U/L heparin. No incompatibilities were found with
contrast agents or saline. However, a fine layer of precipitate formed when 0.3% papaverine was added to serum,
which rapidly dissolved as more serum was added.27 This
indicates that papaverine should be infused slowly and at
low concentrations (0.3% or less) to allow adequate dilution in serum and prevent precipitation. The precipitation
risk was minimized in our patient by using a 0.3% papaverine solution at a slow infusion rate, which has been
described by other authors without angiographically documented embolic events.5,8,17,25–27,29,33 Our postpapaverine
cerebral angiogram demonstrates significant narrowing of
the M3 branches without “cropping” secondary to distal
embolic obstruction (Fig. 4 center and right). We believe
that the significant M3 vessel narrowing in our patient represents vasospasm and is not consistent with embolic phenomena.
Finally, catheter-induced vascular spasm can also occur
with cerebrovascular angiography or endovascular interventions. Flow-induced vascular relaxation has been demonstrated in several studies, with the mechanism probably
involving second messengers and not simply physical
forces.6,11 The introduction of microcatheters into distal
branches in the cerebrovascular system is known to cause
spasm in some patients and may be a result of decreased
flow through these segments, which diminishes flow-induced relaxation. The aggravated vasospastic segments in
the present case involved primarily distal MCA vessels
that were never catheterized. Although the left ACA underwent repeated attempts at catheterization, no spasm
around the region of the catheter tip in the ICA was seen
694

on angiography (Fig. 4). It is unlikely that the catheter
positioned in the ICA resulted in significant flow reduction. Therefore, the appearance of paradoxical aggravation of vasospasm in our patient was probably not flow
related or due to catheter or flow-induced vasospasm.
Conclusions
Selective intraarterial papaverine infusion may be an
effective treatment for vasospasm following aneurysmal
SAH, although reports of the efficacy of this therapeutic
modality are still few and reported complications uncommon. The papaverine-induced aggravation of vasospasm
that we encountered has not been reported previously, and
it may be the clinical correlate of microvascular vasoconstriction demonstrated in the laboratory.14 This mechanism
may explain other previously reported complications as
well as the preponderance of complications encountered
in vertebrobasilar infusions in which very small microvascular territories control vital functions, which become
clinically evident when compromised.
The absolute indications for use of intraarterial papaverine infusion have not been fully defined, although
integration of clinical, quantitative CBF, and angiography
data will aid in the selection of patients at greatest risk for
subsequent infarction without further intervention. When
distal cerebral vasospasm is present, beyond the reach of
angioplasty catheters, intraarterial papaverine treatment is
presently one of the few available alternative treatments
of refractory vasospasm. Aggressive attempts at selective
catheterization of affected territories should be undertaken to limit the amount of vascular territory exposed to
potential complications of papaverine infusion. Intraarterial papaverine should be administered in dilute solutions at slow rates.
If adverse effects occur, cessation of infusion should
be immediately followed by arteriography. Although no
effective alternative treatment has been established, consideration of angiotensin and/or nitroglycerin infusions
may be warranted, albeit not supported by clinical experience. Ideally, more effective and safer intraarterial agents
will be developed for treatment of patients with refractory
symptomatic vasospasm.
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Manuscript received February 9, 1995.
Accepted in final form October 24, 1995.
Address reprint requests to: Brent L. Clyde, M.D., Department of
Neurological Surgery, University of Pittsburgh Medical Center,
Suite B-400 PUH, 200 Lothrop Street, Pittsburgh, Pennsylvania
15213.

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