Intra-arterial nicardipine infusion improves CT perfusion-measured cerebral blood flow in patients with subarachnoid hemorrhage-induced vasospasm.
ABSTRACT Our aim was to determine the effects of intra-arterial (IA) nicardipine infusion on the cerebral hemodynamics of patients with aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm by using first-pass quantitative cine CT perfusion (CTP).
Six patients post-aSAH with clinical and transcranial Doppler findings suggestive of vasospasm were evaluated by CT angiography and CTP immediately before angiography for possible vasospasm treatment. CTP was repeated immediately following IA nicardipine infusion. Maps of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were constructed and analyzed in a blinded manner. Corresponding regions of interest on these maps from the bilateral middle cerebral artery territories and, when appropriate, the bilateral anterior or posterior cerebral artery territories, were selected from the pre- and posttreatment scans. Normalized values were compared by repeated measures analysis of variance.
Angiographic vasospasm was confirmed in all patients. In 5 of the 6 patients, both CBF and MTT improved significantly in affected regions in response to nicardipine therapy (mean increase in CBF, 41 +/- 43%; range, -9%-162%, P = .0004; mean decrease in MTT, 26 +/- 24%; range, 0%-70%, P = .0002). In 1 patient, we were unable to quantify improvement in flow parameters due to section-selection differences between the pre- and posttreatment examinations.
IA nicardipine improves CBF and MTT in ischemic regions in patients with aSAH-induced vasospasm. Our data provide a tissue-level complement to the favorable effects of IA nicardipine reported on prior angiographic studies. CTP may provide a surrogate marker for monitoring the success of treatment strategies in patients with aSAH-induced vasospasm.
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ABSTRACT: Cerebral perfusion analysis is useful in the diagnosis and treatment of cerebral vasospasm. A new modality of real-time cerebral perfusion imaging and analysis has been developed using standard 2-dimensional angiography. We report our initial experience with this technique to assess response to therapy during endovascular vasospasm procedures. Colorized angiographic perfusion maps were obtained immediately before and after endovascular vasospasm treatment. Semiquantitative perfusion parameters (cerebral blood flow, cerebral blood volume, mean transit time, and time to peak) were calculated from time-density curves obtained from intraarterial contrast injection. The effects of intraarterial vasospasm therapy were assessed. Eight vascular territories in 4 patients with vasospasm underwent interventional angiography and angiographic perfusion analysis. Pretreatment perfusion maps demonstrated variable perfusion deficits in specific vascular territories. After endovascular treatment in 6 vessels, improvement was seen to varying degrees in both angiographic appearance and perfusion parameters. Clinical improvement and reduction in transcranial Doppler velocity was also observed. Real-time angiographic perfusion imaging is feasible during endovascular procedures for vasospasm. Perfusion analysis may aid in assessment of efficacy of the intervention. Comparison with traditional perfusion imaging is needed to validate this technique.Journal of neuroimaging: official journal of the American Society of Neuroimaging 09/2013; · 3.36 Impact Factor
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ABSTRACT: Cerebral vasospasm is one of the leading causes of morbi-mortality following aneurysmal subarachnoid hemorrhage. The aim of this article is to discuss the current status of vasospasm therapy with emphasis on endovascular treatment.Interventional neurology. 10/2013; 2(1):30-51.
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ABSTRACT: The inclusion of dynamic contrast-enhanced computed tomography (CT) or CT perfusion (CTP) scan into the imaging workup for acute stroke patients is widespread. Along with vessel occlusion status from CT angiography, CTP provides pathophysiological information a non-contrast CT cannot provide during the hyperacute stages of cerebral ischemia. Measurement of parenchymal perfusion at the capillary level can be used to characterize tissue viability, a target for thrombolysis. Further, CTP is useful for the detection of blood brain barrier disturbances with the permeability surface area product parameter (PS). Although new to stroke imaging, PS has diagnostic and prognostic implications for primary hemorrhage and secondary hemorrhagic transformation of ischemic stroke. The purpose of this article is to provide an overview of the CTP imaging concepts and their uses for imaging in stroke.Translational Stroke Research. 3(2).
Intra-Arterial Nicardipine Infusion Improves CT
Perfusion–Measured Cerebral Blood Flow in
Patients with Subarachnoid Hemorrhage–Induced
BACKGROUND AND PURPOSE: Our aim was to determine the effects of intra-arterial (IA) nicardipine
infusion on the cerebral hemodynamics of patients with aneurysmal subarachnoid hemorrhage
(aSAH)–induced vasospasm by using first-pass quantitative cine CT perfusion (CTP).
MATERIALS AND METHODS: Six patients post-aSAH with clinical and transcranial Doppler findings
suggestive of vasospasm were evaluated by CT angiography and CTP immediately before angiography
for possible vasospasm treatment. CTP was repeated immediately following IA nicardipine infusion.
Maps of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were
constructed and analyzed in a blinded manner. Corresponding regions of interest on these maps from
the bilateral middle cerebral artery territories and, when appropriate, the bilateral anterior or posterior
cerebral artery territories, were selected from the pre- and posttreatment scans. Normalized values
were compared by repeated measures analysis of variance.
RESULTS: Angiographic vasospasm was confirmed in all patients. In 5 of the 6 patients, both CBF and
MTT improved significantly in affected regions in response to nicardipine therapy (mean increase in
CBF, 41 ? 43%; range, ?9%–162%, P ? .0004; mean decrease in MTT, 26 ? 24%; range, 0%–70%,
P ? .0002). In 1 patient, we were unable to quantify improvement in flow parameters due to
section-selection differences between the pre- and posttreatment examinations.
CONCLUSIONS: IA nicardipine improves CBF and MTT in ischemic regions in patients with aSAH-
induced vasospasm. Our data provide a tissue-level complement to the favorable effects of IA
nicardipine reported on prior angiographic studies. CTP may provide a surrogate marker for monitoring
the success of treatment strategies in patients with aSAH-induced vasospasm.
deed, the presence of cerebral vasospasm has been associated
with a 1.5 to threefold increase in mortality during the first 2
patients with aSAH die from vasospasm.1,2According to the
Cooperative Aneurysm Study, 70% of the patients who
present with aSAH develop vasospasm, with symptomatic
brain ischemia or infarcts occurring in 36% of all patients.3
the management of patients with aSAH is the prevention, de-
tection, and treatment of vasospasm. The most commonly
used approaches include oral nimodipine; induced hyperten-
sion, hemodilution, and hyperdynamic (triple-H) therapy;
and endovascular techniques, including intra-arterial (IA) in-
elayed cerebral ischemia represents one of the leading
causes of morbidity and mortality in patients with aneu-
gioplasty (PTA), or a combination of the 2.
Given its short duration of action and several potential
complications, papaverine has been largely replaced by other
dene IV),6or nimodipine7as the drug of choice for IA vaso-
the primary endovascular vasospasm treatment at our hospi-
tal. Nicardipine is known to affect positively both angio-
graphic (increasing vessel diameter) and clinical vasospasms.6
The degree to which nicardipine actually augments tissue-
level perfusion, however, has not, to our knowledge, been
evaluation of patients with clinically significant aSAH-in-
duced vasospasm has been previously demonstrated.8-11The
IA nicardipine infusion on the cerebral hemodynamics of pa-
tients with aSAH-induced vasospasm as measured by first-
esis that CTP may be a useful tool in the quantification of the
future clinical trials.
Materials and Methods
aSAH between September 2002 and June 2004. Approval was ob-
tained from the institutional review board at our institution to con-
Received March 28, 2008; accepted after revision July 11.
From the Endovascular Neurosurgery/Interventional Neuroradiology Section, Departments
of Radiology and Neurosurgery (R.G.N., J.A.H., J.D.R., J.C.P.); Neurocritical Care and
Vascular Neurology Section, Department of Neurology (R.G.N., G.A.R.); Diagnostic Neuro-
radiology Section, Department of Radiology (M.H.L., L.R., R.G.G., E.F.H.); Vascular Neuro-
surgery Section, Department of Neurosurgery (C.S.O.), Massachusetts General Hospital,
Harvard Medical School, Boston, Mass.
Paper previously presented in part at: Annual Meeting of the American Society of
Neuroradiology, June 5–11, 2004; Seattle, Wash.
Please address correspondence to Raul G. Nogueira, MD, Department of Interventional
Neuroradiology and Endovascular Neurosurgery, Massachusetts General Hospital, 55 Fruit
St, GRB-2-241, Boston, MA, 02114; e-mail: RNOGUEIRA@PARTNERS.ORG
Nogueira ? AJNR 30 ? Jan 2009 ? www.ajnr.org
duct this retrospective review. Informed consent for endovascular
treatment was obtained as part of routine clinical care. All patients
with aSAH are treated under a standard protocol, which includes
admission to the neuroscience intensive care unit for preoperative
and postoperative monitoring. After surgical or endovascular treat-
ment of the aneurysm, patients are routinely maintained in a rela-
tively hypertensive and euvolemic state in anticipation of cerebral
vasospasm. Daily clinical observations and transcranial Doppler
(TCD) measurements are used to detect vasospasm. Patients with
TCD findings suggestive of vasospasm are typically treated with in-
duced hypertension (with phenylephrine and/or norepinephrine)
and hypervolemia (crystalloids ? albumin to maintain central ve-
nous pressure above 12 mm Hg).
CT angiography (CTA) and concomitant first-pass quantitative
cine CTP are typically performed in patients with clinical findings
reliable neurologic assessment cannot be obtained (eg, intubated pa-
the CTA and/or CTP, then IA vasodilation with nicardipine and/or
PTA are typically used. A retrospective review of our aSAH data base
and right after undergoing vasospasm treatment with IA nicardipine
CTP scans. These 6 patients are the subjects of this study.
CT was performed by using a multidetector (16 sections) helical CT
scanner (LightSpeed; GE Healthcare, Milwaukee, Wis) in the head-
first supine orientation. An 18-gauge cannula was placed into an an-
tecubital vein before the patient’s entry into the scanner. Once in the
pump was connected to the cannula. A precontrast axial study was
obtained from the foramen magnum to the vertex. Immediately fol-
mL/s (Omnipaque, 300 mg I/mL; Amersham Health, Princeton, NJ).
The imaging parameters used during this phase were 140 kilovolt
(peak) (kV[p]), 170 mA, 0.8-second rotation time, 2.5-mm section
thickness, 512 ? 512 image matrix, and standard algorithm recon-
struction. Maximal attenuation projection and 3D images were then
constructed by using GE Healthcare and Vitrea (Vital Images,
Minnetonka, Minn) workstations.
istration of 50 mL of iodinated contrast material by using the same
intravenous route at 7 mL/s with a 5-second delay. The imaging pa-
rameters used were 80 kV(p), 200 mA, 1-second rotation time, 4
per section, 5-mm section thickness, 512 ? 512 image matrix, and
selected from axial cuts of the supraclinoid internal carotid artery
(ICA) or the A2 segment of the anterior cerebral artery (ACA).12The
same AIF was used for both pre- and posttreatment studies. CTP
images were obtained just before and immediately after the endovas-
Endovascular Treatment Protocol
Digital subtraction angiography (DSA) was performed by use of the
transfemoral Seldinger technique. Once vasospasm was confirmed,
0.1 mg/mL and administered in 1-mL aliquots through a Prowler
microcatheter (Cordis Neurovascular, Miami Lakes, Fla) into the af-
imal basilar artery). All patients had a ventriculostomy catheter. If
ventriculostomy was opened and allowed to drain to lower the ICP.
Continuous blood pressure monitoring was also available in all pa-
tients through a radial arterial line. Cerebral perfusion pressure was
maintained above 70 mm Hg throughout the procedure.
Data Processing and Analysis
(Advantage Windows; GE Healthcare) and analyzed with commer-
cially available perfusion analysis software (CT Perfusion-2 software,
FuncTool 3.0; GE Healthcare) to create maps of mean transit time
(MTT), cerebral blood volume (CBV), and cerebral blood flow
The CBF, CBV, and MTT data were transferred to a personal
computer for analysis. Regions of interest were outlined by using a
the CTA and angiographic procedure results. One slab for each terri-
tory on each scan was selected on the basis of the levels that looked
most comparable between the pre- and posttreatment scans. Region-
of-interest contours were delineated in the bilateral middle cerebral
ment perfusion maps. The regions of interest were copied on the
anatomically corresponding locations on the posttreatment CTP
maps. For each region, mean pre- and posttreatment CBF, CBV, and
MTT values were calculated.
The relative rate of change (eg, percentage change in the posttreat-
ment values when compared with the pretreatment values) in CBF,
Comparison of pretreatment with posttreatment changes in CBF,
variance with the patient as a fixed effect and pre- and posttreatment
computations were performed with the aid of SAS software (Version
9.1; SAS Institute, Cary, NC).
aSAH, age, sex, Hunt and Hess grade, Fisher group, location
and treatment of the aneurysm, location and severity of the
vasospasm, IA nicardipine dosage per location, and pre- and
posttreatment CTP data are summarized in the Table.
A total of 15 vessels were successfully treated in 6 patients.
One patient underwent PTA in addition to IA nicardipine in-
fusion. The remaining patients were treated only with IA ni-
cardipine. The total dose ranged from 6 to 30 mg per patient.
In 1 patient, we were unable to quantify improvement in flow
parameters, due to section-selection differences between the
pre- and posttreatment CTP examinations. This patient was
not included in our quantitative analysis; however, subjective
analysis of the 2 closest pre- and posttreatment sections was
suggestive of posttreatment improvement.
A total of 16 vascular territories were analyzed in the re-
AJNR Am J Neuroradiol 30:160–64 ? Jan 2009 ? www.ajnr.org
ries in 2 patients, bilateral MCA and PCA territories in 1 pa-
tient, and bilateral MCA territories in 2 patients. One patient
mg of nicardipine infusion in the right ICA, resulting in only
minimal angiographic response. In another patient (case 5),
only the left ICA was treated because the procedure had to be
aborted due to seizures. In the remaining 14 vascular territo-
ries, treatment resulted in satisfactory angiographic response.
Both CBF and MTT improved significantly in the affected
regions in response to IA nicardipine therapy. Mean CBF in-
creased from 38.2 ? 13.1 mL/100 g/min in the pretreatment
CTP scan to 50.7 ? 12.9 mL/100 g/min in the posttreatment
1.3 seconds in the posttreatment CTP scan, resulting in a rel-
ative MTT reduction of 26.2 ? 24.2% (range, 0%–70%; P ?
pretreatment CTP scan and 2.9 ? 0.8 mL/100 g in the post-
?44%–34%; P ? .63). Fig 1 illustrates the effects of IA nicar-
dipine infusion on DSA and MTT maps.
To assess the possibility that the aforementioned benefit
was mostly related to PTA, we performed a second analysis
excluding the 4 vascular territories (case 2) that were also
ics remained statistically significant, with a relative CBF in-
crease of 25.7 ? 25.9% (range, ?9%–69%; P ? .01) and a
In the present study, we have described the direct effects of IA
nicardipine on reduced CBF in patients with hemodynami-
cally significant vasospasm after aSAH by using first-pass
1) the characterization of the acute CBF response to IA nicar-
dipine infusion; and 2) the validation of the use of CTP in the
assessment of new treatment modalities for vasospasm.
The mechanism by which aSAH-induced vasospasm oc-
curs is not yet fully understood; however, both experimental
and clinical data strongly suggest the efficacy of calcium an-
tagonists in the treatment and prevention of vasospasm.13-15
Nimodipine, an oral dihydropyridine calcium antagonist, has
been shown to reduce the incidence of vasospasm-induced
cerebral infarction by 34% and the rate of poor outcomes by
40%.16Nicardipine is another dihydropyridine calcium an-
tagonist, which has more selective effects on vascular smooth
muscle than on cardiac muscle. Several studies have demon-
strated that continuous intravenous nicardipine infusion sig-
nificantly decreases the incidence of symptomatic, angio-
graphic, and TCD vasospasm.15,17,18However, the efficacy of
monary edema, and renal dysfunction.
Badjatia et al6have previously demonstrated that IA nicar-
dipine infusion improves angiographic vasospasm with an ef-
fect more sustained than what has been reported with papav-
ment as demonstrated by the lack of correlation between an-
giographic and clinical improvement in many situations. For
instance, patients treated with IA papaverine may still have
further neurologic deterioration despite angiographic im-
Patient data summary
10 mg, R ICA
10 mg, L ICA
10 mg, BA
2.0424 44F33 L ACA,
4 mg, R ICA
R ACASeverePTA, R ICA
PTA, R M1
4 mg, L ICA
PTA, L ICA
2 mg, L A1
PTA, L A1
4 mg R ICA
31155F23 No aneurysm
R MCAModerate4.794.44 45.2656.112.793.38
2 mg, R A1
4 mg, L ICA
2 mg L M2
8 mg, R ICA
6 mg, L ICA
45 44F33BA, clipping
5 11 42M23 AcomA,
L MCAModerate7.5 mg, L ICA5.324.2768.2073.734.714.32
Note:—HH indicates Hunt and Hess; Rx, treatment; R, right; L, left; BA, basilar artery; Mod/sev, moderate to severe; AcomA, anterior communicating artery; MTT, mean transit time; CBF,
cerebral blood flow; CBV, cerebral blood volume; ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; ICA, internal carotid artery.
* Near-complete occlusion of the M2 segment of the right MCA on angiographic evaluation with only minimal angiographic response after IA nicardipine infusion.
† Procedure aborted due to seizures.
Nogueira ? AJNR 30 ? Jan 2009 ? www.ajnr.org
may demonstrate remarkable clinical improvement despite
L-arginine has been shown to markedly increase CBF in a pri-
mate model of SAH, despite the lack of any angiographic
changes.20Changes in perfusion at the microvasculature level
probably account for this clinicoangiographic dissociation.
Therefore, assessment of cerebral perfusion as opposed to an-
novel therapies for vasospasm.
As an example, Firlik et al19have demonstrated that IA
papaverine may fail to improve CBF despite reversal of angio-
graphic vasospasm. These authors reported a series of 15 pa-
tients with symptomatic vasospasm who underwent a total of
reversed following treatment on 18 of 23 occasions (78%).
Associated clinical improvement was major on 6 occasions,
but either minor or none on 17. Pre- and posttreatment CBF
was assessed by stable xenon-enhanced CT on 13 occasions
6 of these (46%).19
CTP has been shown to be a useful tool in the selection of
proper candidates for acute stroke thrombolysis21and has
more recently been used to diagnose and guide medical and
endovascular therapy in patients with delayed cerebral isch-
emia after aSAH.8,9,22The application of CTP to assess the
response to vasospasm treatment has also been previously re-
ported. Ono et al23performed CTP in 8 patients with aSAH-
induced vasospasm before, immediately after, and 4.5–6
hours after IA infusion of fasudil hydrochloride with an aver-
cluded that, though initially effective, fasudil hydrochloride is
a short-lived treatment for vasospasm.23In our study, pre-
treatment and immediately posttreatment mean CBF was
38.2 ? 13.1 and 50.7 ? 12.9 mL/100 g/min, respectively.
Our analysis is somewhat limited by its overall small sam-
ple size and by the fact that PTA was performed in 1 of our
patients, and differences in section selection did not allow the
inclusion of that last patient in the analysis. In addition, our
in increasing CBF in patients with vasospasm, we did not as-
Fig 1. Panels 1, 2, and 3 illustrate cases 1, 2, and 3, respectively. Panels A–D show pre- and posttreatment angiograms and MTT maps, respectively. Panel 1: A, Severe vasospasm of
the left PCA, which had a marked response to nicardipine infusion in the basilar artery (1B) resulting in 28% reduction in MTT (1C, -D) and 62% increase in CBF (not shown) at the left
PCA territory. Panel 2: A, Severe vasospasm of the left ACA, which had a marked response to PTA of the A1 segment and nicardipine infusion (2B), resulting in 68% reduction in MTT
(2C, -D) and 89% increase in CBF (not shown) at the left ACA territory. Panel 3: A, Moderate vasospasm of the left MCA, which had only a mild angiographic response to nicardipine
infusion (3B). C and D, Despite the suboptimal angiographic result, there was a 37% reduction in MTT and 69% increase in CBF (not shown) at the left MCA territory. This likely reflects
the nicardipine effect in the microcirculation.
AJNR Am J Neuroradiol 30:160–64 ? Jan 2009 ? www.ajnr.org
sess the duration of this effect due to concerns about the ad-
ditional contrast and radiation exposure that would be neces-
sary for another CTP examination. Despite these limitations,
ment in CBF and MTT immediately after IA nicardipine
IA nicardipine infusion improves CBF and MTT in ischemic
regions in patients with aSAH-induced vasospasm. Our data
able effects of IA nicardipine seen with angiographic studies.
In addition, this study reinforces that CTA/CTP is a safe and
promising technique for the evaluation of aSAH-induced va-
sospasm. Indeed, quantitative CTP may provide a surrogate
marker for monitoring the success of treatment strategies in
patients with aSAH-induced vasospasm. Future studies with
larger sample sizes are required to confirm our results and to
answer the questions about the duration of the treatment ef-
fect as well as its overall impact in clinical outcomes.
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