Heparin and Air Filters Reduce Embolic Events Caused by

Intra-Arterial Cerebral Angiography

A Prospective, Randomized Trial
Martin Bendszus, MD; Martin Koltzenburg, MD, FRCP; Andreas J. Bartsch, MD;
Roland Goldbrunner, MD; Thomas Günthner-Lengsfeld, MD; Franz X. Weilbach, MD;
Klaus Roosen, MD; Klaus V. Toyka, MD, FRCP*; László Solymosi, MD*

Background—Intra-arterial cerebral angiography is associated with a low risk for neurological complications, but
clinically silent ischemic events after angiography have been seen in a substantial number of patients.
Methods and Results—In a prospective study, diffusion-weighted magnetic resonance imaging (DW-MRI) before and
after intra-arterial cerebral angiography and transcranial Doppler sonography during angiography were used to evaluate
the frequency of cerebral embolism. One hundred fifty diagnostic cerebral angiographies were randomized into 50
procedures, each using conventional angiographic technique, or systemic heparin treatment throughout the procedure,
or air filters between the catheter and both the contrast medium syringe and the catheter flushing. There was no
neurological complication during or after angiography. Overall, DW-MRI revealed 26 new ischemic lesions in 17
patients (11%). In the control group, 11 patients showed a total of 18 lesions. In the heparin group, 3 patients showed
a total of 4 lesions. In the air filter group, 3 patients exhibited a total of 4 lesions. The reduced incidence of ischemic
events in the heparin and air filter groups compared with the control group was significantly different (P⫽0.002).
Transcranial Doppler sonography demonstrated a large number of microembolic signals that was significantly lower in
the air filter group compared with the heparin and control groups (P⬍0.01), which did not differ from each other.
Conclusions—Air filters and heparin both reduce the incidence of silent ischemic events detected by DW-MRI after
intra-arterial cerebral angiography and can potentially lower clinically overt ischemic complications. This may apply to
any intra-arterial angiographic procedure. (Circulation. 2004;110:2110-2115.)
Key Words: angiography 䡲 ischemia 䡲 magnetic resonance imaging 䡲 complications 䡲 embolism

I ntra-arterial digital subtraction angiography (IA-DSA) has

remained the “gold standard” in the assessment of cerebral
vessels. In such disorders as vasculitis or intracranial aneu-
A high number of microembolic signals (MESs) have been
identified by transcranial Doppler sonography during cerebral
angiography.10 The clinical relevance of this finding, how-
rysms, the sensitivity and specificity of such noninvasive ever, is uncertain, because no correlation between microem-
techniques as CT angiography and MR angiography do not bolism and morphological brain damage or clinical symptoms
suffice to replace intra-arterial angiography.1 IA-DSA har- has been reported.
bors a substantial risk for procedure-related symptomatic In the present study, we investigated the effect of air filters
cerebral ischemia (1% to 3% in previous studies2–5). We have and heparin during IA-DSA on the incidence rate of ischemic
recently shown that clinically silent ischemic events identi- lesions as identified by DW-MRI and of MESs assessed by
fied by diffusion-weighted MRI (DW-MRI) can be found in transcranial Doppler sonography. These findings were com-
as many as 23% of patients undergoing IA-DSA.6 This has pared with those of a control group subjected to conventional
been confirmed by other investigators.7,8 Moreover, silent IA-DSA.
cerebral embolism has also been shown in extracranial
angiographic procedures.9 Basically, embolic events during Methods
IA-DSA may be caused by either thromboembolism or air Patients and Protocol
embolism introduced by injection of contrast medium or From March 2000 to June 2002, all patients scheduled for IA-DSA
catheter flushing. were assessed for eligibility in the study. Patient characteristics are

Received January 27, 2004; de novo received April 6, 2004; revision received May 26, 2004; accepted May 28, 2004.
From the Departments of Neuroradiology (M.B., A.J.B., T.G.-L., L.S.), Neurology (M.K., F.X.W., K.V.T.), and Neurosurgery (R.G., K.R.), University
of Würzburg, Würzburg, Germany.
*Drs Toyka and Solymosi are joint senior authors.
Correspondence to PD Dr M. Bendszus, Department of Neuroradiology, University of Würzburg, Josef-Schneider-Straße 11, D-97080 Würzburg,
Germany. E-mail [email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000144301.82391.85

2210
 Bendszus et al Heparin and Air Filters Reduce Embolic Events 2211

TABLE 1. Patient Characteristics of the 3 Groups Under Study

Heparin Air Filter Control
Age, mean⫾SD, y 49.3⫾13.5 (55⫾8.7) 49.4⫾13 (60.3⫾8.1) 51.5⫾14.2 (55⫾11.3)
Female/male 30/20 (2/1) 25/25 (3/0) 26/24 (6/5)
Vascular risk factors 16 (1) 16 (3) 17 (8)
Preexisting lacunae on MRI 5 (1) 6 (1) 9 (3)
Vascular encephalopathy (DWMH and PVH) on MRI12 8 (1) 11 (3) 14 (7)
Mean fluoroscopy time, min⫾SD 13.2⫾15.7 (16.1⫾3.8) 11.3⫾11 (34.3⫾14) 13.2⫾15.7 (21.6⫾27.7)
Mean contrast medium, mL⫾SD 108.6⫾53.1 (183.3⫾57.7) 116.6⫾50.6 (240⫾52.9) 112.6⫾46.1 (111.8⫾44.3)
DWMH indicates deep and subcortical white matter hyperintensities. Values in parentheses represent patients with ischemic lesions on DW-MRI.

summarized in Table 1. Exclusion criteria were recent hemorrhage, Vertebral or Head Hunter, Terumo), a standard guidewire (Radifo-
any preexisting anticoagulation, need for interventional angiographic cus, Ø⫽0.035 in, Terumo) and nonionic contrast medium (Imeron
procedures, necessity of a power injector for the aortic arch, age ⬍18 250, Bracco-Byk Gulden) injected manually using a 10-mL plastic
years, emergency angiography, or no consent to participate in the angiographic syringe. All IA-DSAs were performed by one of 5
study. Patients were randomized shortly before the procedure to one experienced board-certified neuroradiologists. The medical indica-
of the 3 groups (conventional technique, heparin, or air filter) by tions for angiography are shown in Table 2. In patients receiving
means of closed envelopes containing the group allocation that were heparin, an intravenous bolus of 50 IU/kg BW (Liquemin, Hoffmann
opened by a person not involved in the study. The study was La Roche AG) was applied over a period of 15 minutes after
approved by the Ethics Committee of the University of Würzburg, placement of the transfemoral sheath and before beginning IA-DSA,
and written informed consent was obtained from every patient 24 followed by a maintenance dose of 25 IU · kg BW⫺1 · h⫺1 throughout
hours before the examination. the procedure. Heparin was not reversed at the end of the procedure.
Patients underwent a neurological examination before, immedi- In the air filter group, filters (Intrapur, Braun; filter pore size, 1.2
ately after, and 1 day after IA-DSA. A neurological complication ␮m) were placed between the catheter and both the catheter flushing
was defined as any new cranial nerve, motor or sensory deficit, reflex and the syringe containing the contrast medium. In the control group,
change, pyramidal sign, or mental alteration during angiography or a technique identical to that used in group A or B was used except
within the 24-hour follow-up period. All patients were assessed for for heparin or air filters. For every patient, total fluoroscopy time,
cerebrovascular risk factors, which were defined as previous stroke amount of contrast medium, and the number of catheters used were
or transient ischemic attack, hypertension, diabetes, and carotid recorded. At the end of the procedure, manual compression of the
artery stenosis. MRI was applied before and within 3 days (median, puncture site was performed for 15 minutes, followed by strict bed
1 day) after angiography on a 1.5-T unit (Magnetom Vision or rest and a tight compression bandage for 24 hours.
Magnetom Symphony, Siemens). The MRI protocol included a
T2-weighted double spin echo sequence (TR 2000 ms, TE 20/80 ms) Statistical Analysis
and a diffusion-weighted sequence (EPI, 3 orthogonal-axis diffusion- For statistical analyses, the R environment for statistical computing
weighted images, TR⫽5400 ms, TE⫽103 ms, b⫽0, 500 and 1000 (R 1.8.1, http://www.r-project.org/; sm library version 2) was used.
s/mm2). Blinded to clinical examination and group assignment, 2 Pearson’s ␹2 test was performed on tabulated contingencies of the
neuroradiologists (M.B. and L.S.) independently analyzed the im- incidence of new lesions on DW-MRI and preexisting vascular
ages with respect to diffusion abnormalities on DW-MRI and encephalopathy on MRI. Because the continuous and ordinal data
preexisting cerebral vascular encephalopathy on T2-weighted images were not normally distributed (Pⱕ0.001, Shapiro-Wilk normality
according to the criteria of Fazekas et al.11 This classification defines test), nonparametric tests were applied as indicated.
and grades vasculopathy as deep and subcortical white matter The sample size calculation was based on previous data revealing
hyperintensities, periventricular hyperintensities, and lacunae. a total of 32 new ischemic lesions in 66 diagnostic angiographies.6
Continuous transcranial Doppler examination (Neuroguard, EME Assuming a reduction in the number of lesions by 50%, a minimum
Nicolet) of the right and left middle cerebral arteries was performed of 50 patients per group would be required to reject the null
through the temporal bone windows starting 5 minutes before the hypothesis at a significance level of P⫽0.05 difference with a power
catheterization until the end of the procedure, applying an embolus of 0.8.
detection software (Embotec, Stac GmbH). The investigation was
run with two 2-MHz probes fixed to the patient’s head. The depth of Results
insonation was between 48 and 55 mm. All data were stored on Of the 1499 patients seen in the study period, 178 met the
digital audio tapes (DAT) for offline analysis, and the evaluation was
performed with the observer blinded with regard to the patient data. inclusion criteria (Figure 2). Twenty-eight patients had to be
According to Markus et al,10 2 patterns of MESs were identified excluded after randomization because of withdrawal of con-
(Figure 1): First, we observed single MESs, which were seen during sent (n⫽5) or for lack of MRI after angiography (n⫽23). The
any phase of IA-DSA, mostly with vessel probing or flushing of the 3 patient groups entering the trial were homogeneous with
catheter (Figure 1A). These were identified according to published respect to age, sex, and history of vasculopathy and were
criteria12 and counted manually. Second, we identified dense show-
ers of MESs, which were observed during injection of contrast balanced as to the presence of lacunae (P⫽0.552,
medium (Figure 1B). Because it was impossible to resolve single H-ANOVA) or diffuse vascular encephalopathy on MRI11
MESs in this pattern, the overall time of the MES shower was (P⫽0.227, H-ANOVA; Table 1). Neither fluoroscopy time
determined in seconds, as described previously.10 (P⫽0.554, H-ANOVA) nor the amount of contrast medium
given (P⫽0.408, H-ANOVA) differed between the study
Procedures groups (Table 1).
In all patients, an established angiographic technique6 was applied,
including the following criteria: transfemoral approach, high- There was no new neurological deficit after any IA-DSA.
pressure (300 mm Hg) continuous catheter flushing with saline Before angiography, there were no lesions on DW-MRI.
unless a guidewire was used, a 4F or 5F standard catheter (4F After angiography, 17 patients (11%) revealed a total of 26
2212 Circulation October 12, 2004

Figure 1. MESs during intra-arterial cere-

bral angiography. Transcranial Doppler
sonography of both middle cerebral arter-
ies during angiography using a conven-
tional IA-DSA technique. A, A dense
shower of MESs is depicted during injec-
tion of contrast medium. Single MESs are
not discernible. B, Single MESs are
shown in same patient during probing of
common carotid artery. Time scale
applies to A and B.

new ischemic lesions. All lesions were suggestive of an graphic lesions (P⬍0.001, ␹2), and they more often revealed
embolic pattern (ie, cortical or subcortical location and/or in a diffuse white matter hyperintensity (P⬍0.001, ␹2) and
the vascular territory of perforating arteries, Figure 3). In the periventricular hyperintensities (P⬍0.001, ␹2) on MRI (Table
control group, 11 patients (22%) developed 17 lesions. In the 1). Patients with preexisting vasculopathy (n⫽49) required
heparin group, 3 patients (6%) revealed 4 new lesions. longer fluoroscopy times and more contrast medium than
Similarly, in the air filter group, 3 patients (6%) exhibited 4 those without vascular risk factors (P⬍0.001, U test).
new lesions (Table 2). Thus, the total lesion count was lower Furthermore, the postangiographic frequency of ischemic
in the 2 treatment groups than the control group (P⫽0.002, lesions correlated positively with the angiographic fluoros-
␹2). Moreover, the number of patients revealing a new lesion copy time (Kendall’s ␶⫽0.18, z⫽3.24, P⬍0.001). This asso-
was lower in both the heparin and air filter groups than the ciation was reduced by treatment with either heparin or air
control group (P⫽0.044, ␹2). There was no interobserver filters (nonparametric ANCOVA testing for equality,
disagreement in the detection of ischemic lesions. P⫽0.009, and parallelism, P⫽0.793). However, the longer
Patients with ischemic lesions more frequently had a the fluoroscopy time, the more the initial benefit of air filters
history of vasculopathy than patients without postangio-
seemed to vanish compared with the group treated with
heparin (nonparametric ANCOVA testing for equality,
TABLE 2. Medical Indication for IA-DSA
P⫽0.014, and parallelism, P⫽0.002). These findings are
Medical Indication Heparin Air Filter Control illustrated by the nonparametric logistic regression plots of
Tumor 7 (1) 4 6 fluoroscopy time versus the probability to develop 1 or more
Arteriovenous fistula 8 (1) 9 (1) 6 (4) ischemic lesions (Figure 4): both air filters and heparin
Aneurysm 13 18 (1) 22 (4)
reduced the probability to acquire an ischemic lesion com-
pared with the control group. This effect, however, was
Extracranial/intracranial stenosis 4 (1) 3 4 (2)
dependent on the fluoroscopy time: At short fluoroscopy
Arteriovenous malformation 11 8 7
times, the protective effect of the air filter appeared more
Vasculitis 3 4 (1) 4 (1) clearly, whereas at longer fluoroscopy times, this effect
Other 4 4 1 diminished and then disappeared, whereas the protective
Values in parentheses represent patients with ischemic lesions on DW-MRI. effects of heparin became more apparent. Even in the heparin
 Bendszus et al Heparin and Air Filters Reduce Embolic Events 2213

Figure 2. Trial flow chart. Figure 3. Ischemic lesions on postangiographic MRI: axial
T2-weighted (top left) and orthogonal axis diffusion-weighted
images at same level. MR images of a 66-year-old patient
group, the incidence of ischemic lesions increased with undergoing intra-arterial angiography for suspected vasculitis.
longer fluoroscopy times, but to a lesser degree than in the On T2-weighted images, there is marked hyperintensity of white
control and air filter groups (Figure 4). matter, indicating preexisting vasculopathy (arrowheads). On
DW-MRI, a new, presumably embolic ischemic lesion is present
Catheter exchanges were not performed more frequently in in right lentiform nucleus (arrow).
patients with new lesions on DW-MR (3 catheter exchanges
in 17 patients with lesions versus 5 catheter exchanges in 133
Discussion
patients without lesions, P⫽0.07, Fisher’s exact test). More-
Over recent years, minimally invasive endovascular proce-
over, the total number of catheters used was not increased in
dures have become increasingly important. Nevertheless, all
the group of patients with ischemic lesions (21 catheters in 17
intra-arterial procedures harbor a certain risk for procedure-
patients versus 141 catheters in 133 patients, P⫽0.79, ␹2).
related vessel occlusion, with the risk for subsequent tissue
The results of MES detection are shown in Table 3. In six
infarction. DW-MRI is a novel specific and sensitive MR
patients, transcranial Doppler sonography was technically not
technique for detection of acute cerebral ischemia.13 Re-
feasible because of an inaccessible bone window (2 in the
cently, DW-MRI was introduced as a surrogate marker for
heparin group, 1 in the air filter group, 3 in the control group).
subclinical ischemic brain damage not only after IA-DSA6 – 8
The median number of single MESs was lower in the air filter
group than in the heparin group (P⫽0.006, U test) and in the but also after extracranial angiographic procedures9 and such
control group (P⬍0.001, U test). There was no difference nonangiographic interventions as cardiac surgery.14 As the
between the heparin and the control groups (P⫽0.179, U principal finding of this study, we show an independent
test). The overall duration of MES showers was significantly reduction of ischemic lesions from 22% in a control group
reduced in the air filter group compared with the heparin undergoing IA-DSA to 6% by treatment with either heparin
group (P⬍0.001, U test) and with the control group or air filters. This finding underscores the relevance of both
(P⬍0.001, U test), which did not differ from each other thromboembolism and air embolism to the overall ischemic
(P⫽0.280, U test). Dense showers of MESs were observed complications after intra-arterial angiography.
exclusively during injection of contrast medium. The begin- Symptomatic air embolism15 and thromboembolism16 are
ning and end of these MES showers was slightly delayed in recognized complications known to occur after various an-
relation to the contrast injection. Single MESs, however, were giographic procedures, including coronary angiography.
not related to any specific angiographic procedure but rather However, little is known about the frequency of procedure-
were observed during all phases of angiography. Patients related subclinical ischemic tissue damage. An asymptomatic
revealing a new ischemic lesion on DW-MRI had more single elevation of cardiac enzymes has been described in a sub-
MES events (P⫽0.041, U test), whereas the duration of MES stantial number of patients undergoing endovascular cardiac
showers did not differ (P⫽0.201, U test). There were no groin interventions.17 Because postangiographic lesions on DW-
hematomas in the present series of 150 patients. MRI represent structural tissue damage,6,7 our findings may
2214 Circulation October 12, 2004

be considered a surrogate model and may have implications

not only for cerebral angiography but also for any other
intra-arterial procedure with an intrinsic risk of embolic
complications.
In experimental studies, heparin treatment has been dem-
onstrated to substantially lower the overall thromboembolic
complication in diagnostic and interventional cardiac proce-
dures.18 The risk for embolism in the present study and in our
previous report6 was strongly associated with a history of
vasculopathy and with technical aspects such as fluoroscopy
time and difficulties in probing the appropriate arteries. Our
findings indicate that the longer the angiographic procedure
lasts, the better these procedure-related ischemic events may
be prevented by systemic heparin treatment rather than by the
use of air filters alone. Longer and more difficult angio-
graphic procedures seem to enhance the risk of thromboem- Figure 4. Nonparametric logistic regression plots of fluoroscopy
bolism more than the risk of air embolism, whereas the risk of time (minutes) vs probability to develop 1 or more ischemic
lesions. Study groups were examined with conventional IA-DSA
air embolism may prevail over the risk of thromboembolism (open circle), or with IA-DSA plus air filters (solid circle), or with
during short and less difficult procedures. This may be heparin (*). Note that either treatment reduces angiographic risk
explained by the elimination of air bubbles from the catheter for ischemia, but lesion probability increases with fluoroscopy
and flushing system at the very beginning of the angiographic time in all treatment groups. Although air filtering is more benefi-
cial if total fluoroscopy time is short, heparin treatment has a
procedure. stronger protective effect, with above-average fluoroscopy
A potential disadvantage of using heparin during angiog- times. Curves represent logistic estimates for different proce-
raphy is an increased rate of groin hematomas, which were dures. Symbols denote actual figures from study.
not seen in this study population, probably because of strict
immobilization and local compression. In the study by Dion been demonstrated histologically.25 A large number of micro-
et al,2 patients received a bolus of 2000 IU heparin. Hema- embolic signals in the cerebral vessels has been described not
tomas at the puncture site were reported in 6.9% of those only during cerebral angiography9 but also during cardiolog-
patients. In a recent study by Willinsky et al,5 heparin was ical intra-arterial procedures.25,26 This finding has been attrib-
rarely used (1.7% of patients). In this series, groin hematomas uted primarily to tiny air bubbles introduced by contrast
were observed in only 0.4% of all patients. However, a low medium or flushing solution.9,26,27 In the present study, we
rate of hematomas (1.1%) has also been reported in a large identified 2 patterns of MES: single MESs, which occurred
study of patients with a 7F or 8F femoral sheath receiving a during all phases of angiography, and MES showers, which
bolus of 5000 IU of heparin during angiography.19 In case of were related exclusively to injections of contrast medium.
bleeding or hematomas at the puncture site, heparin can Similar findings have been reported by others.10 Single MESs
quickly be reversed with protamine. may represent air bubbles introduced by the catheter flushing
In the literature, most case reports on symptomatic air or guidewire exchanges, whereas MES showers are probably
embolism are described during cerebral20,21 and coronary caused by tiny air bubbles dissolved in the contrast medium,
angiography.15,22 Numerous small air emboli have been especially if the contrast syringe is drawn up swiftly. As in
demonstrated during catheter flushing23 and contrast medium previous studies,9,26,27 we could not identify a relation be-
injections.9 However, little is known about the actual risk of tween MESs and neurological deficit. However, patients with
air embolism. Here, we demonstrate a marked reduction of ischemic lesions on MRI revealed more single MESs,
ischemic lesions on DW-MRI by using air filters between the whereas the duration of MES showers that occurred during
catheter and both the catheter flushing and the contrast injections of contrast medium did not differ. This finding
medium syringe. This finding suggests that a substantial suggests that these potentially relevant air emboli leading to
number of silent ischemic lesions after angiography may subsequent ischemic lesions may be associated with guide-
indeed be caused by air embolism and can be prevented by wire manipulations or catheter flushing rather than by injec-
appropriate filters. tions of contrast medium. Beyond circumscribed ischemic
In the absence of neurological symptoms, the clinical
relevance of bright lesions on DW-MRI needs to be critically TABLE 3. Median Single MES Count, Median Duration of MES
discussed. These silent lesions obviously represent morpho- Showers (ms), and Number of Ischemic Lesions on DW-MRI
logical brain damage6 and, if located in an eloquent brain area
Heparin Air Filter Control
such as the internal capsule or the precentral gyrus, contralat-
eral hemiparesis may be caused despite a small lesion size.24 Median single MES, n (range) 44 (2–165) 29 (0–112) 66 (4–286)
It can be anticipated that in a cohort of patients larger than the Median MES shower, s (range) 40 (0–177) 5 (0–52) 57 (4–198)
present study groups, symptomatic ischemia caused by small Ischemic lesions on DW-MRI, n 4 4 17
ischemic lesions would be likely. Median number and range of single MES count (top), median duration and
Morphological brain tissue damage caused by microem- range (ms) of the MES showers (middle), and overall number of ischemic
bolic air introduced through intra-arterial angiography has lesions (bottom) in the heparin, air filter, and control groups.
 Bendszus et al Heparin and Air Filters Reduce Embolic Events 2215

lesions, there is also a potential clinical impact on cognitive 12. Ringelstein EB, Droste DW, Babikian VL, et al. Consensus on micro-
embolus detection by TCD. International Consensus Group on Micro-
functions, as described in cardiac surgery patients. In the
embolus Detection. Stroke. 1998;29:725–729.
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bofibrinous or gaseous MESs seems worthwhile. Neverthe- severity, and suggested approaches to treatment. Cathet Cardiovasc
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Acknowledgments during diagnostic and interventional cardiac procedures with nonionic
In this investigator-driven study, the sponsor, Braun, Melsungen, contrast media. Radiology. 1990;174:453– 457.
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