Accuracy of CO2 Angiography in VesselDiameter Assessment: A Comparative Studyof CO2 versus Iodinated Contrast Materialin a Porcine ModelGordon McLennan, MD, Kenneth P. Moresco, MD, Nilesh H. Patel, MD, Andrew Trobridge, MD,

Jerry Dreesen, RT, Jerry Tennery, RT, Roopa Seshadri, PhD, and Cynthia S. Johnson, MS

PURPOSE: To compare, with use of intravascular ultrasound (IVUS) as an internal reference standard in a porcinemodel, arterial diameters measured from arteriograms obtained with use of CO2 to those obtained with use ofiodinated contrast material (ICM).

MATERIALS AND METHODS: In nine pigs, digital subtraction angiograms (DSAs) were obtained in the aorta andiliac arteries to compare vessel diameters measured with use of CO2 to those measured with use of ICM. Thesemeasurements were divided by measurements made with use of intravascular ultrasound (IVUS) to yield a DSA/IVUSratio. Differences between ICM and CO2 were compared with analysis of variance to assess the effect of location (aortavs iliac), contrast material used (ICM vs CO2), and position (posteroanterior, right anterior oblique, or left anterioroblique). Secondary analysis compared measurements of dependent and nondependent iliac arteries and comparedthe use of hand-injected CO2 to that of CO2 injected by an injector.

RESULTS: The DSA/IVUS ratio was 70.7% 6 4.4% with ICM use and 69.6% 6 6.3% with CO2 use, which did notrepresent a significant difference (P 5 .311). Animal position had no effect (P 5 .477). Underestimation was worse inthe iliac arteries than in the aorta (67.4% 6 1.5% vs 71.4% 6 1.7%; P 5 .038). There was no difference in nondependent(P 5 .163) arteries, but CO2 underestimated dependent iliac artery size more than ICM did (66.3% 6 4.8% vs 70.3% 65.4%; P 5 .051). Vessel diameter was underestimated more with the CO2 injector than with hand-injected CO2 (64.3%6 2.3% vs 71.7% 6 1.7%; P < .0001).

CONCLUSION: There is no difference in diameter underestimation between CO2 and ICM in this animal model.Hand-injection of CO2 causes less underestimation of vessel diameter than does the CO2 injector.

Index terms: Angiography • Carbon dioxide • Contrast media, comparative studies

J Vasc Interv Radiol 2001; 12:985–989

Abbreviations: DSA 5 digital subtraction angiogram, ICM 5 iodinated contrast material, IVUS 5 intravascular ultrasound, RAO 5 right anterior oblique

PRECISE measurements are requiredfor safe and accurate arterial and ve-nous interventions such as stent place-ment, angioplasty, and inferior vena

cava filter placement in humans. Cur-rent measurements are based on io-dinated contrast angiography imagesobtained with use of digital subtrac-tion angiography (DSA) and an inter-nal marking catheter. This allows pre-cise measurement of luminal diameterfor selection of stent size and balloonsize for angioplasty.

However, a growing patient popu-lation is confronted with contraindica-tions to the use of iodinated contrastmaterial (ICM). The prevalence ofacute adverse reactions to contrast ma-terial is reported as 5%–8% (1–6). In

patients with baseline renal insuffi-ciency who are not undergoing dialy-sis treatment, the administration oflarge volumes of ICM is considered arelative contraindication (7–9). Theuse of CO2 in this patient populationhas been advocated as a means of as-sessing arterial lesions and planningfor arterial intervention (10–16). Withuse of an aortic aneurysm flow modelmade of synthetic materials, Morescoet al (17) demonstrated that CO2 over-estimated vessel diameters comparedto intravascular ultrasound (IVUS)and ICM. In this study, we compare

From the Departments of Radiology (G.M., K.P.M.,N.H.P., A.T., J.D., J.T.) and Medicine (R.S., C.S.J.),Indiana University School of Medicine, Indianapo-lis, Indiana. Received December 15, 2000; revisionrequested February 6, 2001; revision received April16; accepted April 17. Address correspondence toG.M., Department of Radiology, University HospitalRoom 0279, 550 N. University Blvd., Indianapolis,IN 46202-5253; E-mail gmclenna@iupui.edu

© SCVIR, 2001

985

CO2 angiography to iodinated con-trast angiography in a living systemwith use of IVUS as a reference.

MATERIALS AND METHODS

All aspects of the care and handling ofthe animals in this study conform to therecommendations of the National Insti-tutes of Health’s Guide for the Care andUse of Animal Laboratories, as well asstate and institutional guidelines. Also,the experimental procedures were con-ducted under the Food and Drug Admin-istration’s Good Laboratory Practice forNon-Clinical Laboratory Study Regula-tions (21 CFR, part 58).

Ten outbred swine (mean weight,33.3 kg; range, 23–42 kg) were sedatedintramuscularly with 0.5 mL/kg of asolution of ketamine (1,000 mg/mL;Bristol Laboratories, Syracuse, NY)and xylazine (142 mg/mL; Miles Lab-oratories, Shawnee, KS). Anesthesiawas induced with sodium thiopental(25 mg/kg; Fort Dodge AnimalHealth, Fort Dodge, IA). Anesthesiawas maintained with 2%–4% Isoflu-rane (Schering-Plough, Rochester, NY)via endotracheal tube. One animal wasexcluded because of death from anes-thesia-related malignant hyperthermiaduring the procedure. Animals werepremedicated with Verapamil (2.5 mgintravenous; Abbott Laboratories,North Chicago, IL) to reduce spasm.Spasm encountered during the proce-dure was treated with nitroglycerine(Abbott Laboratories) and the proce-dure was halted until the spasmresolved. If the spasm failed to resolve,this was noted and the data were an-alyzed with the affected measure-ments included and excluded. All an-imals underwent heparin infusion(100 U/kg; Elkins-Sinn, Cherry Hill,NJ). The right neck was shaved, pre-

pared, and draped in sterile fashionand an incision was made to exposethe right carotid artery. An 8-F vascu-lar sheath (Boston Scientific/Medi-tech, Natick, MA) was placed in theright carotid artery via surgicalcutdown. Through the sheath, a 0.035-inch Bentson wire (Cook, Blooming-ton, IN) was advanced into the distalabdominal aorta and a graduatedstraight flush catheter (Cook) was po-sitioned within the juxtarenal aorta.Six arteriograms were then obtainedwith the catheter in this position andthe animal centered in the posterolat-eral (PA) position with use of aToshiba 9800 angiography unit (source-to-image distance 5 100, PID 5 30,12-inch image intensifier; ToshibaAmerica, New York, NY). Three ofthese arteriograms were obtained withuse of ICM (Isovue 300; Bracco Diag-nostics, Princeton, NJ) at a rate of 8mL/min for a total of 16 mL with apower injector (Medrad IV, Indianola,PA). Three were obtained with CO2injected either by hand (35 mL) or witha prototype CO2 injector (AngioDy-namics, Queensbury, NY) at a rate of15 mL/min for 35 mL. Contrast mate-rial injection rates for CO2 and ICMwere optimized in an additional ani-mal before commencement of thestudy. No data were recorded fromthis animal. The order in which con-trast agents were chosen was random-ized with use of a coin toss. After ar-teriography, the catheter was removedover a 0.035-inch guide wire, the distaltip of which was positioned down ei-ther the right or left iliac artery. Overthis guide wire, a 12.5-MHz IVUSprobe (Boston Scientific/Medi-tech)was advanced into the aorta. IVUSwas performed throughout the aortaand both iliac arteries. A radiopaque

ruler was placed below the animal toallow precise location of positions inthe vessel to be correlated between an-giography and IVUS. After IVUS inthe PA position, the animal wasturned to the RAO projection such thatthe right side of the animal was ele-vated above the left side, and the pro-cess was repeated with six arterio-grams followed by additional IVUS.The animal was then positioned in theLAO position, with the left side abovethe right side, and the procedure wasrepeated. In the first experimental an-imal, the right and left iliac arterieswere evaluated with use of IVUS in allprojections. Wire manipulations to al-low IVUS evaluation of the second il-iac artery caused severe spasm. There-fore, the remaining animals had eitherthe ipsilateral oblique iliac artery (leftside in LAO position, right side inRAO position) or contralateral iliac ar-tery evaluated with IVUS (n 5 4 foreach group).

Angiograms were printed with anunsubtracted view of the markingcatheter and a digital subtraction im-age below it with the maximum con-trast material volume filling the aortaand iliac arteries. The images werecontrolled by adjusting contrast andlevel to make the CO2 images appearas close as possible to the iodinatedcontrast images. At the conclusion ofthe procedure, the animals were killedwith Beuthanasia (Schering-Plough).

Because interobserver variability wasaddressed in a previous study (17), a sin-gle reviewer performed all angiographicand IVUS measurements. The angio-grams were measured from the level ofthe aorta above the renal artery throughthe iliac arteries in 2-cm intervals on eachfilm of each animal. Each measurementwas correlated with the IVUS measure-ment obtained with the animal in thesame position at that same location. Ves-sel diameters were measured from theangiograms. Two diameters were mea-sured on the IVUS measurements andthese were averaged (Fig 1). The ratio ofangiographic measurements (CO2 orICM) to IVUS measurements was calcu-lated (DSA/IVUS).

Statistics

A generalized estimating equationmodel was fit to examine the effect oflocation (aorta vs iliac artery), contrast ma-terial (CO2 vs ICM) and position (RAO,

Table 1Diameter Measurements with Each Contrast Material and IVUS

Location

Contrast Material

CO2 ICM IVUS

Aorta 6.95 6 1.11 (9) 7.17 6 1.10 (9) 9.89 6 1.28 (9)Nondependent iliac 4.3 6 0.64 (5) 4.11 6 0.85 (5) 6.05 6 0.72 (5)Dependent iliac 4.25 6 0.43 (5) 4.53 6 0.56 (5) 6.45 6 0.72 (5)Overall 5.89 6 0.75 (9) 6.03 6 0.81 (9) 7.19 6 0.75 (9)

Note.—Values expressed as means 6 SD. Number of animals measured presentedin parentheses.

986 • CO2 versus Iodinated Contrast Material for Angiography August 2001 JVIR

LAO, and PA) on the DSA/IVUS ratio.The same model was also fit to excludethe LAO and RAO projections in one an-imal that had spasm that was unrespon-sive to nitroglycerine. The model wasthen fit separately for each level of anysignificant effects. The 95% CIs of the ra-tios, and for the difference between theratios, were calculated for each level ofany significant effects. A secondary anal-ysis was performed to compare the ratiosin hand-injected CO2 studies to the ratiosin CO2 injector studies.

To examine the effect of measure-ments in dependent versus nondepen-dent iliac arteries, a generalized estimat-ing equation model was fit to use onlythe iliac measurements. The type of iliacmeasurement (dependent vs nondepen-dent) was included in this model, in ad-dition to contrast and position. Finally,to examine the contrast effect in depen-dent and nondependent iliac arteriesalone, generalized estimating equationmodels were fit separately for measure-ments of dependent and nondependentiliac arteries.

RESULTS

Diameters measured angiographicallywith ICM were 70.7% 6 4.4% of corre-sponding IVUS measurements. Thosemeasured with CO2 were 69.6% 6 6.3% ofcorresponding IVUS measurements.There was no difference between CO2 andICM (P 5 .311). Animal position had noeffect when analyzing all data (P 5 .477)or when analyzing only iliac measure-ments (P 5 .499). Contrast material under-estimation (with either ICM or CO2) wasslightly worse in the iliac arteries than inthe aorta (67.4% 6 1.5% vs 71.4% 6 1.7%;P 5 .038). There was no difference be-tween ICM and CO2 underestimation ofnondependent (P 5 .163) or dependentiliac arteries, but CO2 angiography tended

to more greatly underestimate vessel sizein the dependent iliac artery (66.3% 64.8% vs 70.3% 6 5.4%; P 5 .051). Exclu-sion of data in the one animal that hadunresponsive spasm in the iliac arteriesdid not change these results. The CO2 in-jector underestimated vessel diameter byan additional 7.4% 6 2.9% compared tohand-injected CO2 (64.3% 6 2.3% for theinjector, 71.7% 6 1.7% for hand injections;P , .0001).

DISCUSSION

In current practice, vessel measure-ments for planning arterial interventionare most commonly based on contrast an-giography measurements. This is oftenperformed with an internal marking cath-eter as a calibration guide. Previous stud-ies have evaluated the accuracy of con-trast angiography compared to IVUS forthe purposes of measuring vessels forintervention. Although several studies in-dicate that angiography underestimatesvessel size compared to IVUS (18–21),Froelich et al (22) demonstrated a slightincrease in diameter measurements withangiography compared to IVUS andperfusion fixation measurements. Inprevious studies with phantom models,IVUS demonstrated excellent correla-tion to actual phantom measurements(23,24). For this reason, we chose to useIVUS rather than perfusion fixation asour reference standard.

In a previous study of CO2 angiog-raphy versus angiography with ICMin a flow model, Moresco et al (17)demonstrated that CO2 overestimatedvessel measurements compared toIVUS. Also, CO2 failed to opacify thenondependent iliac limb of the flowmodel. This is in contrast to previousresults with contrast angiography inliving systems (18–21).

Our results indicate that both CO2

and ICM angiography underestimatevessel sizes compared to IVUS. In ad-dition, there is no significant differ-ence between CO2 angiography mea-surements and ICM angiographymeasurements. Size underestimationwas greater in the iliac arteries forboth CO2 and ICM. One explanationfor this is that the marker catheter wasin the aorta and not the iliac arteries.Because iliac arteries lie in a differentplane than the aorta, magnificationsfor these vessels are different than themagnification of the marker catheter.Despite the significance of the differ-ence (P 5 .038), the magnitude of thedifference is very small (67.9% DSA/IVUS ratio for iliac arteries and 71.4%DSA/IVUS ratio for the aorta). There-fore, both CO2 and ICM underesti-mated vessel diameter by approxi-mately 30% in the iliac arteries andaorta.

With CO2 injections, the size of thedependent iliac artery was moregreatly underestimated than it waswith ICM injections (66.3% 6 4.8% vs70.3% 6 5.4%). This approached sig-nificance (P 5 .051) and can be ex-plained on the basis of CO2’sbuoyancy. CO2 floats on blood, so itwill tend to fill the nondependent ves-sels more so than the dependentvessels. However, in this experiment,CO2 injections filled both the depen-dent and nondependent iliac arteriesand the magnitude of the differencewas very small. The CI for these datainclude 70% undersizing for both CO2and ICM.

It was notable that hand-injectedCO2 underestimated vessel size lessthan injections with a prototype CO2injector. We used the CO2 injector inan attempt to standardize ourinjections. Hand injections were usedbecause, midway through the experi-ment, the CO2 injector failed to reli-ably inject contrast material withoutcausing significant pain in theanimals. We believed that it was be-cause blood backed up into the tubingconnected to the injector and causedthe formation of carbonic acid, whichcan be painful on injection. When thecatheter is maintained without salinesolution in it, no water contacts theCO2 to form carbonic acid, and there-fore the injections cause no pain in thepigs. Despite this discovery, we wereunable to reliably use the CO2 injectorin the last five pigs, so 35 mL of CO2

Table 2Percentage of IVUS Measurement Calculated by Dividing Contrast Measurementby IVUS Measurement and Multiplying by 100

Location CO2/IVUS IC/IVUS P Value

Aorta 70.4 6 6.8% (9) 72.4 6 4.5% (9) .311Nondependent iliac 71.4 6 11.0% (5) 67.4 6 6.8% (5) .163Dependent iliac 66.3 6 4.8% (5) 70.3 6 5.4% (5) .051Overall 69.6 6 6.3% (9) 70.7 6 4.4% (9) .311

Note.—Values presented as mean 6 SD with number of animals measuredpresented in parentheses.

McLennan et al • 987Volume 12 Number 8

was hand injected for each CO2 studyin these animals. With hand injections,CO2 underestimated vessel size by71.7% 6 1.7%, whereas the injector un-derestimated size by 64.3% 6 2.3%.This suggests an approximate 70% un-dersizing with hand-injected CO2,which is not significantly differentthan undersizing with use of ICM.

In one animal, severe spasm was notedduring the IVUS phase of the PAprojection. This continued throughout theprocedure. The analysis was repeatedwith these data excluded from the set andno significant change was noted in thedata set or the difference between CO2 orICM.

In conclusion, CO2 and ICM bothunderestimate vessel size by approxi-

mately 70% in this animal model. Thissuggests that CO2 may be used asreadily as ICM for measurements forthe purpose of intervention. Both con-trast agents underestimate vessel sizescompared with IVUS. Because CO2and ICM both underestimate vesselsize by approximately 70%, no correc-tion factor is needed to measure vesselsize with CO2 injections as long as thevolume injected is sufficient to opacifythe vessel to be measured.

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Figure 1. Arteriography and IVUS measurements: CO2 (a) and ICM (b) in the PA projection. Measurements were made every 2 cmfrom the renal arteries to the distal iliac arteries. As an example, measurements at position 8 (arrow) were 8.9 mm for CO2 and 8.9 mmfor ICM whereas the measurement with IVUS (c) was 11.1 mm 3 11.3 mm. With the animal in the LAO position, CO2 (d) and ICM (e)measurements were obtained. In the dependent iliac artery, the measurement was 5.3 mm at position 14 (open arrow) for CO2 and 4.8mm for ICM whereas the measurement with IVUS (f) was 7.8 mm 3 7.1 mm.

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