3 Contrast Medium Delivery for Vascular MDCT:Principles and Rationale

DOMINIK FLEISCHMANN

CONTENTS

3.1 Introduction 273.2 Physiologic and Pharmacokinetic Principles 273.2.1 Early Contrast Medium Dynamics 273.2.2 Effects of Injection Parameters on Arterial

Enhancement 283.2.3 Effects of Physiologic Parameters on Arterial

Enhancement 283.3 Mathematical Modeling 293.4 Consequences for Vascular MD-CTA

Applications 303.4.1 Basic Injection Strategies for MD-CTA 313.4.2 Scanning Delay and Automated Bolus

Triggering 323.4.3 Saline Flushing of the Veins 323.5 Conclusion 33

References 33

3.1Introduction

Optimal vessel opacification remains one of themost crucial but difficult aspects of multiple detec­tor-row CT angiography (MD-CTA). With each newgeneration of MDCT scanners, acquisition timeshave become, and will become substantially shorter.Thus, controlling the level and time-course of arterialenhancement and correct synchronizing CT acqui­sition relative to arterial enhancement has becomemore difficult and "less forgiving:'

The purpose of this review is to explain the physi­ologic and pharmacokinetic principles as well as theeffect of user selectable contrast medium injectionparameters on arterial enhancement. From there,strategies for the rational design of contrast medium

D. FLEISCHMANN, MDAssistant Professor of Radiology, Department of Radiology,Stanford University Medical Center, 300 Pasteur Drive, RoomS-068B, Stanford, CA 94305-5105, USA

injection strategies for vascular multiple detector­row CT (MDCT) will be derived.

3.2Physiologic and Pharmacokinetic Principles

When iodinated contrast medium (CM) is injectedintravenously, one will observe a subsequentenhancement response in a patient's arterial system.In general, this enhancement response is dependenton physiologic parameters, which are beyond thecontrol of the observer, and which are characteristicfor a given vascular territory of interest in a givenindividual. Within physiologic limits , however, theenhancement response can be modified by userselectable parameters, like the volume and theinjection flow rate of the CM.

3.2.1Early Contrast Medium Dynamics

Intravenously injected contrast medium travels fromthe arm veins to the right heart, the lungs, and theleft heart before it reaches the arterial system for thefirst time ("first pass") (BAE et al. 1998). The timeinterval between the beginning of the i.v. injectionand the subsequent arterial enhancement is alsoreferred to as the contrast medium transit time(tCMT)' After the contrast medium is distributedthroughout the organs with their intravascular andinterstitial fluid compartments it reenters the rightheart ("recirculation"). It is important to recognizethat within the time-frame relevant for CTA one willnot only observe the first pass of contrast mediumbut also its recirculation. As illustrated in Fig. 3.1,theinjection of a small test-bolus of CMcauses an initialarterial enhancement peak (the "first pass" - effect),followedby a low,shallow enhancement which is dueto recirculation effects (primarily due to early venousreturn from the brain and the kidneys).

M. F. Reiser et al. (eds.), Multislice CT© Springer-Verlag Berlin Heidelberg 2004

28 D. Fleischmann

8 ,.-- - - - - ---, 400,- - - - - - - - - - ----,

16mlCM6 •••. .. . . .••••• .... •.•••• 300 .

Fig. 3.1. Intravenous contrast medium (CM) injectioncauses an arterial enhancement response, which con­sists of an early "fist pass" peak, and a lower undulat­ing "recirculat ion" effect.There is a proportional rela­tionsh ip between the CM injection rate (mils), and theresulting arterial enhancement response. Doubling theinjection flow rate (doubling the iodine admini stra­tion rate) results in approximately twice the art erialenhancement. tCMT> Contrast medium transit time

1---., tCMY

200

400,-- - - - - - - - - - ---,

100

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300 •••••••••••• ••••• •••••••••• •••••• ••••••• • ;;;.;;:

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o+--,hl...,---,--r-~=:::;:=;::~9 17 25 33 0 8 16 24 32 40 48 56 64 72 80

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3.2.2Effects of Injection Parameterson Arterial Enhancement

Arterial enhancement can be modulated by two userselectable parameters: the CM injection rate (moreprecisely: the iodine administration rate), and theinjection duration. Both parameters together deter­mine the total CM volume (or total iodine dose).

InjectionFlowRate (IodineAdministration Rate)

The arterial enhancement response to intravenouslyinjected CM is proportional to the iodine administra­tion rate . Thus, doubling the iodine administrationrate (and dose) causes approximately twice the arterialenhancement (Fig. 3.1).The iodine administration ratecan be increased either by increasing the injection rate,or by increasing the iodine concentration of the CMused. For example, instead of increasing the injectionrate from 4 ml/s to 6 mlIs with standard concentrationCM (300 mg I /rnl), the same iodine administration ratecan be achieved with only 4.5 ml/s if a high concentra­tion agent (400 mg I ImI) is used . Low concentrationcontrast media, on the other hand, have the advantagethat they cause less perivenous artifacts at the level ofthe brachiocephalic veins and the superior vena cavain thoracic MDCT, particularly if no saline flushing ofthe veins is employed (RUBIN et al. 1996).

InjectionDuration

The arterial enhancement effect caused by a pro­longed injection of CM is more difficult to under-

stand, because it requires the integration of first-passas well as recirculation effects (FLEISCHMANN 2002).This is illustrated in Fig. 3.2: A prolonged injectionof 128 ml of CM can be viewed as a series of eightconsecutive test boluses of 16 ml. Each of these testboluses has its own effect on arterial enhancement.The cumulative arterial enhancement to the totalvolume of a 128 ml bolus is the sum (time inte­gral) of each of the eight individual enhancementresponses to the small test injections. Note, that therecirculation effects of earlier test boluses overlapwith first-pass effects of later test boluses.

The most important consequence of this phe­nomenon is, that a continuous injection of CM leadsto a continuous increase of vascular enhancement.This is in contradistinction to the intuitive but erro­neous notion, that a continuous CM injection leadsto a vascular enhancement plateau, which is desir­able for MD-CTA.

In other words, a prolonged injection durationleads to a stronger arterial enhancement, whereasshorter injections will not reach the same level ofenhancement if the injection rate is unchanged.

3.2.3Effects of Physiologic Parameterson Arterial Enhancement

The degree of arterial enhancement following thesame intravenous contrast medium injection ishighly variable between individuals. For example,arterial enhancement in the abdominal aorta mayrange between 140 HU and 440 HU between patients

Contrast Medium Delivery for Vascular MDCT:Principles and Rationale

8 -------- -, 400.,-- - - - - - - - - - - --,

16ml CM6 •••. •••••• •••••••••••••• 300 ••••••••••••••••••••••••••••••••••.••••.•

4 mils t (MY200 .....••..•..••.••. ••. .•• .•• .••.••. ••••••

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29

Fig.3.2.Simple"additive model" illustrates therelationship between contrast medium (CM)injection duration and cumulative arterialenhancement. Note that due to the asymmetricshape of the test-enhancement curve and dueto recirculation effects, arterial enhancementfollowing an injection of 128 ml (the "timeintegral of 8 consecutive 16ml") increasescontinuously over time. There is no enhance ­ment plateau. (From FLEISCHMANN (2002),with permission)

receiving the same amount of i.v, CM (SHElMAN etal. 1996). The key physiologic parameters affectingindividual arterial enhancement are cardiac outputand the central blood volume.

Cardiac output is inversely related to the degreeof arterial enhancement, particularly in first passdynamics: If more blood is ejected per unit of time,the contrast medium injected per unit of time will bemore diluted. Hence, arterial enhancement is stron­ger in patients with low cardiac output (despite theprolonged contrast transit time).

Central blood volume is also inversely related toarterial enhancement but more importantly toorgan enhancement (DAWSON and BLOMLEY 1996).Central blood volume correlates with body weight.If total contrast medium volumes are chosen rela­tive to body weight, then 1.5-2.0 mllkg bodyweight(450-600 mg I/kg) are a reasonable quantity.

3.3Mathematical Modeling

Ideally, one wants to predict and control the timecourse as well as the degree of vascular enhancementin each individual - independent of an individual'sunderlying physiology.Twomathematical techniquesaddressing this issue have been developed.

The first is a sophisticated compartmental model,which predicts vascular and parenchymal enhance­ment using a system of more than 100 differential

equations to describe the transport of contrastmedium between intravascular and interstitial fluidcompartments of the body (BAE et al. 1998).For CTangiography, this model suggests multiphasic injec­tions to achieve uniform vascular enhancement. Theinjection flow rate is maximum at the beginning ofthe injection followed by a continuous, exponentialdecrease of the injection rate (BAE et al. 1998).

The second black-box model approach is basedon the mathematical analysis of a patient's char­acteristic time-attenuation response to a smalltest bolus injection {FLEISCHMANN and HITTMAIR1999).Assuming a time-invariant linear system, onecan mathematically extract and describe each indi­vidual's response to intravenously injected contrastmedium ("patient factor") and use this informationto individually tailor biphasic injection protocols toachieve uniform, prolonged arterial enhancementat a predefined level. The principle of this tech­nique is outlined in Fig. 3.3. The method is robustand has been successfully used in clinical practice(FLEISCHMANN et al. 2000) .

Despite the advantages of mathematically derivedinjection protocols, both models are not widelyused because they are not commercially availableand because of the additional time needed for cal­culating individual injection protocols and becauseof the need for a test-bolus injection. The greatestvalue of mathematical modeling, comes from thegained insights into early contrast medium dynam­ics for the time frame relevant for current andfuture CT technology, which allows a more rationaldesign of empiric but routinely applicable injectiontechniques.

D.Fleischmann30

a Testbolus b Test Enhancement

16ml @4/5 I10 I

:'!1 5 100 1-:I:oS 5 s~

~ 0 0

0 10 20 5 20 35 50 65Injecti on duration (5) time (5)

Fig.3.3a-h. Flowchart illustrates the fourmain steps to characterize, predict , andoptimize arterial enhancement in e TA ofthe aorta using the "black-box" model. Thecalculation of the optimized biphasic bolusfor this 65-year-old patients is based on theselection of an "ideal" enhancement of 200tl.HU for 30 s, with slopes of increase anddecrease of 200 HU/6s. Step 1: The pat ientf unction is calculated in Fourier space fromthe relation of a 16ml test bolus (a) to thepatient's correspond ing aort ic time attenua­tion response, the test enhancement (b). Step2: Once the pat ient f unction is known, thestandard enhancement (d) to an arbitrarybolus, like, e.g. a 120-ml standard bolus (c)can be predicted. Step 3: With the use of thepatient funct ion, it is also possible to calculatea theoretically "ideal" bolus (e), which is sup­posed to achieve an "ideal;' near rectangularenhancement (f). Step 4: As the theoretically"ideal bolus" (e) contains "unreal" compo­nents in the time domain, like oscillations, ornegative flow rates, a fi tting algorithm has tobe introduced, to approximate the "ideal" flowrates into a practically applicable "optimized"biphasic (k: 113ml)bolus (g).The correspond­ing optimized enhanc ement (h) can be pre­dicted as described in step 2. Despite the pro­nounced simplification of the optimized bolus(g) the resulting optimized enhancement (h)does not deviate much from the desired formin the scanning period. Note: Bolus descrip­tors are given as: total volume (ml) at flowrate (mils) . tl.HU: arterial enhancement overbaseline attenuation in Hounsfield units; p.f ,patient function . (From FLEISCHMANN andHITTMAIR 1999, with permission)

d StandardEnhancement

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0 10 20 30 5 20 35 50 65Injecti on du ration (5) time (5)

3.4Consequences for VascularMD-CTA Applications

Depending on the scanner type, the acquisitionparameters, and the vascular territory of inter­est, MDCT scanning times may vary substantially.Whereas high -resolution acquisitions of large

anatomic volumes (e.g. peripheral or whole bodyCTA) and ECG-gated acquisitions (coronary CTA)have scan times in the order of 30 s, a thoracic CTAmay be acquired with in 5 s with a 16-channel MDCTscanner. Independent of the scanner type , the key tooptimal CMadministration for vascular MDCTis anadoption of the injection strategy to the acquisitiontime , and correct scan timing.

Contrast Medium Delivery for Vascular MDCT: Principles and Rationale 31

3.4.1Basic Injection Strategies for MD-CTA

Having early contrast dynamics in mind (notablythe effect of the injection duration) it is obvious, thatthe traditional concept, where the injection dura­tion equals the scanning duration cannot be upheldwithout modifications. Injection protocols should beadopted for longer scan times, and have to be adoptedfor short scan times. Examples of empiric injectionparameters for both, uniphasic and biphasic injectionsare provided in Tables 3.1 and 3.2. Individualizing thedose is only recommended for patients with a bodyweight less than 60 kg and more than 90 kg (reduce

or increase injection rates and volumes for 20%,respectively).

eM Administration for SlowMDCTAcquisitions

When MDCT acquisition times are greater than 15s,injection durations can be chosen traditionally, i.e.equal to the scan time. As a continuous injection ofCM leads to a continuous increase of enhancement,however,vascular opacification will be non-uniformover time, with the brightest enhancement occur­ring at the end of the acquisition. A more uniformprolonged enhancement can be achieved if biphasic(or multiphasic) injection profiles are employed.

Table 3.1. Biphasic Contrast Medium Injection Protocols for MD-CTA

(300 mg J I ml) (400 mg J I ml)

Scanning Delay Total CMvolumes Total CM volumestime (s) tCMT +s" volume at flow rates volume at flow rates

(mI) (ml @ mils) (ml) (ml@ ml/s)

40 tCMT+ 2s 145 ml I: 30@ 6.0 110ml I: 23 @4.5II: 115 @3.1 II: 87 @ 2.4

30 tCMT+ 2s 120ml I: 30@ 6.0 90 ml I: 23 @4.5II: 90 @ 3.3 II: 67 @ 2.5

25 tCMT+ 2s 110 ml I: 30 @6.0 83ml I: 23 @4.5II: 80 @3.5 II: 60 @2.6

20 tCMT+ 2s 100 ml I: 30@ 6.0 75ml I: 23 @4.5II: 70@4.0 II: 52 @2.8

15 tCMT+ 2s 90 mI I: 30 @ 6.0 68 ml I: 23 @4.5II: 70@4.3 II: 45 @ 3.0

10 tCMT+ 4s 80 mI I: 30 @6.0 60ml I: 23 @4 .5II: 70 @4.5 II: 37 @3.0

5 tCMT+ 7s 70ml I: 30@6.0 53ml I: 23 @4.5II: 70@5.0 II: 30 @ 3.0

"2 s is the min imum trigger delay if automated bolus triggering is used; salineflushing is always recommended.tCMT ' Contrast medium transit time. I, initial injection phase; II, continuing injectionphase.

Table 3.2. Uniphasic contrast medium injection protocols for MD-CTA

Scanningtime (s)

403530252015105

DelaytCMT +s"

tCMT + 2 S

tCMT + 2 stCMT + 2 stc MT + 2 stCMT + 7 S

tCMT + 12 S

tCMT + 16 S

tCMT + 20 s

(300 mg J I ml)

Total volume at flow rate(ml @mlls)

160 ml @4.0 mils140mI @4.0 mils120 ml @ 4.0 ml/s115 ml @4.5 ml/s105 mI @ 5.0 mils100 ml @ 6.0 ml/s90 ml @ 6.0 mils80 ml @6.0 mils

(400 mg J I ml)

Total volume at flow rate(ml @mils)

120 ml @ 3.0 mils105 ml @ 3.0 ml/s90 ml @3.0 mils85 ml @ 3.4 mils80 mI @ 3.8 ml/s75 ml @4.5 mils70 ml @ 4.5 ml/s60 ml @4.5 mils

"2 s is the minimum trigger delay if automated bolus triggering is used; salineflushing is always recommended.tCMT> Contrast medium transit time; I, initial injection phase; II, continuing injectionphase.

32

Such injections consist of an initial high-rate injec­tion, followed by a longer slow rate injection phase(FLEISCHMANN et al. 2000).

eM Administration for FastMDCTAcquisitions

Short injection durations with standard injection flowrates (e.g,4 mlJs of 300 mg IIrnl CM) cannot achievethe desired enhancement. To ensure adequate vesselopacification with fast MDCT acquisitions «15 s),the iodine administration rate needs to be increased,if the rule ' injection duration equals scanning dura­tion' is followed. This is achieved either by an increaseof the injection flow rate and/or by using a higheriodine concentration of the CM.Alternatively, one canalso increase the scanning delay in order to allow theenhancement to increaseas well. This strategy,however,requires that the injection duration is also prolonged,which - in return - increases the total CM volume.

3.4.2Scanning Delay and Automated Bolus Triggering

A fixed, empiric injection-to-scan delay may beadequate for slow (>20-30 s) MD-CTA acquisitionsin patients with a low likelihood of cardiovascularcompromise (e.g. living renal donors scanned with afour-channel MDCT scanner). In patients with car­diocirculatory disease, a fixed scanning delay cannotbe recommended, because the arterial contrastmedium transit time (tCMT) can be as short as 8 s,but also as long as 40 s. One might completely missthe bolus with fast MDCTA acquisitions (<20 s) if thedelay is not properly chosen in this patient group.

Accurately synchronizing the acquisition with theinjection requires timing relative to the contrast tran­sit time (tCMT)' It is important to realize that with thepossibility of very fast MDCT acquisitions the tCMTitself does not necessarily serve as the scanning delay,but rather as a means of individualizing the delayrelative to it. Depending on the vessels or organs ofinterest an additional delay relative to the tCMT needsto be selected. In CTA, this additional delay may be asshort as 0-2 s added to the tCMT ("tCMT + 2s").

Test Bolus: The injection of a small test-bolus(15-20 ml) while acquiring a low-dose dynamic(non-incremental) CT acquisition is a reliable meansto determine the tCMT from the intravenous injectionsite to the arterial territory of interest (VAN HOEetal.I995).The tcMTequals the time-to-peakenhance­ment interval measured in a region-of-interest

D. Fleischmann

(ROI) placed within a reference vessel. Furthermore,time attenuation curves obtained from one or moreregions of interest can be used for individual bolusshaping techniques using one of the previouslydescribed mathematical models.

Bolus Triggering: Many CT scanners have this featurebuilt into their system. A circular region-of-inter­est (ROI) is placed into the target vessel on a non­enhanced image. While contrast medium is injected, aseries oflow-dose non-incremental scans are obtained,while the attenuation within a ROI is monitored orinspected visually. The tCMT equals the time when apredefined enhancement threshold ("trigger level")is reached (e.g. 100 ilHU) or observed by the personperforming the scan. The minimal delay to initiate theMDCTacquisition after the threshold has been reached("trigger delay") depends on the scanner model andon the longitudinal distance between the monitoring­series and the starting position of the actual MDCTseries.The minimal "trigger delay" is currently between2 and 8 s.Bolustriggering is a very robust and practicaltechnique for routine use and has the advantage that itdoes not require an additional test-bolus injection.

3.4.3Saline Flushing of the Veins

Flushing the venous system with saline immediatelyafter CM injection pushes the CM column from theveins into the circulation. This has two desirableeffects in MDCT.

First, because the CM which would otherwiseremain in the arm veins after the end of the injec­tion contributes to vascular enhancement, vascularopacification is improved. This effect can also beexploited to reduce the total CM volume in routinethoracic MDCT (HAAGE et al. 2000).Second, becausesaline flushing removes CM from the brachioce­phalic veins and the superior vena cave, it reducesperivenous streak artifacts in thoracic and cardiacCT. This effect is particularly useful for coronaryCTA, because it avoids artifacts arising from the rightatrium and ventricle to obscure the right coronaryartery (Fig. 3.4).

The most convenient technique for routine salineflushing after CM injection are new programmabledouble piston power injectors (one syringe for con­trast material, one for saline) similar to those usedin MR angiography. Furthermore, these devices mayallow not only to vary the injection rates, but alsoto vary the contrast material concentration during

Contrast Medium Delivery for Vascular MDCT: Principles and Rationale 33

Fig.3.4. Coronary CTA with saline flushing. Thin -slab maxi­mum intensity projection (MIP) of ECG-gated coronary CTangiogram shows excellent opacification of the left ventricle,aorta, and right coronary artery, while CM is already flushedout of the right atrium and ventricle ("laevo-cardiogram").(Image courtesy of C. BECKER, Munich)

a single injection (through saline admixture). Sucha strategy might enable one to achieve the desiredenhancement profile by initially injecting non-dilutedcontrast medium, followed by a phase of diluted con­trast medium injection, with subsequent saline flush­ing to avoid artifacts.

3.5Conclusion

MDCT is a powerful and continuously evolving tech­nology for non-invasive (minimally-invasive) cardio­vascular imaging. CM administration is an integralpart of this evolution, and needs to be continuously

adopted and optimized to take full advantage of thistechnology. A basic understanding of physiologicand pharmacokinetic principles and understand­ing of the effects of injection parameters on arterialenhancements are the ingredients for optimized CMdelivery and utilization for current and future vascu­lar MDCT applications.

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Haage P, Schmitz-Rode T, Hubner D, Piroth W, Gunther RW(2000) Reduction of contrast material dose and artifacts bya saline flush using a double power injector in helical CT ofthe thorax. AJRAm J Roentgenol 174:1049-1053

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Sheiman RG,Raptopoulos V,Caruso P,Vrachliotis T,PearlmanJ (1996) Comparison of tailored and empiric scan delaysfor CT angiography of the abdomen. AJRAm J Roentgenol167:725-729

Van Hoe L, Marchal G, Baert AL, Gryspeerdt S, Mertens L(1995) Determination of scan delay-time in spiral CT­angiography: utility of a test bolus injection. J ComputAssist Tomogr 19:216-220