Infusion of Contrast Agent

Modeling Infusion Assuming a rate of infusion of n (mg/second) and a plasma volume of

Vp, and if we assume no loss of contrast agent in the interstitium (blood pool agent) then

dp n
= n
dt V p

Blood Pool
n
p= ⋅t
€ Vp

€
Plasma Concentration

Time
 Infusion of Contrast Agent
Modeling Infusion Assuming a rate of infusion of n (mg/second) and a plasma volume of
Vp, and we assume a one-way rate of loss from the plasma to interstitium of K12p then

Change in plasma concentration dp n

= − K12 p K12
of contrast reagent over time dt V p Blood Pool

To simplify, lets substitute K12 = K/VP, where K is an constant.

€

dp n − Kp
=
dt Vp
Figure 6.10
# −
K &
t Dawson
n% Vp
p(t) = 1− e (
€ K %$ ('

€
 Infusion of Contrast Agent
Modeling Stoppage of Infusion When infusion stops the plasma levels of contrast agent
immediately begins to decline, in accordance with our two-compartmental model

Figure 6.1
p(t) = Ae− λ1 t + Be− λ2 t
Dawson

Figure 6.12 Blood curve modeling for

contrast agent injection rates of
Dawson n = 2, 3, and 5 mg/s

Faster infusions produce higher, earlier peaks but the blood concentrations fall to lower levels
faster than for the slow infusions.
 Infusion of Contrast Agent
Biphasic Infusion Below is an example of a biphasic infusion: 5 mg/second for ten seconds
followed by 1 mg/second for 100 seconds.

The values of Cis(t) were calculated in a

step-wise manner from the difference
equation.

Figure 17.9 ‘A’ corresponds to Cis for the monophasic

Dawson infusion.

‘B’ corresponds to Cis for the biphasic

infusion.

The regimen above produces more prolonged elevation of blood levels of contrast agent
compared with single infusion rates of equal volume.

The later equilibrium point may be important for slower incremental scanners.
 Bolus Dynamics
Bolus Dynamics Bolus dynamics is defined as the study of time-attenuation curves observed
in one set of vessels, such as the arteries (arterial curve), after injection of a short bolus of
contrast medium into the proximal circulation, usually the systemic veins.

Contrast density (CT number)-time curves

for the aorta following intravenous bolus
injection of contrast medium

Figure 7.3 CT number is also known as the Hounsfield

Dawson number

CT Number The CT number (i.e. contrast density/

attenuation) obtained post-injection of contrast agent is
linearly related to iodine concentration, if the
Figure 7.4
background, pre-contrast, CT number is first subtracted.
Dawson

CT Number = (µROI - µwater)/ µwater * 1000

 Bolus Dynamics
Bolus Quality In general, for optimal bolus quality we wish to
AUC = Area Under Curve
1.  Maximize AUC
PH = Peak Height
2.  Maximize PH MTT = Mean Transit Time
RT = Rise Time
3.  Minimize MTTc and RT for most applications

Figure 6.8
Dawson

The faster the injection the higher and narrower the time-attenuation curve, but only up to a point after which there is no
further improvement
 Modeling Phamacokinetics
Practical Limitations: There are several practical limitations to our understanding of early
phase contrast medium pharmacokinetics including

1.  Data Collection: It is difficult to measure rapidly changing data (particularly when blood
samples are used). In the literature, there is considerable variation in the early phase, λ1,
constants.
2.  Mixing: At very early times, plasma is not a well mixed compartment.

Ionic vs. Non-Ionic In general, ionic and non-ionic iodinated contrast agents exhibit
different bolus dynamics.

1.  Early Phase, λ1, values: Non-ionic agents have a lower λ1 value (i.e. slower distribution)
because their lower osmolality and larger molecular size cause reduced osmotic effects
and slower transfer to the extra cellular fluid (better retained in the vasculature).
Non-ionic reagents have a higher peak height (PH) on the time-attenuation curve.
2.  MTT and RT: Mean transit time and rise times are longer for non-ionic reagents due to
due to more iodine in the bolus.
3.  CBV: Ionic compounds have a larger volume of blood between the injection and
sampling site (central blood volume, CBV) due to osmolality effects ⇒ lower PH
 Functional and Physiological Imaging
Perfusion Perfusion is defined as volume per unit time of blood entering a unit mass of tissue
(i.e. mL/minute/mg). Perfusion is an important physiological relevant index.

Typically, radiologists work with ROI volumes of tissue as opposed to mass (i.e. mL/minute/mL)

Blood flow into an ROI volume (i.e. voxel)

F
Perfusion =
ROI V
ROI volume (i.e. voxel)

The net change in iodine concentration,

€ δc(t), during the time interval t to t + δt in the volume V
can be written as
Fa(t)δt = amount of
Conservation of Mass Equation δc(t)V = F [ a(t) − v(t)]δt iodine arriving

Fv(t)δt = amount of
Arterial concentration Venous concentration iodine leaving
of iodine of iodine
€
Rearranging and integrating with respect to t gives

F c(t)
= t t
V ∫ a(t) − ∫ v(t)
0 0
 Functional and Physiological Imaging
Perfusion w/ No Washout If we look at perfusion in a tissue assuming that the contrast
medium has not yet left the tissue (no washout), but a maximum concentration value has been
achieved (at t = tmax) then

Known as the Mullani-

Gould Relationship
F c(t) F c(t max )
= t t = t max
V ∫ a(t) − ∫ v(t) V ∫ a(t)dt tmax must be less than the
0 0 0 time at which venous
outflow begins

€ €
Figure 7.5
The arterial curve (time-attenuation curve)
Dawson must be corrected for recirculation using a
gamma-variate curve fit.

The assumption of no venous washout causes the perfusion to be underestimated when it is above
approximately 2.5 mL/min/mL
 Functional and Physiological Imaging
Alternative Approach to Measure Perfusion
dc(t)
F c(t) F
= t t = dt
V ∫ a(t) − ∫ v(t) V a(t) − v(t)
0 0

Again if we assume tmax < tven, where tven is the time at which venous outflow begins we have
€ €

" dc(t) % Maximum slope of tissue attenuation

curve (g0)
$# dt '& Figure 7.7
F t max
= Dawson
V a(t max ) Peak height of the arterial curve (ga)

€ Not necessary to perform a gamma-variate fit, since

This method of finding perfusion is referred to as the
gradient method. only the peak height of the arterial curve is of interest.
 Functional and Physiological Imaging
Alternative Approach to Measure Perfusion The “gradient method” is less sensitive to
venous outflow since the peak slope of the tissue attenuation curve occurs sooner than the
peak height

This example is more representative or raw data with

venous outflow (washout) and recirculation
Figure 7.8
Dawson

The gradient method is noisier than the Mullani-Gould method due to difficulty in measuring the
peak slope.

It is better to use the gradient method on organs with fast transit times (e.g. kidney) and the
Mullani-Gould method on organs with slower transit times (e.g. spleen) to get less noisy data.
 Functional and Physiological Imaging
Example Data Below are typical curves obtained for a region of interest analysis in dynamic
CT using electron beam (ultrafast) CT.

Aorta

Figure 7.9
Dawson

Spleen
 Functional and Physiological Imaging
Linear Systems Analysis Each organ traversed by a tracer bolus adds its own mean transit
time (MTT) to that of the bolus, thereby broadening it.

Following intravenous injection, the bolus arriving on the arterial side of the circulation must pass
through the heart and the lungs

Assuming an instantaneous venous injection:

Figure 15.1 MTT on arterial side MTT of heart MTT of lungs

Shier
t arterial = t heart + t lungs

€
 Functional and Physiological Imaging
Compartmentalization When contrast enhancement of tissue is considered, the contrast
agent in the ROI will not only provide information on perfusion, but also compartmentalization.

Compartments within organs typically include the interstitium, intracellular locations, and
intravascular (blood) space.

∅B + ∅is + ∅c = 1
VBlood/VROI Vinterstitium/VROI Vcell/VROI

Figure 7.13
Dawson
 Functional and Physiological Imaging
Compartmentalization Since, in general, iodinated x-ray contrast agents do not enter cells,
the two compartments between which the contrast agent is distributed is the intravascular and
interstitial spaces.
Concentration of contrast agent in interstitium

C(t) = ∅isCis (t) + ∅B B(t)

Effective concentration of contrast Weighting factors, the proportionate Concentration of contrast agent in blood
agent in the tissue interstitial and blood volumes in the ROI

€ (i.e. ∅B=VB/VROI and ∅is=Vis/VROI)

Rearranging the above equation we get an equation describing the enhancement of tissue
contrast over blood

C(t) C
= ∅is is + ∅B
B(t) B(t)

Remember B(t) = (1− Hct ) p(t) where Hct is the haematocrit

€
C(t) Cis
= ∅is + ∅B
€
B(t) (1− Hct ) p(t)
 Functional and Physiological Imaging
Measuring Proportionate Blood Volumes For a blood pool agent (i.e. no extravascular
leakage) we can simplify our tissue enhancement equation
C(t) Cis
= ∅is + ∅B
B(t) (1− Hct ) p(t)

€ C(t)
= ∅B
B(t)

The time-attenuation curve of tissue and the arterial curve can therefore be used to determine the
proportionate blood volume
€

∞ Can be calculated from the time-

∅B =
C(t)
=
∫ 0
C(t)dt attenuation curve of the tissue
∞
B(t) ∫ a(t)dt Can be calculated from the
0 arterial curve

€
 Functional and Physiological Imaging
Compartmentalization If a blood pool agent is not used, the background-subtracted CT
numbers can still be substituted for C(t) and B(t) in the equation below; however, Cis(t) cannot
be directly measured.
C(t) Cis
= ∅is + ∅B
B(t) (1− Hct ) p(t)
At very early time points there is very little contrast in the interstitium so

€ C(t)
Cis ~ 0 = ∅B
B(t)

At later times (i.e. equilibrium phase)

€
€
C(t) ∅is
Cis ~ p(t) = + ∅B
B(t) (1− Hct )

€ €
 Functional and Physiological Imaging
Compartmentalization Interstitial and cellular proportionate blood volume, ∅is and ∅c,
can be determined by first using the aortic and tissue time-attenuation curves to determine B(t)
and C(t), respectively, and then plotting C(t)/B(t) vs. time (known as a Patlak-type plot).

Figure 7.20
Dawson

Although the equation for C(t)/B(t) predicts a y-intercept of ∅B, in reality this is not the case
because when the bolus first arrives in the ROI it must first displace the non-contrast
containing blood.

The Patlak-type plot can be used to solve for ∅is using the equation
$C( t ) '
∅is = & − ∅B )(1− Hct )
% ()
B t (

Further, ∅c can be determined using ∅B + ∅is + ∅c = 1.

€
 Functional and Physiological Imaging
Compartmentalization of the kidney For the kidney, compartmentalization includes the
contrast agent in the blood vessels and in the renal tubules (having been filtered by the
glomeruli).

In the kidney the interstitial space is small, and because of the very high permeability is
effectively part of the vascular space.

X-ray contrast agents do not significantly enter cells.

Poorly perfused Well-perfused kidney -

kidney Compartmentalization
Figure 7.5 Figure 7.14
Dawson Dawson
 Functional and Physiological Imaging
Compartmentalization of the kidney The effective concentration C(t) of contrast agent
at any time, t, in the kidney may be expressed as

Clearance by the kidney (mL/sec) VBlood/VROI

α t
C(t) =
V
∫ 0
B(t)dt + ∅B B(t)

Volume of ROI
Contribution of Contribution of
contrast agent in contrast agent in
renal tubules blood
€

Divide by B(t)

α t
C(t) V ∫ 0 B(t)dt
= + ∅B
B(t) B(t)

€
 Functional and Physiological Imaging
Compartmentalization of the kidney Clearance and proportionate blood volume, ∅B,
can be determined by first recording the aortic (a) and renal cortical (b) time-attenuation
curves.
(a) (b)

Figure 7.16
Dawson

t
t C(t) ∫ B(t)dt
∫ 0
B(t)dt can be calculated and then a plot of
B(t)
vs. 0
B(t)
yields a straight line
α t
C(t) V ∫ 0 B(t)dt
since B(t) = B(t) + ∅B
€ €
€
Figure 7.17
€
This is known as a Patlak plot Dawson
 Functional and Physiological Imaging
Patlak Plot An example of aortic and renal cortical contrast density (attenuation)-time
curves and the corresponding Patlak plot are shown below

Figure 7.3 Figure 7.18

Dawson Dawson

α
Gradient = ≈ 0.035mL / min/ mL
V
∅B ≈ 30%

€
 Functional and Physiological Imaging
Renal Transplants Patlak plots can be used to distinguish between normally functioning
and abnormal (rejecting) transplant kidneys.

Figure 7.19
Dawson

The gradient of the plot (the blood clearance per unit volume) and the intercept (proportionate
vascular volume) are both reduced.

A reduced proportionate vascular volume may reflect microangiopathy (disease effecting

walls of very small blood vessels, capillaries, become so thick and weak that they bleed, leak
protein, and slow the flow of blood).
 Functional and Physiological Imaging
Compartmentalization in Cancer Tumors tend to exhibit different and distinct
enhancement characteristics from the background normal tissue.

Malignant Breast Tumor

Figure 7.21
Dawson
Normal Breast
 Functional and Physiological Imaging
Compartmentalization in Cancer As discussed earlier, the concentration of contrast
agent in a tissue depends on four variables: ∅B, ∅is, Cis(t), and B(t) as follows

C(t) = ∅isCis (t) + ∅B B(t)

For simplicity, if we assume one-way transfer (i.e. no contrast agent leaving the tumor) then
The number of mL/min of blood
€ that cross the capillary wall.
Note the similarities between compartmentalization
PS t in cancer and compartmentalization in the kidney,
∅isCis (t) =
V
∫ 0
B(t)dt where PS is similar to clearance (α).

where PS/V is called the “PS product” per unit volume of the ROI considered and

PS = Capillary permeability · Capillary surface area PS is indicative of blood vessel leakiness

€

The concentration of contrast agent in the tissue is therefore

PS t
C(t) =
V
∫ 0
B(t)dt + ∅B B(t)
 Functional and Physiological Imaging
Compartmentalization in Cancer After 30 seconds or so following bolus injection
∅isCis(t) dominates since most of contrast agent enters the interstitial tissue due to leaky
vasculature.
∅isCis(t)

PS t
C(t) =
V
∫ 0
B(t)dt + ∅B B(t)

B(t) fall dramatically from its peaks as the

contrast agent rapidly enters the interstitium.

∅B in a tumor is only about 5%.

€
PS t
C(t) =
V
∫ 0
B(t)dt

€
 Functional and Physiological Imaging
Compartmentalization in CancerAt early time points, the slope of the C(t) against t
curve is dominated by the term PS/V, which can be estimated to be the initial slope.

Figure 7.22
Dawson

The initial slope is indicative of blood vessel leakiness or the permeability-surface area (PS) product per unit volume.

Typically, the PS products of tumors are several-fold greater than those of normal tissue.
 Functional and Physiological Imaging
Equilibrium point in Cancer The C(t) vs. t curve stops rising when Cis(t) ~ p(t) (i.e.
equilibrium point).

C(t) = ∅isCis (t) + ∅B B(t)

Remember B(t) = (1− Hct ) p(t) where Hct is the haematocrit

€ C(t) Cis
= ∅is + ∅B
B(t) (1− Hct ) p(t)
€
In the equilibrium phase Cis(t) ~ p(t)

€
This is the same equation we
C(t) ∅is
= + ∅B
used earlier for normal tissue
B(t) (1− Hct ) Figure 7.22
Dawson

$ ∅ '
is
€ C(t) = & + ∅B )B(t)
%(1− Hct ) (

This plateau is typically several-fold higher in tumors than in normal tissue.

€
 Functional and Physiological Imaging
Contrast Ehancement in Tumors Taking typical normal tissue and tumor indices

Table 17.2
Dawson

It can be shown that

$ ∅T '
Tumor concentration & is T
+ ∅B ) 0.45
of contrast agent
C (t) % (1− Hct )
T + 0.05
( 1− 0.4
= = = 2.18
N
C (t) $ N
∅ is ' 0.16
+ ∅NB ) 1− 0.4 + 0.1
Normal tissue
concentration of &
contrast agent % (1− Hct ) (

This explains the greater plateau height of tumor curves.

€
 Functional and Physiological Imaging
Low Density Lesions It should be noted that some lesions are less dense than normal tissue.
For example, lets consider a liver lesion that has a CT number that is 25 HU (Hounsfield units)
lower than normal liver tissue on a pre-contrast scan.
Δ = C N (t) − C T (t) = 25 HU
Following intravenous injection of contrast agent, the difference between normal liver and
tumor concentration of contrast agent can be written as

€ % ∅N ( % ∅T (
N T
Δ =' is
+ ∅ B *B(t) − ' is
+ ∅ B *B(t)
&(1− Hct ) ) &(1− Hct ) )

Using some typical values we get

€ $ 0.16 ' $ 0.45 '
Δ =& + 0.1)B(t) − & + 0.05)B(t) = −0.43B(t)
%1− 0.4 ( %1− 0.4 (

When B(t) = 50 HU, Δ ~ -25 HU, which would eliminate the 25 HU difference we began with.
€
The equilibrium phase (as shown here) can present a diagnostic pitfall.
 Functional and Physiological Imaging
Imaging Liver Metastases The liver has a dual blood supply comprising the hepatic artery
(20% of blood flow) and the portal vein (80% of blood flow).

Hepatic Vein

Hepatic Artery

Gallbladder
Common Portal Vein
Bile Duct

Liver metastases (i.e, tumor growth at a site distant from the primary tumor site) are supplied
predominantly by the hepatic arterial supply alone.

The pharmacokinetics of the liver can be taken advantage of to maximize lesion contrast.
 Functional and Physiological Imaging
Imaging Liver Metastases Following intravenous injection, contrast medium arrives in the
hepatic artery after 8 - 12 seconds.

The time taken for the concentration of contrast agent in the hepatic artery to peak depends on
the infusion rate.

Contrast medium does not arrive in the portal vein until another 12 seconds or so have passed.

Figure 17.10 a and b Requires fast imaging (i.e spiral/

helical technology). Incremental
Dawson imaging is too slow.

Hepatic Arterial Phase: Early imaging (i.e. within 20 seconds) will yield a largely hepatic
arterial phase and may show vascular metastases as enhanced more brightly than normal liver.
 Functional and Physiological Imaging
Imaging Liver Metastases
Portal Phase: During the later portal phase there is a bright enhancement of the normal liver
and poor enhancement of liver metastases.

Figure 17.10
Dawson

Timing: It is desirable to delay commencement of scanning until the portal enhancement curve
is near its peak, but it is also desirable to complete scanning before ‘equilibrium’.