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APPLICATIONS OF MRI CONTRAST IN HIGH-DOSE
Category 1 Continuing Medical Education
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After completing this program, the reader will:
* Understand the current use of gadolinium contrast agents for
MRI, particularly applications that use high-dose contrast media or
high injection rate contrast infusions
* Recognize the ways that radiologists use high-dose MRI
contrast agents in specific clinical applications
* Understand how the advancements in imaging technology and
contrast media can be used to improve MRI procedures in clinical
THIS PUBLICATION WAS SUPPORTED BY AN EDUCATIONAL GRANT
FROM AMERSHAM HEALTH, PRINCETON, NJ. THE OPINIONS EXPRESSED IN
THIS PUBLICATION ARE THOSE OF THE AUTHORS AND NOT NECESSARILY
THOSE OF AMERSHAM HEALTH.
Thomas Grist, MD Professor of Radiology, Chief of MRI
University of Wisconsin, Madison, WI
In April 2002, I was pleased to serve as the moderator for
's focus group discussion of high-dose contrast-enhanced magnetic
resonance imaging (MRI) procedures. This focus group discussion was
aimed at describing a number of issues and challenges facing the
use of high-dose MRI procedures. These presentations and
discussions are published in this supplement to
to share these important insights with the radiology community.
Since the introduction of MRI, we have seen a significant
development in both anatomic and functional imaging procedures, as
well as tremendous technological breakthroughs. At the same time,
there's also been the important development of gadolinium contrast
media for the evaluation of both structure and function with MRI.
In the last decade, since the introduction of the gadolinium
chelates, there has been a tremendous increase in the use of these
agents, which has also presented some challenges.
The physicians using these agents need to understand what dose
to use, what injection rate to use, and what the clinical
indications are for their use. They must also learn some of the
techniques for perfusion imaging, anatomic imaging, and functional
imaging. These all increase the complexity of using these contrast
agents in humans.
This focus group was designed to discuss these areas and the use
of gadolinium agents. We asked each of the speakers to target a
specific anatomic area of interest that is under significant
change, and address how high-dose contrast agents are being
There were several objectives of our discussion. First, we
wanted to review the current use of gadolinium contrast agents for
MRI, and particularly those applications that use either high-dose
contrast media or high injection rate contrast infusions, or have
some other nuance related to the media itself. We also reviewed
some of the similarities and differences in how the various
physicians active in MRI use these agents and how they incorporate
them into their clinical practice. Finally, we wanted each
participant to determine through their clinical experience and
demonstrate exactly how these tools, both the advanced imaging
tools and the available contrast media, fit into their approach to
patients. I would like to make specific mention of the
distinguished panel of experts who participated in this focus
Dr. David Bluemke is experienced in all aspects of body MRI, and
has been involved in the development of these techniques for some
time. He's currently the Clinical Director of MRI at Johns Hopkins
University, Baltimore, MD.
Dr. Nola Hylton is an Assistant Professor of Radiology at the
University of California at San Francisco. She is a leader in the
role of MR in breast imaging.
Dr. Larry Kramer is the director of MRI at Memorial Herman
Hospital in Houston, TX and is a very active practitioner of MRI.
He has performed body and contrast-enhanced MRI procedures for
quite some time, and has incorporated those into his clinical
practice, which is a combination of academic and community
Dr. Russell Low is in practice in San Diego and has been
developing contrast-enhanced MRI procedures in the abdomen for some
time in a private practice setting, with extraordinary results.
Dr. Martin Prince is really credited with bringing forward the
use of 3D contrast-enhanced MRA procedures and the use of high-dose
contrast media for evaluation of the vascular system anatomy. Many
consider him the pioneer of contrast-enhanced MRA. Dr. Prince is
currently a Professor of Radiology at the Weill Medical College of
Dr. David Roberts is an Assistant Professor of Radiology at the
University of Pennsylvania Medical Center, Philadelphia, PA. He is
a recognized leader in MR.
Dr. Howard Rowley is a Professor of Radiology at the University
of Wisconsin in Madison and is Chief of Neuroradiology there. Dr.
Rowley has specific interests in MR perfusion imaging for CNS
Dr. Richard Semelka from the University of North Carolina-Chapel
Hill. Dr. Semelka has been a pioneer in the use of abdominal
imaging with MR, and is credited with many developments in the use
of gadolinium-enhanced imaging, with particular emphasis on the
This focus group offered valuable information on how these
leading radiologists in the field of MRI use high-dose contrast in
their practices. This supplement shares their experience,
articulate presentations, and insightful discussions with the
Focus Group Participants
Thomas Grist, MD
Professor of Radiology, Chief of MRI University of Wisconsin
David A. Bluemke, MD, PhD
Clinical Director of MRI Johns Hopkins Hospital Baltimore, MD
Nola Hylton, PhD
Associate Professor of Radiology University of California--San
Francisco San Francisco, CA
Larry A. Kramer, MD
Director of MRI Memorial Hermann Hospital Houston, TX
Russell N. Low, MD
Medical Director Sharp and Children's MRI Center San Diego, CA
Martin Prince, MD, PhD
Professor of Radiology Weill Medical College of Cornell University
New York, NY
David Roberts, MD
Assistant Professor of Radiology University of Pennsylvania Medical
Center Philadelphia, PA
Howard A. Rowley, MD
Sackett-Bascom Professor of Radiology Chief of Neuroradiology
University of Wisconsin Madison, WI
Richard C. Semelka, MD
Director of MR Services, Professor of Radiology Vice Chair of
Clinical Research University of North Carolina Hospital Chapel
CNS Perfusion Imaging: The Role of High-Dose
Howard A. Rowley, MD Sackett-Bascom Professor of Radiology,
Chief of Neuroradiology, University of Wisconsin, Madison,
High-dose or rapid-infusion gado-linium contrast MRI has many
applications in neuroradiology, including perfusion imaging of the
central nervous system (CNS). Ischemic stroke is a natural
application of CNS perfusion imaging, as it results from a
reduction in blood flow to the brain, and the severity of the
resulting injury depends on the duration and degree of oligemia.
It is important to note, however, that perfusion imaging can also
be used in the assessment of cerebral blood volume in tumors
and holds promise for future studies into the pathophysiology of
such conditions as infection, dementia, and trauma.
Beyond their use in perfusion imaging, high-dose gadolinium
techniques offer several advantages. One is an improvement in
tissue contrast when imaging small or multiple metastases, or in
magnetic resonance angiography (MRA) of the brain, neck, or aortic
Further, the use of elevated doses of gadolinium can improve the
efficiency of scan protocols. For example, when evaluating a
patient with suspected stroke, it is possible to conduct both
perfusion and angiographic studies quickly, in addition to
obtaining parenchymal images.
In some cases, high-dose gadolinium can improve detection rates
and hasten oncologic studies.
The benefits of such an approach are particularly apparent in
patients who are difficult to image. A good example is a child with
a primary CNS tumor who is being evaluated for subarachnoid
metastases (so-called drop metastases). An increase in the
gadolinium dose of 50% to 100% enables the entire exam to be done
at one time, without the need for reinjection or repeat anesthesia.
Increasing the contrast dose may also be necessary when repeating
an exam, for example, when evaluating the results of an
intervention. Such modest increases in gadolinium dose are well
tolerated and adverse reactions are rare.
CNS perfusion refers to the delivery of blood to the brain,
along with its essential nutrients and oxygen. There are several MR
techniques for evaluating CNS perfusion.
This article will focus on dynamic susceptibility
gadolinium-enhanced contrast mechanisms.
The minimum normal cerebral blood flow is approximately 55
mL/100 g/min (Figure 1). Through a wide range of lower blood flow
rates, the brain is able to maintain normal function. Among the
brain's autoregulatory mechanisms for responding to low-flow
states, the first is usually an increase in collateral flow, which
on perfusion studies is reflected in a longer mean transit time
(MTT). Initially, there is also vasodilation of the capillary bed,
with a corresponding increase in cerebral blood volume (CBV).
Eventually, however, perfusion pressure drops low enough that
vascular collapse ensues and cerebral blood flow (CBF) is
At a threshold of approximately 15 to 20 mL/100 g/min, neuronal
dysfunction becomes evident. The neurons are stunned, but if
perfusion is reestablished quickly enough, they can recover fully.
Tissue in this reversible injury zone is known as the ischemic
penumbra, a word derived from the astrological term describing the
part of a planetary body lost in a partial eclipse.
The brain is particularly susceptible to a shortfall in its
blood supply, because it does not have long-term energy stores. If
the duration and degree of ischemia are severe enough, infarction
will be the ultimate result. A complete interruption of blood flow
is followed by irreversible injury within just a few minutes. In
many situations, however, the low-flow state or vascular occlusion
develops over time, presenting an opportunity to intervene and
salvage tissue. Even in acute stroke, MR perfusion techniques can
capture and characterize blood flow changes in the critical hours
after symptom onset, offering a chance to intervene.
Gadolinium-enhanced MR studies enable us to evaluate the
critical components of perfusion and define the hemodynamic
conditions in the brain. There are several goals for MR perfusion
imaging of stroke.
The first is the characterization of the dynamic pathophysiology of
the ischemic state. The second is the use of such data to select
patients for therapy, identifying those most likely to benefit from
thrombolysis, for example, and withholding therapy from those in
whom the risks outweigh the potential benefits. A third goal is to
follow-up the effects of an intervention, such as stenting or
At our institution, perfusion imaging is conducted in the
context of a more comprehensive stroke evaluation. We start with an
MR of the brain, including diffusion-weighted imaging (Table 1). We
use time-of-flight MRA in the head and the neck, then a
gadolinium-enhanced double-dose elliptic-centric MRA study to look
at the aortic arch, the origin of the great vessels, and the
Next we do perfusion imaging, using a single-dose gadolinium
bolus tracking study captured with a gradient-echo/echo-planar
sequence. We inject the gadolinium contrast media at 3 to 5 mL/sec
through a standard intravenous catheter, capturing the wash-in and
wash-out of the contrast over approximately 1 minute. We then
produce parameter maps and signal intensity-time curves to
establish region-by-region perfusion characteristics. Finally, we
obtain post-contrast images of the brain to look for intravascular
stasis and, perhaps, subacute parenchymal ischemia, which are both
better visualized after contrast than without it.
The use of gradient-echo/echo-planar perfusion sequences may
result in susceptibility artifact in certain regions of the brain,
such as the brain stem. We have found in clinical practice that
approximately two-thirds of strokes are in the distribution of the
middle cerebral artery, where susceptibility is not a major
problem. When we suspect that a patient has an infarct of the brain
stem or posterior fossa; however, we do perfusion imaging with a
spin-echo sequence to reduce artifact and couple it with a double
dose of gadolinium.
Perfusion Curves and Maps
The patient in Figure 2 underwent MR imaging approximately 6
hours after an acute infarction of the brain territory supplied by
the left middle cerebral artery. On CT and gadolinium-enhanced T1,
T2, and fluid-attenuated inversion recovery (FLAIR) MR images
(Figure 2A), evidence suggestive of stroke is very subtle.
Diffusion-weighted imaging (DWI), however, demonstrates the
"lightbulb" sign of restricted diffusion, a hallmark of acute and
usually irreversible ischemia. Indeed, today diffusion-weighted
imaging conducted with echo-planar sequences is the most sensitive
way to detect ischemia.
Selected slices from the patient's perfusion study demonstrate
wash-in of a bolus of gadolinium contrast media (Figure 2B). Areas
with normal perfusion darken in seconds, but only during the final
half-minute of the sequence is it possible to observe the slow
arrival of contrast in the infarcted left hemisphere.
Perfusion data can be used to create signal intensity-time
curves for selected regions of interest. When evaluating perfusion
dynamics, the important attributes to consider are those related to
the temporal course of blood delivery, as they reflect the time it
takes for gadolinium to arrive and then wash through the
microcirculation. These parameters include time to peak and various
estimates of transit time. In Figure 2C, the signal intensity-time
curve shows a precipitous drop in signal intensity upon arrival of
gadolinium in the normal right side of the brain, followed quickly
by wash-out. By comparison the arrival of contrast in the ischemic
region is delayed, and the washout takes longer.
By measuring the area under the signal intensity-time curve
during the first pass of the contrast bolus, it is possible to
calculate relative cerebral blood volume. The width of the curve
that depicts the wash-in and wash-out of gadolinium contrast
conceptually represents an estimate of the mean transit time (MTT).
The next step is to calculate the net cerebral blood flow in
milliliters per 100 grams of brain per minute, using the central
volume principle and an equation that, in its simplest form, can be
represented as: CBF = CBV/MTT. Cerebral blood volume is given in
milliliters per 100 grams of brain, and transit time, in seconds or
minutes. In practice, this is a complicated mathematical problem
that requires computation of additional derivatives of the raw
curves and can be approached in several ways.
The best way to calculate perfusion parameters, and which to use
on a routine basis, are the subject of intense research.
Fortunately, the rich data sets characteristic of MR perfusion
studies offer many hemodynamic parameters to study. Ultimately a
measure of the timing of blood delivery, an estimate of blood
volume, and a calculation of overall cerebral blood flow will be
optimal to fully characterize brain perfusion.
Color-coded parameter maps enable rapid identification of areas
of low or slow blood flow, which are depicted in red. In Figure 2D,
top row, the mean transit time is much longer in the left
hemisphere when compared with the right, and the cerebral blood
volume map shows complete vascular collapse, with low blood volume.
This defect is perfectly matched in anatomic extent to the
diffusion-weighted image, indicating an absence of potentially
reversible ischemia, or penumbra, in the surrounding tissue.
The color maps in Figure 2 are created with standard commercial
software. We have developed in-house software that rapidly creates
similar maps, while automatically deriving the arterial input
This additional piece of information can be used to mathematically
process the images more precisely, in a process called
deconvolution. The result is a family of black-and-white maps
(Figure 2D, bottom row) that depict not only mean transit time and
cerebral blood volume, but also cerebral blood flow.
In many cases, imaging can identify patients with ongoing
ischemia who may potentially benefit from therapy. A small or
modest diffusion abnormality, coupled with a very large perfusion
abnormality--a perfusion-diffusion mismatch--identifies an area
with very low blood flow but no infarction (Figure 3). Such an area
is a realistic target for rapid intervention.
The patient in Figure 4 was experiencing transient ischemic
attacks in the right hemisphere of the brain. Diffusion-weighted
imaging (Figure 4A) demonstrates a few abnormalities in the deep
white matter, while perfusion imaging reveals a very prolonged
transit time and very low blood flow in a larger surrounding area.
The color maps clearly show prolonged transit through the right
hemisphere (Figure 4B). Angiography revealed a tight carotid
stenosis, which was corrected with stenting. The same-day
post-stent perfusion study shows a complete reversal of the
perfusion abnormality (Figure 4C). On clinical follow-up, the
patient demonstrated no neurological deficits.
A comprehensive approach to CNS imaging can be used to follow
the effects of other interventions, such as thrombolysis, as well
as to evaluate vascular compromise in trauma. For example, Figure 5
depicts a patient with a skull fracture resulting from a rollover
motor vehicle accident. There is no apparent blood flow on the
T2-weighted images (Figure 5A), and a carotid occlusion can be seen
down to the level of the bifurcation on angiography (Figure 5B).
Perfusion parameter maps (Figure 5C), however, demonstrate that
there is no resting perfusion abnormality and no need for
The ability to perform perfusion studies in combination with MRA
enables global assessment of the patient with stroke or CNS
compromise. It is an approach that can be summarized by the "4
P's": We look at the
, which are the great vessels supplying blood to the brain; the
, and the
, the surrounding area of ischemia that requires intervention if
infarction is to be avoided. This global approach is possible only
through the use of gadolinium contrast media. Its use will
undoubtedly be expanded to include other applications of CNS
imaging in the future. *
1. Detre JA. MR perfusion imaging of hyperacute stroke.
AJNR Am J Neuroradiol
2. Kidwell CS, Saver JL, Mattiello J, et al. Diffusion-perfusion
MRI characterization of post-recanalization hyperperfusion in
3. Wittsack HJ, Ritzl A, Fink GR, Wenserski F, et al. MR imaging
in acute stroke: Diffusion-weighted and perfusion imaging
parameters for predicting infarct size.
4. Wu O, Koroshetz WJ, Ostergaard L, et al. Predicting tissue
outcome in acute human cerebral ischemia using combined diffusion-
and perfusion-weighted MR imaging.
5. Provenzale JM, Wang GR, Brenner T, et al. Comparison of
permeability in high-grade and low-grade brain tumors using dynamic
susceptibility contrast MR imaging.
AJR Am J Roentgenol
6. Randoux B, Marro B, Koskas F, et al. Carotid artery stenosis:
Prospective comparison of CT, three-dimensional gadolinium-enhanced
MR, and conventional angiography.
7. Van Dijk P, Sijens PE, Schmitz PI, Oudkerk M. Gd-enhanced MR
imaging of brain metastases: Contrast as a function of dose and
Magn Reson Imaging
8. Shellock FG, Kanal E. Safety of magnetic resonance imaging
J Magn Reson Imaging
9. Ball WS Jr, Holland SK. Perfusion imaging in the pediatric
Magn Reson Imaging Clin N Am
10. Barbier EL, Lamalle L, Decorps M. Methodology of brain
J Magn Reson Imaging
11. Yamada K, Wu O, Gonzalez G, et al. Magnetic resonance
perfusion-weighted imaging of acute cerebral infarction: Effect of
the calculation methods and underlying vasculopathy.
12. Sunshine JL, Bambakidis N, Tarr RW, et al. Benefits of
perfusion MR imaging relative to diffusion MR imaging in the
diagnosis and treatment of hyperacute stroke.
AJNR Am J Neuroradiol.
13. Rowley HA. The four Ps of acute stroke imaging: Parenchyma,
pipes, perfusion, and penumbra.
AJNR Am J Neuroradiol.
14. Schlaug G, Benfield A, Baird AE, et al. The ischemic
penumbra: Operationally defined by diffusion and perfusion MRI.
15. Warach S. New imaging strategies for patient selection for
thrombolytic and neuroprotective therapies.
. 2001;57(5Suppl 2):S48-S52.
16. Carroll TJ, Rowley HA, Haughton VM. Automatic determination
of the arterial input function for assessment of cerebral blood
flow with DSC-MRI.
2002; In press.
THOMAS GRIST, MD:
Thank you very much, Dr. Rowley, for an excellent discussion of the
role of perfusion techniques in the CNS system. In the specific
technique for perfusion, you mentioned that you're using a gradient
echo-planar perfusion sequence. I noticed in some of the images
that it looked like there was a little susceptibility artifact at
the base of the brain.
Some people are using spin-echo echo-planar imaging (EPI), I
think with perhaps a higher dose of contrast agent, because the
spin-echo EPI may be less sensitive to the T2* effects. But on the
other hand, it reduces the susceptibility of artifact. Do you have
any comments on that?
HOWARD ROWLEY, MD:
Yes, I think that either approach can be successful, depending on
the susceptibility artifacts. Of course, susceptibility is a
dual-edged sword. You need some susceptibility to see the perfusion
changes. But the more susceptibility you have in your sequence, the
greater the extent of the skull-based and brain-stem region
artifacts. We've found that in clinical practice, two-thirds of the
strokes are in the middle cerebral distribution, so susceptibility
isn't a major problem. When we suspect a brain stem or posterior
fossa infarct, we have chosen to do a spin-echo planar technique.
In that situation, we would use a double-dose of gadolinium, and
process it in a similar way. There are several groups around the
country that prefer that method. Spin echo also gives you better
sensitivity to the capillary bed, as opposed to some large veins,
at least if you don't use deconvolution.
So then at the brain stem is where you're using it, brain-stem spin
echo. Then you give a double dose of contrast agent, just for the
MARTIN PRINCE, MD:
You mentioned that you use a first significant dose of contrast for
your 3D MRA of the arch carotid vessels. Then after that, the
perfusion study is done. So, does that then limit the amount of
gadolinium you have available to use on the perfusion study? Also,
what effect does the gadolinium that has already been introduced
into the circulation have for your MRA study?
Great question. Well, I think one reason that we have chosen the
gradient echo technique is that it only requires a single dose of
contrast. We performed the gadolinium-enhanced MRA with a double
dose, 0.2 per kilo. Then, we follow it with a single dose, which
keeps us within a triple-dose range. However, in situations in
which we might need a spin echo technique, for example, we'd be up
to four times the standard dose, which we still feel very
comfortable with. Also, one of the benefits of the perfusion
sequence is that you can perform that after other standard imaging,
or after gadolinium-enhanced MRA, because you are only looking at
the relative change compared with the baseline. So baseline signal
changes don't interfere with the measurement of perfusion.
With regard to the dose rate for these perfusion sequences, in
order to identify the arterial input function, it's nice to have as
compact a bolus as possible. So at what rate do you give the
gadolinium? Can you inject this by hand; or do you use a power
We strongly prefer a power injector, because of the reliability and
sequencing of the time that we acquire the data. So our standard
procedure is to use a single dose injected through a standard IV
catheter. We like at least a 22-gauge catheter. We'll go as low as
2 mL per second in an infant (we've done a number of infants
successfully), up to about 5 mL, if we have a large patient with a
large-bore IV. The arterial input function can be derived manually
using a region of interest drawn near a vessel or on a vessel; or,
as in our case, it can be acquired automatically. To some extent,
that removes the problem of needing to have a very tight bolus,
because the arterial input function is used to deconvolve that
curve, no matter what its shape.
RICHARD SEMELKA, MD:
Do you find that it's essential to have an imaging window in which
to perform the studyparticularly looking for the penumbra from
the start of patient symptoms to when you image them to have
maximum therapeutic benefit? What is the time that you look at?
That's a terrific question, Richard. The only FDA-approved therapy
right now for stroke is IV tPA within 3 hours. So technically, we
would be doing these studies within 3 hours, to try to help
determine what's going on with the patient and whether there is a
target for intervention. However, I think that there have been a
number of studies, including the intra-arterial PROACT study, which
have shown time windows out to 6 hours. There have also been many
case series and anecdotes showing success in individual cases, at
least carefully selected, out to 12 or even 20 hours.
The important point is that we're not looking as much at time
windows anymore. We're actually looking at physiology, and we are
looking at the individual patient, and it's a status of their
collateral blood flow that may allow one patient to go many hours
and still have a successful intervention. Another patient who might
be only at 1 hour could potentially be excluded. So it's the
physiologic window as opposed to time window that I think is
important, and that's what perfusion is giving us.
Well, even in this time window, there is both the time required to
acquire the data, and then there is the time required to do the
color mapping and various other post-processing. What is your sense
of how long it takes you from the time you've completed the data
acquisition, to the time when you can confidently say whether or
not there is a penumbra?
The sequence itself takes about 72 seconds. We run on the console
using our in-house software, which uses an algorithm that produces
these maps within 1 minute. Those maps are deconvolved. With our
vendor-supplied software, we are able to pull it across a network,
which is actually a rate-limiting step. It takes 4 or 5 minutes for
a large study like this to come across to my workstation. Then,
even my fellows and residents can perform this offline analysis in
2 or 3 minutes per case. It's actually quite easy, once you've done
a couple of them.
You also mentioned that the number of images is extraordinary. It
can't possibly be that you could film such a study and get it to
the interventionalist who might act on the results. How do you
provide this information to the referring physicians?
There are two components of that. One is the review of these
studies, which I think is best done on a workstation, as opposed to
on film. We don't film the source images, the 504 images that are
standard for our sequence. But instead, we have 14 slices for each
of the different parameter maps. Those are filmed as part of
clinical routine, put in the jacket, and conveyed to the referring
Total Body MRA
Martin Prince, MD, PhD Professor of Radiology, Weill
Medical College of Cornell University, New York, NY
The ability to use gadolinium contrast in MR angiography
represents a tremendous opportunity to improve imaging results and
reduce risk. For this reason, over the past decade we have observed
an expansion in the use of MRA to encompass the entire body. A
search of Medline, for example, shows that the number of papers
citing MRA grew from a mere trickle before 1988, when gadolinium
contrast was approved by the Food and Drug Administration, to more
than 600 in 2000.
The popularity of MRA is understandable. It provides an accurate
depiction of the vascular anatomy over large regions of the body.
It produces images of luminal anatomy that can be combined with
other MR sequences to show physiological information. It is
three-dimensional, enabling the creation of an essentially infinite
number of projections of the vascular anatomy, even after the
patient has left the MR scanner. More important, it eliminates the
risks of ionizing radiation, and gadolinium contrast agents have no
and are very rarely associated with allergic reactions.
Last, MRA is highly accurate.
There are disadvantages to MRA. Some patients cannot be scanned
because of claustrophobia. In older scanners with a long bore, as
many as 10% to 20% of patients may experience claustrophobia, but
the incidence is greatly reduced in newer scanners with shorter
bores. MRA is more expensive than many other noninvasive imaging
techniques, though it is certainly much less costly than
conventional angiography. Because top-of-the-line scanners are
needed for MRA, its availability is limited. And a high level of
skill is required to run those scanners, which may also be in short
supply in some locations. Finally, there are important
contraindications to MRA, including implanted pacemakers, brain
aneurysm clips, and orbital metal.
The opportunity to eliminate ionizing radiation deserves special
note. In general, the exposure to ionizing radiation from computed
tomographic angiography (CTA) and conventional angiography is
within acceptable limits. Nonetheless, a technique that completely
eliminates ionizing radiation offers the opportunity to repeat
scans over and over, and acquire multiple phases of time-resolved
information as the contrast bolus passes through the body. It is
also possible to repeat the examination day after day, without
worrying about cumulative radiation exposure.
Advantages of Contrast
MR angiography can be performed without contrast, and such
techniques often provide excellent information and may, in many
instances, produce images of adequate quality. It is important,
however, to be aware of the limitations of non-contrast techniques.
In Figure 1A, a two-dimensional time-of-flight (TOF) sequence gives
a false appearance of only moderate disease of the carotid
bifurcation. But on the three-dimensional high-dose
gadolinium-enhanced MRA (Figure 2B), it is clear that bifurcation
anatomy is more complex. A maximum intensity projection that zooms
in on the bifurcation shows that, although the degree of luminal
narrowing is only moderate, there is a large ulceration in the
atherosclerotic vessel wall that may be contributing to the
patient's symptoms (Figure 2C). This abnormality is not visualized
by flow-based, non-contrast MRA techniques.
Another shortcoming of flow-based MR techniques, such as 2D TOF,
is the tendency for the signal to drop out in sites of very severe
stenosis as a result of jet flow--so-called spin dephasing.
As shown in Figure 2, 3D gadolinium-enhanced MRA, which is not
flow-based, more accurately depicts the true lumen and enables more
precise appreciation of anatomic details.
Artifact associated with metal objects in the body represents a
challenge for MR imaging. The 3D gradient echo sequence we use for
high-dose gadolinium-enhanced MRA employs a very short echo time
that helps to eliminate this artifact. Nevertheless, some metal
produces such a severe artifact that it cannot be eliminated. The
stainless steel Palmaz stent is an example. In the case of platinum
stents, the metal stent configuration creates a Faraday cage
phenomenon that attenuates the penetration of radiofrequency (RF)
energy both into and out of the stent. By increasing the flip angle
to 75°, however, it is possible to deliver sufficient RF
penetration into the stent to enable visualization of the vessel
lumen (Figure 3).
Another important advantage of 3D contrast-enhanced MRA is the
elimination of in-plane saturation. This is critically important in
patients with alteration of the normal vascular anatomy.
In Figure 4, the patient has an occlusion of the left subclavian
artery, and flow to the left subclavian is provided by a
carotid-to-left subclavian artery graft. Three-dimensional
contrast-enhanced MRA readily depicts the unpredictable course and
direction of such vessels and, in this case, reveals a complex
plaque at the carotid bifurcation.
Patient safety in the MR scanner is an issue that must be
considered. In general, MR is not suited to imaging high-risk
patients. For example, in the evaluation of dissection, MR would
typically be reserved for evaluating Type 3, stable dissections. It
is, however, capable of imaging high-risk patients, and may
represent the best approach even in an emergency if the risk of
subjecting a particular patient to radiation or iodinated contrast
is sufficiently high.
In summary, gadolinium-enhanced MRA is able to visualize the
origins of the great vessels; it is fast and, therefore, produces
less motion artifact than non-contrast techniques; it is associated
with less spin dephasing; it can demonstrate plaque features and
luminal anatomy in enough detail to reveal ulcerations; it is not
hampered by in-plane saturation; it enables the evaluation of small
vessels, such as the vertebral arteries; and postprocessing is very
simple. Moreover, if gadolinium is already being used for brain MR,
there is no extra cost associated with obtaining 3D
gadolinium-enhanced MRA at the same time.
Several factors must be considered when selecting the dose of
First, it is important to realize that the bolus of contrast
evolves as it travels through the body. Initially, at the point of
injection, it is very compact. It spreads out as it passes through
the pulmonary circulation, and becomes even less concentrated after
it passes through the systemic capillary bed.
The selection of gadolinium dose, therefore, must take into
account the distance between the injection site and the area of the
body that will be imaged, as well as how much gadolinium will be
extracted along the way. As might be expected, the higher the dose
of contrast, the greater the visualization of vascular detail. This
is demonstrated in Figure 5. At a gadolinium dose of 0.1 mmol/kg,
it is not possible to see the venous anatomy in the liver, but as
the dose is increased to 0.2 mmol/kg and 0.3 mmol/kg, the portal
venous anatomy can be appreciated.
The injection method itself is also important to consider.
Manual injection has several advantages in MRA, because so many
factors must be coordinated perfectly. The delivery of the bolus,
the breathholding of the patient, and the initiation of the
acquisition all have to occur simultaneously. In my experience, it
is easier to coordinate each of these factors while standing next
to the patient and performing the injection by hand.
In addition, hand injection necessitates consideration of the
viscosity of the contrast agent, which in turn influences decisions
on the size of angiocatheter, length and caliber of intravenous
tubing, and type of gadolinium contrast to use.
In subclavian venography, for example, two operators are
required in order to simultaneously inject the right and left
antecubital veins with dilute gadolinium contrast media (20 mL
gadolinium in 250 mL normal saline) in order to image the
subclavian veins and superior vena cava (Figure 6).
Optimal contrast administration requires an understanding of the
basic physics of k-space and how it influences the features of an
image. In particular, the center of k-space dominates the contrast
features of the image, whereas the periphery of k-space dominates
It is important, therefore, to time the delivery of the contrast
bolus so that arterial contrast is at its maximum during the
central portion of k-space, to achieve the maximum contrast effect.
A perfectly timed injection of contrast may provide excellent
quality with a relatively low dose of contrast media. But with a
small contrast dose, small bolus timing errors can ruin a study.
Increasing the contrast dose allows for a greater margin of error
in bolus timing. In essence, contrast dose can make up for
variations in the skill of the operator. The most talented
operators may be able to use a lower contrast dose. On the other
hand, if the operator is less skilled or performs MRA infrequently,
a larger contrast dose may be warranted in order to demonstrate
more angiographic features.
MRA offers the exciting opportunity to expand beyond a scanner's
usually limited field of view to image extensive regions of
anatomy, simply by moving the table during contrast injection.
For example, after performing an initial image in the pelvis, we
can pull the table and acquire another image of the thigh, then
pull the table again and image the calf. It is also possible to
deliver several small injections of gadolinium contrast as the scan
moves from the feet to the knees, then finish with a bolus chase.
The ability to scan large regions of the body is especially
exciting because of the systemic nature of atherosclerotic
Bolus-chase MRA has been extrapolated to cover arteries of the
entire body, beginning with the aortic arch and carotid arteries,
and moving sequentially down the body to image arteries of the
chest, abdomen, pelvis, thigh, calf, and feet.
The patient in Figure 7 was unable to undergo conventional
angiography, because access through the iliac and common femoral
arteries was not possible. But with MRA, only a peripheral
intravenous line in the arm was needed before imaging the arteries
of the entire body with a single bolus injection.
Contrast-enhanced MRA offers important advantages over other
forms of angiography. It poses no risk of ionizing radiation or
nephrotoxicity. Source data can be reformatted for any view. It can
depict anatomy and physiology in great detail, and it is highly
accurate. As researchers continue to work on refining and advancing
the techniques of MR angiography, its future looks bright. *
1. Runge VM. Safety of magnetic resonance contrast media.
Top Magn Reson Imaging
2. Prince MR, Arnoldus C, Frisoli JF. Nephrotoxicity of
high-dose gadolinium compared to iodinated contrast.
J Magn Reson Imaging
3. Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to
gadolinium contrast media: A review of 36 cases.
AJR Am J Roentgenol.
4. Prince MR, Grist TM, Debatin J. Berlin
. 3D Contrast MR Angiography
ed. New York: Springer; 1999.
5. Shellock FG.
Reference Manual for Magnetic Resonance Safety
. Salt Lake City, UT: AMIRSYS; 2002.
6. Evans AJ, Blinder RA, Herfkens RJ, et al. Effects of
turbulence on signal intensity in gradient echo images.
7. Urchuk SN, Plewes DB. Mechanisms of flow-induced signal loss
in MR angiography.
Magn Reson Imaging.
8. Meyer JM, Buecker A, Spuentrup E, et al. Improved in-stent
magnetic resonance angiography with high flip angle excitation.
9. Prince MR. Gadolinium-enhanced MR aortography.
10. Hany TF, Schmidt M, Hilfiker PR, et al. Optimization of
contrast dosage for gadolinium-enhanced 3D MRA of the pulmonary and
Magn Reson Imaging
11. Schoenberg SO, Knopp MV, Prince MR, et al. Arterial-phase
three-dimensional gadolinium magnetic resonance angiography of the
renal arteries. Strategies for timing and contrast media injection:
12. Maki JH, Prince MR, Londy FJ, Chenevert TL. The effects of
time varying intravascular signal intensity and k-space acquisition
order on three-dimensional MR angiography image quality.
J Magn Reson Imaging.
13. Wilman AH, Riederer SJ, King BF, et al. Fluoroscopically
triggered contrast-enhanced three-dimensional MR angiography with
elliptical centric view order: Application to the renal arteries.
14. Meaney JF, Ridgway JP, Chakraverty S, et al. Stepping-table
gadolinium-enhanced digital subtraction MR angiography of the aorta
and lower extremity arteries: Preliminary experience.
15. Wang Y, Lee HM, Khilnani NM, et al. Bolus-chase MR digital
subtraction angiography in the lower extremity.
16. Ho KY, Leiner T, van Engelshoven JM. MR angiography of
17. Ruehm SG, Goyen M, Barkhausen J. Rapid magnetic resonance
angiography for detection of atherosclerosis.
Thank you, Dr. Prince. Let me ask a few specifics about how you
administer the contrast, and what doses you use. You mentioned that
you give this by hand injection, and that viscosity is an issue.
Does that effect your decision to use different agents?
Yes, if you need a small caliber angiocatheter, then the higher
viscosity agents are going to be more difficult to inject,
especially by hand. Or especially if you are going to be imaging a
baby with a very small caliber angiocatheter, then the viscosity
becomes very important. So, we would prefer agents that have the
Another important detail is that viscosity is related to
temperature. So if you find that the resistance to injection is too
great, you can warm up the gadolinium to body temperature. And that
will drop its viscosity by approximately a factor of two. Then that
reduces the force required to inject the contrast by hand.
DAVID ROBERTS, MD:
We routinely give high-dose gadolinium for peripheral bolus-chase
MRA applications. We find that the injection protocol is critically
important for these studies. If we inject too quickly, certainly
anything above 1 mL/sec, we notice significant superficial femoral
venous (SFV) enhancement and tibial venous enhancement, which can
really degrade the studies. For that reason, we have found that we
really can't get by with hand injection, because many of the
fellows and residents, despite training and stressing this point,
simply inject too quickly. Therefore, we found power injectors
fairly mandatory for these studies. What's your take on this?
We've had the same experience. When we are performing a
multistation examination with one bolus and are trying to share
that bolus between multiple stations, if we time it for the first
station, our timing for the second and third station may not be
accurate, depending on whether the patient has fast or slow flow.
So we have begun doing a test bolus at the calf. Then that gives us
a better sense of the timing for all three stations. If a patient
has very fast flow, if it is <20 seconds to the calf, for
example, then we won't even attempt to do a bolus-chase exam,
because we know that we just cannot move the table fast enough to
keep up with really fast flow.
How do you address the problem of asymmetry, left to right, in a
Our pattern has been to try to figure out which leg is the
clinically significant leg, which is the one that's on track for
being operated on first or is providing the most difficulty for the
patient. Then we time for that leg, and hope for the best on the
I have a question about a potential pitfall with great vessel and
carotid imaging. Most of these patients, of course, are going to be
injected in one arm or the other and as that tight bolus goes past
the common carotid artery, especially with a left-sided injection,
we sometimes get a false drop-out in signal over a short segment
related to the venous gadolinium passing there. How do you approach
that? Do you routinely inject the right arm? Do you sometimes
inject a femoral vein?
That's an excellent point. It brings up one of the advantages of
the hand injection. We always try to inject the right arm. As we
are injecting, we want to get the bolus in and flushed out of the
vein before we start collecting the central k-space data. So we use
a fluoroscopic triggering technique for our carotids, If we are
injecting and also tracking the pace of the passage of the contrast
through the lungs and as it reaches the great vessels, if we see
that it is going quickly and we are not going to get all the
contrast in and flushed, I may actually terminate the gadolinium
and immediately switch to flush earlier, just to get it flushed out
of the subclavian vein and innominate vein.
If you have to inject the left arm, you may not be able to
escape some venous artifact, superimposing it over the great vessel
origins. Part of the reason for that is that in a lot of older
patients, the aorta is unfolded and very hard and it pinches the
brachycephalic vein between the aorta and the sternum. It causes
the gadolinium to hang up there, and despite with your best efforts
to flush it through, you may not be able to clear that.
LARRY KRAMER, MD:
Martin, you showed in one graph that as you increase your contrast
dose, that you see more and more detail. Is there a point at which
as you increase dose, susceptibility takes over and you actually
decrease signal and detail?
Yes, that's an excellent question. I think it's more related to
injection rate. There's going to be an injection rate at which the
concentration of gadolinium in the blood becomes so high that you
begin to have T2* effects, which actually cause the signal to drop.
In my experience, with hand injecting, it's hard to inject fast
enough to reach that point. But if you are performing venography
and injecting that vein, you have to dilute the gadolinium to avoid
that T2* effect. So that is a very important point.
For venography, how much do you dilute the gadolinium?
I typically take a bottle of 15 or 20 mL of gadolinium and inject
that into a 250 mL bag of normal saline. Then I'll load up four
60-mL syringes. That gives me a very large volume of diluted
contrast to work with, so I can slam that diluted gadolinium in, in
such a way that it will tend to distend the veins. Yet it will not
be excessively concentrated. I'll inject a full 60 mL before
beginning the 3D acquisition. Then I will continue to inject
another 60, then that would be two syringes on each arm, so that I
can get bilateral information.
MRI of the Myocardium
David A. Bluemke, MD, PhD Clinical Director of MRI, Johns
Hopkins Hospital, Baltimore, MD
Although magnetic resonance imaging of the heart does not always
necessitate the use of contrast media, increasingly the most
interesting and clinically important applications do. Today, for
example, we are using high-dose contrast in new ways to evaluate
myocardial viability, perfusion, and atherosclerotic disease.
Advanced MR scanners also play a key role in myocardial imaging,
not only by offering tremendous imaging speed--crucial for
functional studies--but also by helping to achieve the goal of
conducting examinations in a single breathhold, an important
advantage in using MR to image patients who are very ill.
The evaluation of patients who have had a myocardial infarction
(MI) often starts with functional imaging, which usually consists
of the acquisition of cine images and their analysis for wall
motion abnormalities. Figure 1 demonstrates the use of myocardial
tagging, a technique that aids in the evaluation of regional wall
motion throughout the myocardium. In this case, it reveals severely
disordered contraction of the myocardium. Wall motion analysis is
unable to answer a crucial question, however: whether the areas of
abnormal contraction are still viable or represent infarction. An
assessment of myocardial viability using contrast techniques is,
therefore, the next step.
In assessing myocardial viability, we acquire first-pass
myocardial perfusion images following a single dose of gadolinium
contrast media delivered at a 5 mL/sec, a fairly high injection
rate (Table 1). We use power injectors for all viability and
perfusion studies. Because these patients often are quite sick,
they typically have a large-bore catheter already in place, which
enables us to inject using a large-bore Angiocath.
We image the entire heart every 2 heart beats for about 1 minute
after contrast injection to assess microvascular integrity. Next,
we inject a second dose of gadolinium contrast, wait for 10 to 20
minutes, and obtain myocardial viability images using gradient-echo
techniques with myocardial suppression.
Consider the application of MR viability imaging in a patient
with an extensive MI. Even though many such patients have the
infarct-related artery opened in the cardiac catheterization
laboratory and undergo implantation of a coronary stent, some still
have small-vessel disease or capillary occlusion. MR is the only
noninvasive method that can assess disease at the capillary level
reliably, and this is accomplished during first-pass perfusion
If on the first-pass images the capillaries remain
occluded--evident as a dark area that is not perfused--we inject
the second dose of contrast and wait for approximately 10 minutes.
During this time, as contrast washes out from the rest of the
myocardium, there is a redistribution of contrast between areas of
nonviable and normal myocardium, such that the contrast agent is
retained in the area of infarction. Figure 2 demonstrates this
concept in a patient with large transmural infarction of the
inferior and basal walls.
Even though infarcted myocardium can be mapped on delayed
viability imaging, it is the core of the infarct, which appears on
first-pass images and corresponds to microvascular obstruction,
that predicts patient prognosis. Wu et al
found that patients with evidence of microvascular obstruction
following MI were more likely to experience a cardiovascular event
during follow-up when compared to those without microvascular
obstruction (45% versus 9%). The size and presence of microvascular
obstruction predicted an increase in left ventricular mass and
volume, and a decrease in ejection fraction, at 6 months.
MR can be used to evaluate both acute and chronic MI. The
purpose of the study is often quite different in these two
settings, however. In acute MI, the primary issue is the size of
the infarction, an assessment that can sometimes be difficult to
make clinically. For example, cardiac enzyme levels may be
challenging to interpret in a patient who has received a
thrombolytic agent. In another example, a woman may delay coming to
the hospital for chest pain because her symptoms are atypical, thus
skewing interpretation of the troponin levels.
In chronic MI, patients typically are being evaluated before
revascularization procedures, and the question is one of viability,
rather than infarct size. If the target myocardium is
dysfunctional, but still viable, bypass grafting could markedly
improve cardiac function.
In both acute and chronic MI, cine images demonstrate an absence
of motion in the area of infarction. In the acute infarct, there
may also be areas of dysfunctional myocardium that is stunned but
will eventually recover.
Wall thickness can be analyzed by anatomic imaging. In acute MI,
the myocardium typically does not show thinning, whereas after 3 to
6 months, the chronic infarct is characterized by thinning and
remodeling of the myocardium with scar formation.
Both acute and chronic infarction demonstrate marked enhancement
with gadolinium contrast, although the pathophysiologic mechanisms
are quite different. It is hypothesized that in acute MI, there is
an increase in the distribution volume of the contrast agent in
areas of nonviable myocardium, where myocytes have died. In the
case of chronic infarction, in which the myocardium is replaced by
fibrosis and scar, it is hypothesized that there is a difference in
contrast distribution between the nonviable myocardium and the
scar, when compared with the adjacent myocardium.
Viability imaging can also be useful in the assessment of
patients with idiopathic hypertrophic subaortic stenosis, following
alcohol ablation of the enlarged ventricular septum.
In such patients, the anterior motion of the mitral valve leaflet
is obstructed by the enlarged septum during systole, which
obstructs aortic outflow. The standard treatment at our institution
is coronary alcohol injection to ablate a portion of the
myocardium. These procedures are done empirically and guided by
evidence of decreased wall motion. Gauging how much of the
myocardium has been treated can be quite difficult
Using MR, functional images are obtained before the procedure to
assess outflow obstruction. Following injection of alcohol into the
coronary artery, first-pass perfusion images demonstrate areas
without blood flow (Figure 3). On delayed imaging, approximately 10
minutes after injection, the areas of nonviable myocardium are
clearly mapped out. Patients can also be followed over time to
assess overall cardiac function as well.
Myocardial perfusion imaging is typically used to evaluate
patients with ischemic heart disease, rather than MI. An infusion
of the vasodilator Adenoscan (Fujisawa Healthcare, Inc., Deerfield,
IL), 140 µg/kg/min, augments coronary blood flow. After
approximately 2 minutes, 0.1 mmol/kg gadolinium contrast media is
delivered as a single, rapid-infusion bolus (5 mL/sec), as in the
myocardial viability protocol described previously. Gradient echo,
echo-planar notched interleaved pulse sequences are used to image
the entire myocardium for about 1 minute after a contrast
Because the protocol involves the use of the vasodilator
adenosine to augment coronary blood flow, there are several
contraindications to MR perfusion imaging, including wheezing,
hypertension, the use of caffeine or aminophylline, or greater than
first-degree atrioventricular heart block. Depending on the patient
population, approximately 5% of patients are likely to experience
discomfort during the exam. Approximately 0.5% experience a
potentially serious adverse reaction to adenosine, such as
arrhythmias or heart block. During stress testing, a staff member
with Advanced Cardiac Life Support certification must be
Figure 4 shows a patient with reduced perfusion in the septal
and anterior portion of the myocardium, and another patient with
left ven-tricular hypertrophy and small subendocardial areas of
A major area of investigation involves the quantification of
perfusion defects, as a better alternative to visual estimation of
the extent of stenosis.
Nonetheless, even with visual estimation, the overall correlation
between perfusion abnormalities that are physiologically
significant and angiographic stenosis has been quite good (Table
The imaging of atherosclerosis represents a major new and
developing application of contrast administration. Often, MR
angiography of patients with suspected heart disease shows an
essentially normal coronary lumen. However, there can be tremendous
amounts of disease in the vascular walls. Assessment of the
atheromatous components of plaque represents an important and
active area of investigation today. Key questions in determining
whether a plaque is vulnerable to rupture include whether it has a
large lipid core or is covered by a thin fibrous cap. Both are
thought to increase the risk of plaque rupture, with the ultimate
result being obstruction of the coronary artery and MI.
Figure 5 demonstrates the use of contrast in imaging
atherosclerosis of the carotid artery, where most of the initial
studies have been done.
The area of fibrous cap is well enhanced, enabling assessment of
cap thickness. The lumen is quite small, and adjacent to the
fibrous cap is the lipid core. Within the lipid core is an area of
calcification. All of the plaque components are well delineated on
the MR image, which correlates closely with the histology
The imaging of atherosclerosis can be applied to other vascular
beds as well.
Probably the most interesting and important are the coronary
arteries. Patients with atherosclerosis may have only mild degrees
of coronary arterial narrowing on angiographic sequences, but still
have significant amounts of disease inside the vessel wall (Figure
6). The true extent of disease and risk for subsequent plaque
rupture is probably best assessed using contrast-enhanced MR.
The use of contrast for myocardial viability imaging is a major
new application of MR. Myocardial perfusion, stress imaging, and
the evaluation of myocardial ischemia are active subjects of
investigation as well. Contrast-enhanced imaging for
atherosclerotic disease, particularly in combination with MR
coronary angiography, holds great promise for evaluating the risk
of cardiac events. *
1.Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of
microvascular obstruction by magnetic resonance imaging in patients
with acute myocardial infarction.
2. Wu KC, Heldman AW, Brinker JA, et al. Microvascular
obstruction after nonsurgical septal reduction for the treatment of
3. Schwitter J, Nanz D, Kneifel S, et al. Assessment of
myocardial perfusion in coronary artery disease by magnetic
resonance: A comparison with positron emission tomography and
4. Al-Saadi N, Nagel E, Gross M, et al. Noninvasive detection of
myocardial ischemia from perfusion reserve based on cardiovascular
5. Zhao S, Croisille P, Janier M, et al. Comparison between
qualitative and quantitative wall motion analyses using
dipyridamole stress breath-hold cine magnetic resonance imaging in
patients with severe coronary artery stenosis.
Magn Reson Imaging
6. Bremerich J, Buser P, Bongartz G, et al. Noninvasive stress
testing of myocardial ischemia: comparison of GRE-MRI perfusion and
wall motion analysis to 99 mTc-MIBI-SPECT, relation to coronary
7. Yuan C, Hatsukami TS, O'Brien KD. High-resolution magnetic
resonance imaging of normal and atherosclerotic human coronary
arteries ex vivo: Discrimination of plaque tissue components.
J Invest Med
8. Wasserman BA, Smith WI, Trout HH 3rd, et al. Carotid artery
atherosclerosis: In vivo morphologic characterization with
gadolinium-enhanced double-oblique MR imaging initial results.
9. Fayad ZA, Fuster V. Clinical imaging of the high-risk or
vulnerable atherosclerotic plaque.
Thank you very much, Dr. Bluemke. Let me ask a question
specifically about the perfusion. You mentioned that you give the
bolus at a high rate of injection. Do you use a power injector for
that, or do you do that by hand?
DAVID BLUEMKE, MD:
We are using power injectors for all of our studies. For first-pass
perfusion studies, we typically inject at about 5 mL/sec. These
patients are quite often very sick patients and they typically have
large-bore catheters already in place. So it is quite feasible to
inject using a large-bore angiocatheter with a high injection
I'd like to ask you about the tendency in nuclear medicine to
obtain rest and stress images. Where do you think that fits in?
Concerning injection, when you have to give dynamic gadolinium
injection and pharmacologic injection simultaneously, then you
would need multiple IVs. Or can they be piggybacked?
As far as the the use of stress and rest images, the initial
studies that were done with perfusion MRI definitely considered
that model of application. The reason for doing stress and rest
images is to distinguish viable from nonviable myocardium, ischemic
myocardium versus infarction. That model was used initially. Now it
is a development of these viability MR sequences, where the normal
myo-cardium is suppressed with inversion recovery pulse
The standard model now is to do stress images during adenosine
infusion, and then wait for 10 to 20 minutes, then look at the
areas that are nonviable on the delayed images. There's been a
movement then to not require multiple injections for those images,
during first-pass conditions.
The reason for that is because you don't need the resting image,
because the viability image tells you where the infarct is, if it
That's right. The nonviable myocardium will light up very nicely,
and can be delineated at about 10 to 20 minutes after contrast
So are you then suggesting that the need to image under stress may
be completely eliminated by these new MR perfusion and viability
No, we think that stress conditions are going to be necessary to
distinguish narrowing prior to infarction. If a patient presents
with chest pain and typical anginal type symptoms, the question is,
is that coronary heart disease or is it some other cause of chest
pain. In those conditions, in which an infarction has not occurred,
it is very likely that only under stress conditions will those
areas of coronary narrowing be revealed on the perfusion images,
the first-pass images.
During the stress imaging, who is monitoring the patients? Do you
do it with the cardiologist?
Yes, during the stress cases, someone who is ACLS certified has to
be there. We typically have a very competent nursing assistant
addressing the medication issues. They can be quite complicated
procedures, although they are of relatively short duration. After 4
to 6 minutes, the stress imaging is completely done and the
adenosine has a very short half life of about 1 to 2 minutes. So
when we are done with that stress component, we can rapidly assess
the patient to determine if there is any evidence of heart block,
or any chest pain associated with the stress condition.
RUSSELL LOW, MD:
What's the incidence of complications or symptoms?
Well, the incidence of symptoms can be relatively high, depending
on the patient population you are studying. Some discomfort can
occur in probably <5% of the patients. As far as overall severe
life-threatening conditions, the incidence for adenosine is on the
order of about 0.5%, at least in the literature. If you talk to
labs that do a lot of these studies, I think they believe that that
number is a little bit high. But if you document a large number of
cases in which arrhythmias and heart block are delineated
accurately, it may very well be that those numbers are quite
accurate. So you have to be prepared to treat patients and get them
out of the room rapidly if complications should occur.
In the first-pass images that you showed, I noticed some
misregistration, which I presumed was motion artifact from
breathing. Do you find that interferes with the creation of color
maps of the mean transit time and other parameters?
Yes, we try to do the first-pass images during an extended
breath-hold and ask the patient to hold his or her breath for as
long possible. For some patients, it is about one image. Other
patients do quite well, and hold their breath for 30 or 40 seconds.
The key time is the first 20 to 30 seconds. We have a pretty good
success rate in having patients coordinated with the technologist
in terms of the injection and the scanning, to be able to hold
their breath during that period of time.
Right now most of these images are evaluated qualitatively. With
quantitative evaluation, it's a huge issue. But there are motion
correction software packages that will re-register the images, so
we can place cursors over the areas of interest to map those signal
How soon after a patient arrives in the emergency room, do you feel
safe to do a stress perfusion study? At some point, you have to
decide whether the patient's had an infarction or not.
Well, there are a couple of issues there. Let's say the patient
comes into the emergency room with chest pain. First of all, there
are not a lot of MR centers that are set up to handle that patient
in the acute setting. There have been studies in which MR scanners
have been sited next to the emergency rooms. They have been used
not so much for stress studies, but for nonstress studies for
viability, since the areas of dead myocardium will light up very
rapidly after the event occurs.
In animal studies with 90-minute occlusions of a LAD,
immediately after imaging, those areas will show on the delayed
enhancement images. The more common scenario is with someone with
chest pain who was triaged and is in the CCU when we image them, if
they need to be imaged at all. Usually it's patients who have more
complicated courses, or who have atypical conditions that are
imaged. Women may present differently; the troponin levels may have
been missed because of delayed presentation in the emergency room.
So usually it's a combination of factors.
Not all patients need viability imaging necessarily. We think
that some routine myocardium infarction cases are treated very
nicely, and they get very little imaging whatsoever in the
hospital. It's probably in the sicker patients, more atypical
presentations, that this will be a useful technique.
Do you think MR has the potential in these emergency room patients
to determine whether there has been a myocardium infarction? Would
a normal MR allow safe discharge of the patient; thereby
eliminating the more common pattern of watching the patient
overnight and checking enzymes and so forth?
Yes, and it is a very significant issue for hospital
administrators, because of the substantial costs of keeping people
in the hospital for 24 hours. So, there is a major reason to triage
these patients quickly. Whether that will have an impact, I think
will still unfold.
There have been studies at Washington Hospital, for example, in
which they have triaged patients using MR to determine if they will
be admitted, or if they will be observed for just a short period of
time. Overall, they've shown reasonable success for mapping areas
of myocardium infarction. One of the issues in the nonstress state
is whether you can assess nonviable myocardium versus ischemic
changes. You probably cannot. So in the acute setting, mapping the
myocardium infarction to determine if an infarct has occurred may
be quite useful. But these patients will still need some triaging
and ischemic testing or stress testing, if they go home.
Howard talked about perfusion imaging the brain, and measuring MTT
blood volume and blood flow. Is there any use for those
measurements in the myocardium?
As I mentioned, most studies have looked at qualitative changes.
There is a lot of investigation in the use of quantitative
evaluation. Personally, I think it would be quite valuable. But the
techniques are not widely applied at this point and the software is
not widely available. There are many people who have subtle
perfusion changes, which may be in the realm of normal, that we'd
like to quantify. We think we can triage between the abnormal
patient with ischemia or infarction, versus the normal
Contrast-Enhanced MRI of the Breast
Nola Hylton, PhD Associate Professor of Radiology,
University of California--San Francisco, San Francisco, CA
As research and clinical experience in breast MRI grow, two
fundamental issues are being debated. The first concerns the
circumstances under which MRI is indicated in the evaluation of
breast disease, if at all. Answering this question is made more
challenging by the necessity of determining not only whether MRI
yields valuable information, but also how it compares to a
combination of mammography and clinical breast examination.
The second question involves the optimal technique to use.
Contrast is essential for the diagnosis and characterization of
breast cancer by MRI. It remains to be established, however,
whether the morphologic features of the lesion or information about
its function is of greater importance. This article will review
evolving techniques in and clinical indications for breast MRI as
an adjunct to mammography.
MRI versus Mammography
MRI has certain advantages that make it attractive for the
evaluation of breast disease: Virtually all malignancies enhance
after contrast injection, MRI has a high sensitivity for the
detection of breast cancer--95% or greater, according to several
--and it is able to visualize very small tumors (<5 mm).
Defining precisely how small a tumor MRI
can visualize has been challenging. It is possible to see
submillimeter enhancement that comprises only a few pixels, but
this is a fleeting effect that is impossible to validate
In addition, MRI is not limited by breast density, which is a
major advantage in comparison with mammography, and is effective
even in women who have breast implants or have undergone previous
breast surgery. Finally, MRI has a very high negative predictive
value. Therefore, when no enhancement is seen after a successful
injection of contrast, it is very unlikely that malignant disease
One of the disadvantages of breast MRI is that its specificity
appears to be moderate at best, although the specificity has been
difficult to define. Reports in the scientific literature cite
values of 37% to 97%,
but these findings appear to depend heavily on the selection of
both the MRI technique and the criteria for determining
Additional disadvantages of breast MRI are its relatively long
scan times (multiple sets of images are usually acquired during a
30- to 45-minute examination) and its requirement for contrast
injection, which is unnecessary in mammography. The high cost of
breast MRI is also a disadvantage.
Although mammography and breast MRI are different in many ways,
they are in fact complementary procedures and work well in
combination. Mammography, for example, readily detects
calcifications, whereas MRI does not. Mammography loses some of its
effectiveness in dense breast tissue, whereas MRI appears to work
better in dense breast tissue than in fatty tissue, because fewer
fat-water boundaries mean a better, more homogeneous signal.
Breast MRI Technique
Contrast is considered essential for the evaluation of breast
cancer. A single dose of gadolinium contrast media, 0.1 mmol/kg
body weight, is used in most breast MRI studies. Early studies with
spin-echo techniques used double-dose contrast, but today most
examinations involve gradient-echo sequences in which a single dose
of contrast is most effective. Precision isn't critical in contrast
administration. Injections need to be consistent but do not
necessarily require the delivery of a fast bolus. Manual injection
A dedicated breast coil is required. Patients generally lie in
the prone position in order to minimize the image blurring that can
be caused by cardiac and respiratory motion. Some devices have
compression plates for holding the breast stable, but in most
cases, with a little coaching, patients remain still during the
scan, and image registration is not a problem. With certain coils,
patients can go into the magnet feet first, which seems to reduce
feelings of claustrophobia substantially.
T1-weighted imaging is required for the best sensitivity to the
gadolinium contrast agent; however, the selection of other imaging
parameters depends on the clinical question at hand, the available
equipment, and the radiologist's preference. Variables include
slice thickness and orientation (transaxial, coronal, or sagittal);
the tradeoffs between temporal and spatial resolution; and choices
between unilateral or bilateral acquisition, 2- or 3-dimensional
imaging, spin-echo or gradient-echo sequence, and injection of
contrast by hand or by power injector.
Morphology or Function?
The strategies used in breast MRI depend on whether the goal is
diagnosis or staging. In staging, it is important to determine the
size and extent of a cancerous lesion and whether it is multifocal.
The priority is the sensitivity of imaging. Three-dimensional
spoiled gradient echo techniques are generally used (Table 1)
because of their high spatial resolution, ability to cover the full
volume of the breast, and inclusion of fat suppression. Scans are
longer when the goal is staging, usually taking 2 to 4 minutes to
ensure both adequate coverage and a high signal-to-noise ratio, a
measurement of image quality.
When the purpose of MR is to diagnose a suspicious lesion,
specificity is the priority. In this case, dynamic techniques using
2D spin echo sequences are generally used (Table 2); however, 3D
techniques can be used with reduced resolution, and scan times will
be similar to those of dynamic 2D methods. Dynamic scans, used to
observe contrast uptake, usually take 1 minute or less. In fact,
15-second scans are not uncommon. To achieve high temporal
resolution, it is often necessary to limit coverage, reduce spatial
resolution, and/or forego fat suppression. From time-intensity
curves, pharmacokinetic parameters related to vessel permeability
and blood volume can be calculated.
The approaches to high-resolution and dynamic scans are
beginning to converge. Faster 3D sequences equivalent in speed to
2D spin-echo techniques are possible and, as a result, dynamic
scanning is increasingly using 3D methods. In general, the 3D
methods are not extremely high in either temporal or spatial
resolution; however, they balance the need for both enhancement
morphology and enhancement kinetics. For now, most practitioners
prefer image quality to be high enough to identify specific
features that raise diagnostic confidence--for example, the
interior and border of lesions. Once image quality is adequate,
temporal resolution can be increased as much as possible.
Finally, the limited availability of computer-aided kinetic
analyses also influences the preference for studies that emphasize
morphology over function. There is a general consensus that MRI
should be integrated into breast imaging practices, and that breast
radiologists should do the interpretations. However, without the
aid of effective computer tools to process data rapidly, the
interpretation of functional information and generation of
parametric images is too time-consuming for most mammography
Figure 1 shows a 3D contrast-enhanced breast MR image acquired
with high spatial resolution in a woman with invasive carcinoma in
the lower half of the breast. The lesion is very well characterized
morphologically, and spiculations and dark areas within the lesion
are clearly evident.
Figure 2 depicts the same lesion, in this case acquired using a
2D dynamic MR sequence, a 15-second scan time, and no fat
suppression. The lesion is visible, but the internal morphology is
not as apparent as on the 3D image. It is possible on the dynamic
image, however, to observe the time course of tumor enhancement.
Contrast washout after 2 minutes, or a fast increase with either
stabilization or washout of contrast, as seen in Figure 2, are both
considered suspicious findings. A more gradual uptake without
washout is considered less suspicious. The specificity of these
patterns is a problem, however. The gradual pattern of enhancement
could also be consistent with ductal carcinoma in situ (DCIS). In
cases of DCIS, a linear or segmental morphologic pattern is
extremely helpful in making a diagnosis.
Whether to do bilateral or unilateral imaging is also a source
of ongoing debate. The argument for unilateral imaging is that
keeping spatial resolution as high as possible enables careful
evaluation of symptomatic lesions, particularly their
There is also a strong argument for the importance of symmetry,
which can be evaluated only with bilateral imaging. For example, a
regional area of enhancement is considered less suspicious for
malignancy if it is observed in both breasts. When referring a
patient for surgical staging following detection of a symptomatic
breast lesion, physicians increasingly request evaluation of the
other breast. This represents a screening application of breast
MRI--however, one that is the subject of going research but is not
yet ready for clinical use.
Differential diagnosis represents an emerging application of
breast MRI. Indications that fit in this category include an
inconclusive mammogram, a palpable abnormality without mammographic
findings, and nipple discharge without mammographic findings. MRI
is also used to differentiate recurrent breast cancer from scar
For these indications, MRI has a high sensitivity, but only a
moderate specificity. The frequency of its use for differential
diagnosis depends on how heavily minimally invasive biopsy
procedures, including fine-needle aspiration, stereotactic core
biopsy, and ultrasound-guided core biopsies, are used in a
particular practice. In many areas of the United States, where
these invasive procedures are common, there is less demand for MRI
to determine whether a lesion is malignant. In Europe, however,
breast MRI is more widely used for differential diagnosis.
The patient in Figure 3 had a spiculated mass on mammography,
which may have been either recurrent carcinoma or scar. On MRI, a
distortion caused by a previous biopsy is apparent, but there is no
contrast enhancement. Incidental enhancing foci found elsewhere in
the breast were determined to be ductal carcinoma in situ.
Staging is another emerging application of breast MRI. It is
useful for staging in the case of a biopsy that shows cancer,
tissue margins that test positive for cancer cells following
lumpectomy, or a cancerous lymph node whose source lesion has not
been identified in the breast. There is an increasing need to stage
the extent of disease preoperatively, as needle biopsy procedures
provide no surgical margins for pathological examination, as
excisional biopsy does.
Assessment of the response to preoperative chemotherapy is an
additional staging application. In this indication MRI can be used
to: 1) stage the extent of disease to determine the appropriateness
of preoperative chemotherapy; 2) monitor the response during
treatment and, potentially, change the course of treatment for
patients with non-responsive tumors; and 3) measure the extent of
disease following chemotherapy to determine if breast conserving
surgery is an option.
In staging applications, MRI is proving to be more effective
than mammography. There are several reasons for this.
Contrast-enhanced MRI is very sensitive to breast carcinoma. Its 3D
format results in a superior anatomical representation. Breast MRI
is more accurate for demonstrating tumor extent. Both mammography
and MRI demonstrate malignancy; however, concordance with the
pathological determination of the extent of disease was found in
one study to be considerably higher for MRI: 98%, as compared with
55% for mammography
MRI offers a particular advantage when DCIS is present (Table
4). As shown in Figure 4, MRI easily depicts multifocal disease, as
well as significant axillary involvement, and the distribution of
DCIS over an entire segment of the breast.
Screening represents the most challenging application of breast
MRI, but it may offer the greatest potential to improve patient
outcomes. Genetic testing and statistical models can identify women
at high-risk for breast cancer, but early detection has been more
difficult. High-risk women are likely to develop cancer at a young
age, when breast tissue is still very dense, and mammography is
less effective. Until recently, one of the few options for reducing
breast cancer risk has been bilateral prophylactic mastectomy.
MRI may offer an effective alternative for screening and
surveillance. It is not considered practical in a general
population, but MRI screening is proving useful in women who have
dense breasts or have been determined to be at high risk--those who
carry BRCA1 or BRCA2 gene mutations, have a personal or family
history of breast cancer, or have cancer in the contralateral
MRI does have shortcomings when used for screening, however.
Incidental enhancing lesions are identified in many patients. Most
will turn out to be benign, but positive findings on MRI create a
high level of anxiety. Biopsy is difficult, as the lesions are
neither palpable nor seen on mammography, and MR-guided biopsy
tools are insufficiently developed.
Several trials of MRI for breast cancer screening are under way
in the United States, Canada, and Europe. Participants are BRCA1 or
BRCA2 mutation carriers, or have a high risk for breast cancer on
the basis of family history or statistical modeling. They undergo
an initial screening MRI, with follow-up examinations at least
annually. Data from these studies will be pooled for the evaluation
of sensitivity and specificity. Early results suggest that MRI
screening detects breast cancer in 2% to 3% of high-risk women, a
reasonably high rate.
As effective computer-aided analyses become widely available, a
greater emphasis may be placed on fast imaging. The specificity of
MRI could be improved by the introduction of better contrast agents
that yield more accurate pharmacokinetic measurements or that
target cancer cells specifically. These agents would likely reduce
lesion conspicuity, however, so their overall benefit is not
Improvements are clearly needed in localization and biopsy
methods. This might involve localization of lesions for subsequent
ultrasound-guided, stereotactic, or excisional biopsy, or the
development of MR-guided biopsy tools. Finally, there is intense
interest in the development of tools for noninvasive tumor ablation
by MR-guided cryotherapy, radiofrequency energy, or focused
ultrasound heating. *
1. Harms SE, Flamig DP, Hesley KL, et al. MR Imaging of the
breast with rotating delivery of excitation off resonance: Clinical
experience with pathologic correlation.
2. Orel SG, Schnall MD, LiVolsi VA, Troupin RH. Suspicious
breast lesions: MR imaging with radiologic-pathologic correlation.
3. Kaiser WA, Zeitler E. MR imaging of the breast: Fast imaging
sequences with and without Gd-DTPA. Preliminary observations.
4. Heywang SH, Wolf A, Pruss E, et al. MR imaging of the breast
with Gd-DTPA: Use and limitations.
5. Stack JP, Redmond OM, Codd MB, et al. Breast disease: Tissue
characterization with Gd-DTPA enhancement profiles.
6. Gribbestad IS, Nilsen G, Fjosne H, et al. Contrast-enhanced
magnetic resonance imaging of the breast.
7. Flickinger FW, Allison JD, Sherry RM, Wright JC.
Differentiation of benign from malignant breast masses by
time-intensity evaluation of contrast-enhanced MRI.
Magn Reson Imag
8. Gilles R, Guinebretiere JM, Shapeero LG, et al. Assessment of
breast cancer recurrence with contrast-enhanced subtraction MR
imaging: Preliminary results in 26 patients.
9. Rubens D, Totterman S, Chacko A, et al. Gadopenetate
dimeglumine-enhanced chemical-shift MR imaging of the breast.
AJR Am J Roentgenol.
10. Boetes C, Barentsz JO, Mus RD, et al. MR characterization of
suspicious breast lesions with a gadolinium-enhanced turbo FLASH
11. Hulka CA, Smith BL, Sgroi DC, et al. Benign and malignant
breast lesions: Differentiation with echo-planar MR imaging.
12. Esserman L, Hylton N, Yassa L, et al
Utility of magnetic resonance imaging in the management of breast
cancer: Evidence for improved preoperative staging.
J Clin Oncol.
13. Warner E, Plewes DB, Shumak RS, et al. Comparison of breast
magnetic resonance imaging, mammography, and ultrasound for
surveillance of women at high risk for hereditary breast cancer.
J Clin Oncol.
14. Kuhl CK, Schmutzler RK, Leutner CC, et al. Breast MR imaging
screening in 192 women proved or suspected to be carriers of a
breast cancer susceptibility gene: Preliminary results.
15. Schnall MD. Application of magnetic resonance imaging to
early detection of breast cancer.
Breast Cancer Res
Thank you very much, Dr. Hylton. You mentioned that specificity is
still an issue. There have been some recent reports using dynamic
susceptibility imaging, following the initial T1-weighted gradient
echo. So, this could be analogous to what Dr. Rowley showed in the
brain, where altered perfusion could be identified, probably
reflecting angiogenesis in the lesion.
That would have an impact on the most desirable contrast agent,
because you may want to give that at a high rate of injection. What
do you think about that in the future?
NOLA HYLTON, MD:
I think that it's likely that in the future that we'll do something
like that. Once the ability is there to augment the morphologic
information with a functional over-lay, then perfusion makes sense,
and actually Christiane Kuhl, in Germany, published some work
comparing T2 perfusion imaging in breast lesions. I think her
specificity was either equivalent or slightly better than dynamic
T1-weighted contrast evaluation. These are types of things where
the diffusion information would be added.
But as I mentioned earlier, I believe it could be useful as long
as it doesn't compromise what you can see morphologically about the
lesion. There are important features that have become associated
with certain types of important histologies, for example ductal
carcinoma in situ has some patterns that requires high resolution
in order to be identified on MR. A lot of the ability to diagnosis
depends on what we see at the borders and interior of enhancing
lesions. So, as long as those features are maintained, this is an
early detection method. Clearly, we also want to be able to
characterize small lesions, because we hope to use this in a
screening capacity, so we will need to see these lesions and
characterize them when they're still fairly small. So the addition
of techniques that add physiologic or functional information would
likely be done with a second bolus, and would likely be used to
overlay functional information on what we can already see
But it would be in a second bolus situation. So you would do your
T1-weighted gradient echo and then the second bolus with
susceptibility imaging or some other function.
Well, there are a few other clever pulse sequences that people are
developing to combine both high spatial resolution and high
temporal resolution. I believe it came out of your own work and you
are familiar with it. But, in terms of taking cores or samples of
k-space, you need to get the high temporal resolution and
information about contrast enhancement, then combine it to create
one higher resolution 3D, longer time scan, imaged to see the
I've been working with a method based on a similar idea to TRICKS,
but using a different geometry of acquisition in the k-space. It
offers surprisingly good spatial resolution and temporal
resolution, sort of an optimal solution to that problem.
I think something like that is very attractive. As long as the
reconstruction tools, etc., are there to apply these techniques,
we'll get the best of both worlds out of the data.
Ultimately, you need to cover both breasts very rapidly with high
spatial resolution. How fast do you think we need to image, what
temporal resolution behind which is no longer worthwhile? As you go
to faster acquisitions, do the injection rates start to matter more
and have to be controlled more?
My personal belief is that anything below 30 seconds is going to
compromise imaging, compromise the spatial resolution. But I am
very influenced by the argument that we do need to be imaging
bilaterally, which is actually going against getting better spatial
resolution. So if we realize any improvements in imaging, it would
probably be to get more effective bilateral techniques. I don't see
in the near future that we'll be going incredibly fast in scanning,
unless we're doing two different types of techniques, and looking
at them in combination.
For the implications for contrast and contrast injection, I
would only speculate that if you do some sort of sequential type of
an approach, the secondary functional information would be very
dependent on the injection dose, mode of administration, and rate,
etc., and that those things would need to be very controlled,
likely would be best done with a power injector. The practicality
of the use of a power injector is that if you're not there for
every exam, at least you have some confidence that it was done in a
consistent way. So, you are not asking yourself on any given study,
if there could have been a problem with the injection.
There's an emerging concept in SMASH, in so-called parallel
imaging, which can help to solve the trade-off of being able to
image fast and simultaneously at high resolution, but introducing
the additional trade-off of sacrificing signal-to-noise. One way of
buying back signal-to-noise is to increase your dose of gadolinium.
Right now since you are only operating at a single dose of
contrast, you have a lot of room to increase the dose.
What do you think about this possibility that with techniques
that sacrifice signal-to-noise to address the temporal and spatial
resolution issues, that you'd be willing to buy that back by
bumping your dose up?
You know, at the moment, we're hitting an over-sensitivity with
respect to the objects that enhance. I think by increasing the
dose, we tend to see more of the hyperplasias of fibrocystic
disease, or proliferative diseases that tend to light up, and that
we have a lot of problems trying to decipher them. A lot of the
attempts to differentiate hyperplasias from DCIS have to do with
seeing if you can see changes in the very initial uptake. If you
pump up the contrast dose, you might wash some of that out, you
might lose some of that. I'm not sure that dose as a method of
getting better signal-to-noise is necessarily what the issue
I think that the signal-to-noise needs simply to allow us to see
anatomically what's there. But I think if you use contrast to get
that effect, you are going to lose information about border
differentiation, the rate of enhancement over time, and whether you
have a rim versus a central enhancement, etc. Those are things that
we actually look at and make decisions about.
Dynamic Contrast-Enhanced MRI of the Liver and
Richard C. Semelka, MD Director of MR Services, Professor
of Radiology, Vice Chair of Clinical Research, University of
North Carolina Hospital, Chapel Hill, NC
The role of magnetic resonance imaging (MRI) in the liver is
well established, and gadolinium-enhanced studies represent the
state of the art.
One variation, the use of high-dose gadolinium, holds a more
limited place in liver MRI. Nonetheless, it has the potential to
play a much larger part in clinical management by improving the
detection and characterization of cancerous lesions and, thereby,
guiding treatment decisions.
There are both practical and theoretical roles for high-dose
gadolinium MRI of the liver. The practical role, which encompasses
applications in clinical use today, involves a combination of
tissue imaging and magnetic resonance angiography (MRA). This
combination can be achieved through two approaches, either a
three-dimensional (3D) technique that enables simultaneous
acquisition of both tissue imaging and MR angiographic information
(VIBE, or volumetric interpolated breath-hold examination), or a
combination of a two-dimensional (2D) spoiled gradient-echo
technique, followed by 3D MRA.
When image quality is paramount, it is preferable to choose the
2D spoiled gradient-echo technique, followed by 3D MRA. This
approach is often used for surgical planning, involving either a
living related transplant donor scheduled for hemiliver donation,
or a patient with liver metastases, in whom a complex surgical
procedure necessitates the creation of a high-quality vascular road
The first step is high-quality tissue imaging using a 2D
gradient-echo sequence and a single dose of gadolinium contrast. On
the first-pass postgadolinium image, we look for the presence of
contrast in the portal veins and a lack of contrast in the hepatic
veins (Figure 1, top left). Approximately 60 to 90 seconds after
the contrast injection, we image with fat suppression (Figure 1,
bottom right), looking specifically look for such abnormalities as
peritoneal disease, capsule-based disease of the liver, and certain
neoplasms such as cholangiocarcinoma, which are well visualized on
Approximately 15 to 20 minutes after the initial injection of
gadolinium, we do high-definition MR angiography, using a 3D
gradient-echo sequence and, typically, 20 mL of contrast (Figure
2). We routinely use power injection at a rate of 2 mL/sec. At that
rate, the temporal resolution is good and it is possible to capture
the hepatic arterial dominant phase, as well as specific
enhancement characteristics of liver lesions.
Magnetic resonance angiography is especially useful when imaging
patients with vascular anomalies. Figure 3 is an example of a
replaced right hepatic artery. The source image on the top left
shows the left hepatic artery arising from the celiac artery. The
source image on the bottom left shows the take-off of the replaced
right hepatic artery from the superior mesenteric artery, and a
distal branch of the right hepatic artery. The combined multiple
intensity projection (MIP) image shows both the left hepatic artery
coming off the celiac artery, and a portion of the replaced right
Detection and characterization
Although little has been reported or written about the
theoretical roles for high-dose gadolinium MRI of the liver, its
potential to improve the detection and characterization of liver
lesions is very intriguing. One of the few reports on this topic
came from Taupitz et al from the Charité University in Berlin. In
2000, they found that double-dose gadolinium contrast
administration improved the definition of both enhancing nodules
and the progression of enhancement in small hemangiomas when
compared with single-dose contrast administration (M. Taupitz,
personal communication). This finding may be important, as correct
characterization of liver lesions is an essential part of
evaluating patients with malignant disease.
Double-dose contrast may be useful in improving characterization of
lesions, such as hemangiomas, in patients being evaluated for
High-dose gadolinium contrast may also be of value in improving
lesion detection, particularly in assessing malignant lesions that
are amenable to resection or other local therapy. The two most
important of these lesions are colon cancer liver metastases, which
typically are hypovascular, and hepatocellular carcinoma, which
typically is hypervascular.
In imaging hypovascular colon cancer metastases, high-dose
gadolinium contrast may improve the conspicuity of lesions by
increasing enhancement of the ring. Appreciating ring enhancement
is the single most important evaluation to make in correctly
characterizing metastatic colon cancer metastases
(Figure 4). Often, enhancement is best on delayed imaging, 90
seconds after contrast administration.
It is relatively easy to evaluate large lesions with a
combination of T2-weighted, T1-weighted, and early and delayed
postcontrast imaging. High-dose contrast, therefore, is likely to
be most important in detecting small lesions, a crucial factor in
selecting the type of therapy that is most appropriate for each
In hepatocellular carcinoma, the tumors are usually small and
hypervascular. Often, however, they must be imaged on the
background of a heterogeneously enhancing cirrhotic liver. Although
such lesions can be very difficult to see on precontrast T2- and
T1-weighted images, they are easily appreciated on immediate
The appearance of hepatocellular carcinoma as hyperintense lesions
immediately following contrast administration once again raises the
possibility that high-dose gadolinium studies may improve lesion
detection and help guide patient management.
Figure 5 shows a typical small hepatocellular carcinoma. On
T2-weighted precontrast imaging, it is difficult to appreciate the
lesion at all, although it is slightly hyperintense on the
T1-weighted sequences. On immediate post-gadolinium images,
hepatocellular carcinoma shows very intense enhancement, surrounded
by a hypoenhancing capsule around the lesion. On delayed
post-contrast images, we appreciate rapid washout of the lesion and
late capsular enhancement, which are very specific for
In pancreatic imaging, just as in hepatic imaging, high-dose
gadolinium contrast studies have the potential to improve the
detection of both hypovascular and hypervascular lesions. For
example, we would expect better definition of small hypovascular
pancreatic ductal adenocarcinomas by showing improved enhancement
of the surrounding pancreas.
We would expect even more consistently positive results when
high-dose gadolinium contrast is used in the imaging of islet cell
tumors, insulinomas in particular. These tumors are initially very
small, in the range of 1 to 2 cm, and can be difficult to detect.
It is likely that the use of high-dose gadolinium contrast media
will improve the detection of small insulinomas, but this needs to
be demonstrated in clinical studies.
High-dose gadolinium contrast plays a small role in hepatic and
pancreatic imaging today. We use it primarily in studies that
combine tissue imaging with MRA, but it is also valuable for the
evaluation of 2 different organ systems in the same study. For
example, high-dose gadolinium is useful when examining the liver,
followed by MRA of the renal arteries.
In the future, high-dose contrast-enhanced MRI may fill a much
larger and more important clinical role in the evaluation of
malignant disease, enabling better detection and characterization
of cancerous lesions in patients who are being considered for
surgical management. Controlled clinical studies comparing low- and
high-dose contrast MRI, as well as high-dose contrast-enhanced MRI
and other imaging modalities, such as CT, are now needed to
determine whether this potential will become a reality. *
1. Semelka RC, Helmberger TK. Contrast agents for MR imaging of
the liver. State of the art.
2. Semelka RC, Braga L, Armas D, et al. Liver. In: Semelka RC,
Abdominal Pelvic MRI
. New York: Wiley-Lyss; 2002:33-318.
3. Semelka RC, Worawattanakul S, Kelekis NL, et al. Liver lesion
detection, characterization, and effect on patient management:
Comparison of single-phase spiral CT and current MR techniques.
J Magn Reson Imaging
4. Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions:
Comparison of dual-phase CT and multisequence multiplanar MR
imaging including dynamic gadolinium enhancement.
J Magn Reson Imaging
5. Noone TC, Semelka RC, Balci NC, Graham ML. Common occurrence
of benign liver lesions in patients with newly diagnosed breast
cancer investigated by MRI for suspected liver metastases.
J Magn Reson Imaging
6. Kelekis NL, Semelka RC, Worawattanakul S, et al.
Hepatocellular carcinoma in North America: A multi-institutional
study of appearance on T1-weighted, T2-weighted, and serial
gadolinium-enhanced gradient-echo images.
AJR Am J Roentgenol
Thank you very much for an excellent presentation. We have some
time for discussion. Dr. Kramer?
Can you distinguish between doses; that is, quantity of contrast
versus injection rate, in trying to define margins, and having
That's a good question. At this point in time, since most of the
work that we've done has been with single-dose contrast, most
people have been focusing on contrast injection rates. In the past,
we used hand injection, and now we routinely use machine power
injection at 2 mL/sec. At that rate, we have fairly good temporal
resolution that we can get very nicely. We can capture the hepatic
arterial dominant phase, and also the specific enhancement
characteristics of liver lesions.
Going with a higher dose, I think we would still have to at
least match that ejection rate. It's very important to maintain
that very early enhancement, the hepatic arterial dominant phase.
So with higher dose, it will still be very essential. We can't get
away from fast injections. I think if anything, there may be more
importance attached to fast injections.
I had a question about your approach, which is dynamic in the sense
of over several minutes, and is mostly driven by morphologic
characteristics. Do you think there is any potential for parametric
imaging of the earliest wash-in phases, washout of some of these
lesions, region of interest, or maps as we've seen for brain or
Yes, I think that at this point in time I haven't appreciated that
that is important. The reason is that in the liver, there are very
specific enhancement characteristics. So we don't have to resort to
temporal handling of contrast, because the various benign lesions
and malignant lesions have very specific morphologic features in
how they enhance. It's a very interesting topic for the same
reasons that it's interesting in the brain and the breasts, in that
angiogenesis and the pattern of blood supply, is crucial. But I
think we have the advantage that there's better morphologic
characteristics of the various liver lesions, so we haven't had to
rely on dynamic handling or looking at enhancement rates and so on.
But, as with many things, you borrow from one area to go to the
next. One of the nice things about the relationship between brain
and body imaging is that, generally speaking, many of the
advancements have first come in imaging the brain. Then as things
have become well developed in the brain, then other applications,
like body, have developed. So it's interesting to see if the
various approaches that are used in the brain can also be
translated into, for instance, liver imaging. I think that may be
I'd like to comment on that. I think we probably will see that
coming, because just this year there was a paper showing that the
risk of recurrence of hepatoma was a function of microvessel
density, which we can probe with our dynamic contrast-enhanced
methods. Therefore, we may not only have the ability to provide a
specific diagnosis, but also to provide an estimate of prognosis or
recurrence. So, these are intriguing functional methods that I
think we are going to see applied more frequently to the liver in
Right, and along the same lines as angiogenesis, I think what is
also very important is the response to various treatment methods.
In those settings, looking at the different patterns of
enhancement, different rates of enhancement may prove very
important. So we're now starting a number of different studies,
looking at angiogenic qualities of metastases, following
chemotherapy and how it alters. I think that may be where
physiologic information will become important.
In the double-injection scheme, where you want to do some lesion
characterization followed by vascular depiction, is there any
effect from the first injection on the second injection that either
makes it better or worse?
Well, I think there certainly is some effect of the first injection
on the second. But we've generally found that, most often, those
kinds of effects are also worse. But we found that by waiting
approximately 15 minutes, that enough of the gadolinium has left
the system that there isn't much of an impact on the MRA. In
addition, since we routinely now look at the images on PACS, and we
page the source images, we found that the presence of contrast
hanging around another structure becomes less important than it had
been in the past, when we weren't using the PACS system. In fact,
in some areas, as I think Martin may have shown, it may in effect
be of some interest that you can see at 15, 20 minutes contrast in
the renal collecting system. So you can use that as further
information on how the renal collecting system appears. So that is
the one positive thing that we've observed in that approach.
You certainly have the option of retracting if it were a
We're doing more and more CTAs at our institution. We're picking up
more and more asymptomatic liver metastases. After we do that, we
go back and we get a conventional imaging study. In a lot of cases,
it's MR, and we do it according to our standard protocols. We're
not finding those metastases. We are now using the
second-generation multidetector CTs with very high doses, and very
rapid administrations of contrast. I suspect that you're correct,
in that we may have to look at higher doses of gadolinium at higher
rates of injection. But right now we don't have a lot of data on
that. If we decide today to double the dose of contrast, are we
doing research or is it practical non-research to go ahead and do
My approach is that you really have to show that there is a value.
It is probably necessary to identify initial studies involving
patients who have lesions already demonstrated on single dose, and
then administer a double dose and compare the images. I think a
perfect patient population for that are those with hepatocellular
carcinoma, because it is quite often multifocal. I think that's a
great way to evaluate initially, to see if it really is doing
empirically what we think it should do, which is improving the
demonstration of lesions.
I think, though, that the comparison between CT and MR always
enters everything. When you talk about doing CTA, of course you
could also do MRA for evaluating hepatic injection on MR rather
than on CT. I think one of the compelling things that Martin said
is that MR is fundamentally a much safer modality, that will always
be the case, and the contrast agent is much safer.
We haven't compared it with CTA. But we've compared MR to CTAP.
In fact, we stopped doing CTAP mainly because of the higher
specificity of MR using the kind of protocol we're using. But I
think you're right, insofar as if you are going to be looking at
absolute detection of every lesion, you have to do something
different. So either go with the interarterial injection on MR or
start with higher doses and see if that makes a difference. I
always prefer being noninvasive or less invasive to start with. It
may be a good starting point to compare CTA with high-dose
gadolinium, and look at patients with liver metastases who are
being considered for surgical resection.
Gadolinium-Enhanced MRI of Crohn's Disease
Russell N. Low, MD Medical Director, Sharp and Children's
MRI Center, San Diego, CA
At Sharp and Children's MRI Center, body MRI accounts for 30% of
cases, approximately the same proportion as neurological studies.
One of the primary reasons for the large volume of body MRI is our
ability to image not only the liver but also the extrahepatic
abdomen, including the gastrointestinal (GI) tract. The techniques
we use to image Crohn's disease serve as a model, but they are
equally effective in other types of GI disease.
Crohn's disease is characterized by chronic inflammation of the
gastrointestinal tract. It can occur anywhere in the GI tract, from
the mouth to the anus, but involves the distal ileum in about 35%
of cases, the right colon in about 35%, and the gastroduodenal area
and small bowel in about 5% of cases each. In 20% of cases, only
the colon is affected.
The etiology of Crohn's disease is unclear but may include
immunologic and bacterial factors. The symptoms, which can be quite
debilitating, range from cramping and abdominal pain to diarrhea;
fever; weight loss; bloating; and anal discomfort, bleeding and
drainage. Rectal fissures are quite common, as are skin lesions and
other extraintestinal complications, such as joint pain.
Upper and lower endoscopy, which enable direct visualization and
biopsy of diseased GI tissue, represent the gold standard for the
evaluation of Crohn's disease. Radiology plays a significant role
as well, one that traditionally has centered on the use of barium
studies, including the barium enema and upper GI study with small
bowel follow-through. It is important to realize, however, that
barium studies show only the GI lumen and not the diseased
Helical CT holds the predominant role in cross-sectional imaging
of Crohn's disease and the evaluation of its complications.
Magnetic resonance imaging (MRI), however, has many advantages for
the evaluation of the GI tract in general, and Crohn's disease in
We first described the double-contrast technique--combining
intraluminal contrast agents and intravenous gadolinium--for MR
evaluation of gastrointestinal disease in 1997.
This MR technique takes advantage of the high contrast resolution
of MR imaging to depict enhancement of the inflamed bowel wall. We
subsequently performed a study comparing helical CT and MRI in
Crohn's disease, using double-contrast techniques.
Among our conclusions were that MRI is superior for depicting both
normal and inflamed bowel wall; shows more marked enhancement of
inflamed areas; is superior to CT for the depiction of subtle bowel
disease; and is equivalent for depicting such complications as
fistula, abscess, or phlegmon.
Some of the challenges that arise in MRI of the GI tract include
peristaltic motion, respiratory motion, and variability in the
position of the small intestine and colon. In addition, it is
necessary to distend the bowel during imaging, and, until recently,
inexpensive intraluminal contrast agents have not been widely
available. It is also necessary to distinguish subtle changes in
the bowel wall from artifact that may be related to the MR
acquisition or from collapsed bowel. Faster pulse sequences and
improved hardware have overcome many of these challenges, enabling
MR to move to the forefront of GI imaging.
We use a double-contrast protocol for MR of the GI tract (Table
First, the patient drinks two to three bottles of ReadiCat 2
(E-Z-Em, Westbury, NY) or an equal amount of water to provide
intraluminal contrast. Water is effective if scanning is
accomplished very quickly. The disadvantage, however, is that it is
reabsorbed by the colon. If the patient drinks slowly, water may
not be effective in distending the bowel.
Next, we administer 500 to 1000 mL of rectal water through a
balloon-tipped enema. We fill the balloon with water to decrease
susceptibility to artifact from the balloon.
We use single-shot spin-echo sequences to obtain very rapid,
heavily T2-weighted images in both the axial and coronal planes. It
takes approximately 19 seconds on our scanner to acquire a set of
12 images. Multiple breathholds are performed to image the abdomen
and pelvis in the axial and coronal planes.
One mg of glucagon is injected intravenously to decrease
peristalsis. This is followed immediately with a double dose of
gadolinium contrast media (0.2 mmol/kg). We then acquire
two-dimensional images using a breathhold fast spoiled
gradient-echo (SGE) sequence with fat suppression. We typically
image at high resolution, using a matrix of 512 * 192. The
bandwidth is about +20 kHz, and we use a three-quarter field of
view to shorten the time of acquisition. It takes 20 to 24 seconds
to acquire 12 images. We set up two passes in the axial plane, each
of which requires 4 breathholds, and then acquire 1 set of coronal
images. The study is performed very rapidly and takes about 15
minutes from start to finish.
Another technique we often apply is MR enteroclysis. Using the
same bowel preparation and single-shot spin-echo sequence, we
acquire a 10-cm thick section using a very long TE (600 msec),
similar to that used in magnetic resonance cholangiopancreatography
(MRCP). This acquisition takes only 2 sec to obtain, and the
resulting image looks very much like a barium study. This technique
may be used to perform dynamic MR imaging of the GI tract by
obtaining multiple sequential 2-second images following the
administration of oral contrast material. By placing these images
in a cine loop, one can review gastric and small intestinal
Among the advantages of the double-contrast approach are the low
cost and ready availability of intraluminal agents, and the
effectiveness of these agents in distending and separating the
bowel. In addition, very rapid breathhold imaging sequences reduce
motion artifact, particularly when glucagon is administered to
Perhaps most important, the double-contrast technique creates a
set of biphasic images that facilitate depiction of both the bowel
lumen and the bowel wall (Figure 1). On the T2-weighted single shot
fast spin echo images, for example, the water or ReadiCat 2 is
bright, thereby functioning as a positive agent that shows the
lumen of the bowel and intestines. This is useful for demonstrating
changes in the caliber of the lumen and in looking for stricture.
In the same patient, the same intraluminal contrast functions as a
negative agent on T1-weighted fat-suppressed gradient echo imaging.
This enables visualization of the wall of the bowel, which normally
appears as multiple thin lines or rings.
In interpreting MR images, it is important to look at the
thickness of the bowel wall and at its enhancement. The normal
bowel wall should measure 3 mm or less; anything more is considered
thickened. For defining mural enhancement, we use a non-fatty liver
as our standard. If mural enhancement is the same or less than that
of the liver, we consider it normal. Enhancement that exceeds that
of the liver is considered mildly abnormal, and enhancement equal
to that of the intravascular gadolinium is considered markedly
MR versus Helical CT
Most radiologists use helical CT to evaluate patients with
Crohn's disease. Nonetheless, the ability to image the bowel wall
is essential for defining pathology in Crohn's disease and other
intestinal disorders, and represents a critical advantage of MRI
over CT or barium studies.
Figure 2 offers a good example. In this patient, helical CT
demonstrates some mural thickening in the wall of the ileum. With
the MRI double-contrast technique, however, the lumen is distended
nicely, and the thickened wall of the ileum shows intense
enhancement. Superior conspicuity of enhancement in the inflamed
wall is a consistent advantage of MRI, one that accounts for its
having become the exam of choice for the evaluation of Crohn's
disease at our center.
Clear differences in the sensitivity of MRI and helical CT
become even more evident in subtle cases of Crohn's disease, as
depicted in Figure 3. Much of the bowel appears normal on CT. On
MRI, however, the entire bowel wall is distinctly abnormal, a
conclusion that was confirmed by endoscopic findings of pancolitis
and ileitis. We consistently find that the distribution of disease
is much better visualized on MRI than on helical CT.
Correlations with Endoscopy
Because of its close correlation with endoscopy, MRI is able to
guide clinical decision-making. We have discovered that the
activity of Crohn's disease correlates with the degree of
gadolinium enhancement, so that a thickened bowel wall that doesn't
enhance signifies inactive disease. This is an important finding,
as a patient who has chronic inactive disease will receive
different treatment than a patient with acute, actively inflamed
Figure 4 demonstrates the ability of MRI to distinguish active
from inactive Crohn's disease. Barium enema shows a stricture, but
it is impossible to determine whether the Crohn's disease is acute
or chronic. On MRI, the degree of enhancement is minimal and the
T2-weighted image is very dark. In our experience, this pattern
correlates with inactive disease. Endoscopy confirmed this
impression, demonstrating a perfectly smooth mucosa. Biopsy found
some chronic inflammation but no active disease.
By comparison, in patients with active disease, marked
thickening and enhancement of the bowel wall correlate well with
endoscopic findings of erythema, ulceration, pseudopolyps, and a
cobblestone-like mucosa, an appearance that signifies very severe
Crohn's disease (Figure 5). Similarly, MRI is a valuable tool for
the assessment of complications of Crohn's disease. Figure 6 shows
a patient with an enterovesicle fistula. On MRI, the inflammatory
mass in the terminal ileum is well visualized, as is an eccentric
thickening of the wall of the bladder near the fistula.
MRI is able to detect very focal disease as well, even though it
can be subtle. An example of this would be a patient who returns
with abdominal pain after surgical resection. In such a case,
focal, localized recurrent disease at the site of bowel anastomosis
may be seen on gadolinium-enhanced MR images with good bowel
Beyond Crohn's Disease
The same double-contrast MRI techniques that work in Crohn's
disease are equally well suited to other types of GI disease. We
use this approach not only in inflammatory bowel disease, but also
to evaluate patients with infectious enteritis and colitis,
mesenteric ischemia, and cancer. We use MRI fairly regularly to
stage colon cancer, for example, looking at the depth of
penetration of the tumor through the wall. It works well for
evaluating gastric and small bowel malignancies, and serosal
metastases from ovarian cancer and other primary tumors.
Figure 7 serves as another example of the range of applications
of double-contrast MRI. This patient had a 1-month history of
diarrhea. The helical CT was unremarkable. MRI showed that the
terminal ileum demonstrated marked thickening and enhancement,
which was not depicted on the helical CT scan. On endoscopy, there
were ulcerations at the ileocecal valve and in the distal ileum, as
well as ulcerated plaques in the right colon. This case of probable
infectious colitis again demonstrates the superior depiction of
relatively subtle changes by MRI when compared with helical CT.
Superior conspicuity of enhancement gives double-contrast MRI a
clear advantage over helical CT in the imaging of patients with
Crohn's disease. This approach is effective for imaging not only
inflammatory bowel disease, but other forms of GI disease,
including such conditions as infectious colitis, mesenteric
ischemia, and cancer. *
1. Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn's
disease: A statistical study in 615 cases.
2. Low RN, Francis IR. MR imaging of the gastrointestinal tract
with IV gadolinium and diluted barium oral contrast media compared
with unenhanced MR imaging and CT.
AJR Am J Roentgenol.
3. Low RN, Francis IR, Politoske D, Bennett M. Crohn's disease
evaluation: Comparison of contrast-enhanced MR imaging single-phase
helical CT scanning.
J Magn Reson Imag.
4. Low RN, Sebrechts CP, Politoske DA, et al. Crohn disease
endoscopic correlation: Single shot fast spin-echo and
gadolinium-enhanced spoiled gradient-echo MR imaging.
Thank you very much, Dr. Low. We have some time for discussion of
this very interesting topic.
I have a couple of questions. The first one relates to early and
later enhancement. I guess the early enhancement I like to think of
as perfusional, and later as sort of interstitial space. Do you
find that it's very important to keep those two data sets separate?
How do you treat them when you evaluate the bowel?
Particularly, when you are trying to distinguish or determine the
degree of activity, you need to look at the perfusional information
from the first pass. We look at that and then try to distinguish if
it is enhancing a lot or a little. The second set, everything tends
to enhance on those. We do not use those in terms of determining
the activity. That's a good point.
The other question is if you have also used that to distinguish
between Crohn's disease and ulcerative colitis? I noticed in your
cases the same thing we've found in our studies, and that is that
with Crohn's you get transmural enhancement, whereas in ulcerative
colitis, we've seen submucosal sparing consistently.
Right. I think because of the incidence of the disease, our
experience with ulcerative colitis is clearly less. But I think our
experience tends to be less intramural thickening. Although at
end-stage ulcerative colitis, we do tend to see more significant
Russell, I noticed in some of your 2D gradient-echo
gadolinium-enhanced images, that you were getting some dropout
where surgical clips were evident. Have you tried the 3D to
We played around with the 3D pulse sequence. But as Richard said,
we tend to like the appearance of the 2D better. There are
certainly some advantages of the 3D in terms of the thickness of
the sections. At this point, we haven't used that significantly.
The single-shot image is probably in that saline one, you have a
lot of bowel gas or something, and with artifact, tend to work
pretty well too.
Russell, you said you used double dose for these studies, why? Did
you try single dose and it didn't work?
It would work with single dose. It's based on our experience
looking at a lot of extrahepatic disease, particularly peritoneal
tumor. We did a lot of comparisons of single versus high dose for
peritoneal tumor. We found that for particularly things outside the
liver, they enhance more, anything that you are waiting for awhile
to enhance. So it's a logical next step to assume that it would
also work in Crohn's disease. I think clearly that does show us
more. Any time you are looking at subtle enhancement, with the
degree of enhancement of something relatively thin, it's important
and more is logically better.
Now we will begin an open panel discussion to link up many of these
different areas together. One common link they have, of course, is
the use of gadolinium contrast agents. I'd like to start with a
discussion of the ideal contrast agent characteristics, and some of
the features that we would like to see and that have relevance to
clinical practice as it stands today. Each of the contrast agents
can be characterized by their viscosity. We had a discussion about
the approved dose, the ability to give bolus or not, as well as the
osmolarity and the ionicity of the contrast agent.
Let me start by saying that all of the presentations discussed,
of course, applications for patients who were sick or may have
cancer, who may have poor venous access, etc. One question to the
panelists is do you notice a difference in the use of the
gadolinium agents, if you have problems in these patients, such as
extravasation? Low-ionic contrast media is likely to create less of
a problem with extravasation. What do you do if you have
extravasation? We talked a lot about bolus injections, but we
didn't talk about the problems with that. What kind of problems
have you seen?
Well, I've had a lot of experience with extravasation. That's
partly because with CT, we had a very rigorous protocol of
meticulously checking the IV: are you getting a good blood return
only using large caliber IVs. But with MR, we have smaller volume,
and we've been less rigorous about checking the function of the IV
before doing the study. We even will accept IVs that might be in
the hand or the wrist that may not be as reliable as an IV in a
large antecubital fossa vein. So one of the things I've noticed is
that if you have an ionic high-osmolality contrast agent, the
patient will let you know immediately when there is extravasation.
They may want to terminate the study at that point.
But the lower osmolality nonionic features make the agent much
better tolerated in the event of accidental extravasation. I've had
a number of cases where the image would be blank. When I'd examine
the patient, I'd see a huge volume of contrast there that got
extravasated, and the patient hadn't even noticed that
extravasation was occurring. That makes it easy to talk the patient
into just redoing the IV and repeating it.
I think there is one particular instance in which we have to be
very careful: that's when we are doing sedated or anesthetized
patients, because whether the contrast is ionic or not, they won't
notice the extravasation. So, for example, in babies who are asleep
for the MRs, we are always very vigilant to make sure we get a good
blood return before injecting. The other cautionary tale is to
avoid things like PICT lines when you are injecting high doses at
high rates, because they can actually come apart internally with
high injection rates. So we like to have an intercath, not a
butterfly. We want to make sure if we are injecting a central line,
that it is of sufficient size to handle the volume.
We routinely also inject PICT lines in some cases. There I think
the low viscosity really helps because the problem at the PICT line
appears to be at the coupling of the IV to the catheter and the
hub. That's what can blow, if the viscosity is high, because of the
pressures that are developed.
I think the use of the central line is an area where hand injection
should be considered over power injection, because a low viscosity
agent with hand injection might be able to go through a PICT line
or other central line, you might be able to obtain an adequate
study. Whereas using the power injection through a central line may
destroy it and create an even worse situation.
Does anybody else have any experience related to the specific
injection local extravasations?
I think when using a nonionic agent, we're more comfortable because
the patient might be more uncomfortable while they're in our MR
suite. But certainly with CT, we know we've had patients who were
asymptomatic from large volume injections with CT contrast agents,
and these can occur later. So I do think we need to emphasize when
these occur, to maintain good contact with the patient, phone
numbers, symptomatic treatment, and surgical consultation if it's
I have a rule that 50 mL is a dividing line between more serious
and less serious extravasation. Has anyone else heard of the 50 mL
rule? If you extravasate more than 50 mL, you must have a surgical
or plastic surgical evaluation, but extravasations less than 50 mL
are more likely to resolve on their own.
We do a lot of contrast injections, and we're very meticulous in
our technique, in placing the catheter and checking it after we
place it. Or if it has been in there for while, in a patient coming
down from the ward, we meticulously check it again. But we've
recently been going to a higher dose, higher rates of injection,
and we are seeing more and more extravasation. I think it's a
little bit of a comfort margin, in theory, that we are using
nonionics. One, as Martin said, the patients are very asymptomatic.
But I'm hoping that there's less tissue necrosis associated with
nonionic agents, versus the ionic agents, although I don't know if
there's enough data to support that.
We've noticed the lack of any thrombophlebitis that we've ever been
able to identify in thousands and thousands of injections. We use a
nonionic agent, and we haven't done the comparison of ionic versus
nonionic agents, but it's interesting that we just don't see
thrombophlebitis. Has anybody seen that post-gadolinium?
I have had a case of a patient who received an ionic gadolinium
contrast injection; at the time of the examination there was just a
little bit of perivenous erythema. But the patient subsequently
came back to the emergency room with a full-blown thrombophlebitis,
and was admitted to the hospital and heparinized. Then eventually
made a complete recovery.
So it reiterates what Dr. Bluemke was saying, that these patients
really need to be followed carefully and treated accordingly.
Now, let's discuss one of the other features about giving a
bolus. Some of us use bolus injection in particular applications,
some don't. Do you think that the contrast agents today have
adequate "bolus-ability"? Do we need agents that could be given at
higher rates? Have we reached a maximum?
I've been giving gadolinium at tremendous rates, intra-arterially,
which is a very rapidly growing area within interventional
radiology. Many interventional renal cases are now done solely with
gadolinium; and that's our practice. We often inject these at rates
in excess of 5 mL/sec, so in aortic injections we can go as high as
20. In these applications, I like to use a nonionic agent. I don't
have data to support this, but I expect that it's better tolerated
by the patients, and also that the viscosity issues would make for
a lower pressure injection. We've been using a nonionic agent for
several years now in arteriography with wonderful results.
Currently, none of the agents are approved for the arterial
injection, but what is your experience clinically?
It's a judgment; it's off-label usage of the agent. The patient
outcome has been superb, especially in view of the lack of
nephrotoxicity of the agent, when you are dealing with a patient
who has underlying renal insufficiency. This is an area that's
growing rapidly within the IR community.
Right, because of the lack of nephrotoxicity of the agents.
How do you compensate for the relatively lower concentration of
gadolinium molecules within the gadolinium contrast, compared with
the higher concentration of iodine molecules in the iodine
It's a weaker radiodensity; it's not as radiodense as iodine.
However, modern fluoroscopy units coming out have specific kV
settings dedicated for gadolinium. You can select those settings
and get more optimal images that approach the quality of iodine.
But it's not as good, but often good enough to do the procedure
But better for the patient.
Related to other factors that influence the choice of bolus, the
highest bolus rate that we saw in the presentations was Dr.
Bluemke. You spoke about 5 or 6 mL/sec for myocardial perfusion
imaging. Dr. Rowley, what are you using in the CNS?
Typically 3 or 4 mL/sec. For babies we'll go down to 2 mL/sec. It
hasn't been necessary to go to 5 or 6, at least for our
Do you think that there is any reason to go higher for intravenous
injections? Probably not, I imagine.
I guess there's probably not a lot of reason to think that we
should go higher. I think we tend to use 5 as our maximum, both for
our neuro and cardiac applications. The doses we've looked at more
seriously in CT work, and most of the highest CT doses, other
people have certainly used 8 and 10 mL. Most people believe that 5
mL seems to be as high as we could go and I think there's probably
a lot of parallels to what we are doing in MR so far.
But then there is an important factor on the lowest injection rate
that you would use for these perfusion studies, because an
injection rate slower than a certain rate will give a problem in
the arterial input function. It's no longer just a bolus function.
So what do you think is the lowest injection rate that you like to
use for perfusion imaging? It may be different in children versus
adults, so let's talk about adults.
For most of our injections we try not to go below 2 mL/sec. But
empirically, I think that if you are going to capture first-bolus
processes, which may take 10 to 15 seconds for the transit of
contrast, at most, that we feel that you really need to deliver the
contrast in a short concise bolus and get it in there. But we do
feel compromised when we are using that slow an injection rate.
There's actually been interest in modeling the pharmacokinetics for
transfer constance, just with the T1 dynamic techniques, that
actually you might be better able to model the slower infusion. So
even at 1 mL/sec rates, if you know in fact that it's a steady
infusion, than you can model that a little better. You might have
more accuracy when you compute your transfer constance later. So
there's published data suggesting that infusions are better than
In some situations, such as T1-weighted imaging.
Exactly. In T1-weighted dynamic images, when you are trying to
derive for transfer consistence and permeability for breast
On the other hand, most of the data is on susceptibility T2*
imaging, which really indicates a higher injection rate.
Right, there is much more.
Tom, while we are still on this topic, for the body we typically
use 2 mL/sec, that probably translates in Martin's lexicon as a
fast hand-injection rate. I think that's approximately correct. We
used to do hand injections routinely, and it was important to get a
good firm injection. Now going to machine power injection using a
standard dose, 2 mL/sec, seems to be quite adequate. But I think
it's also intriguing if we start talking about higher doses, and
using higher doses to look for small lesions and characterizing
smaller lesions better in the liver; I think it may be essential to
go with faster injection rates. So if we are using double or triple
doses, I think it would make a lot of sense to look at going to 5
In fact, there is some literature comparing MR with standard and
spiral CT; MR is routinely better. We found in our studies that, if
you look in the same patients, MR sees more lesions in at least 50%
of patients, and has an impact on patient management, probably in
that range too, when we compare standard MR with the 2 mL injection
rate, and standard CT with the 2 mL injection rate. But I think it
has been shown that if you increase the injection rate with CT on
spiral or multidetector CT to 5 mL/sec, your results are much
better as far as lesion detection. I think that would be the exact
parallel we'd expect with MR, and maybe that should be the first
step in looking at improving detection in evaluating patients for
surgery. That probably is the more logical first step before going
to looking at a combination of CTA and CTAP, to really look at
increasing the dose and increasing the injection rate.
To parallel CT, it's interesting also from the point of view of the
nature by which we calculate the dose, there is a tendency at our
institution to give a standard volume to every patient for CT. But
in MR, we have a tendency to adjust the volume according to the
patient's weight. There's a difference of opinion, whether the rate
should also be adjusted based on weight, which sometimes can be
done by diluting the gadolinium or if it should be a standard
volume that you use in everyone for a standard rate. So this brings
up several questions. Should we be dosing based on weight? Or
should we go with the CT model of giving everybody the standard
same volume? Should we be adjusting our injection rate based on
weight as well?
The reason to adjust by weight in MR is to get reasonably sane
blood concentration, so that you might give rise to the same amount
of single intensity change for the same amount of material there.
That is the rationale to adjust for body weight.
Okay, but if you are going to inject patients outside of the
scanner, and then put them in and get your image, then adjusting by
weight means that you've given the same amount of contrast per gram
of tissue. But if you are going to image during the dynamic
evolution of the contrast passage through the tissues, the amount
that you inject is not as important as the rate at which you
inject. So to have a correct matching to the patient size, you
would really need to adapt your rate of injection to the patient
That makes sense.
Then also, if you don't adapt the rate but you have the same
duration of scan, then what's going to happen is your bolus
duration is going to be different from patient to patient. So how
it matches up with your mapping of k-space can vary as well. So I
think there is just an enormous complexity in the sort of features
of these injections that remains to be further analyzed.
Cardiac input is also very important in this setting.
Right. If the arterial concentration is related to the injection
rate divided by the cardiac output, people with different heart
functioning have different performance.
Let's get back to the issue of what rate you chose, in the
liver, for example. Richard, you were suggesting that maybe then we
ought to look at higher injection rates. Dr. Kramer, you pointed
out that as the MR technology changes, we are able to image faster
and then may capture the image in a shorter period of time. So that
allows you to increase the rate, and that may in fact improve the
detectability of liver lesions, or it could improve the MRA, for
Let's talk a little bit about dose. Currently, the high-dose
indications for contrast agents is evaluation of intracranial
metastatic disease. Dr. Rowley, do you want to comment on the merit
Well, I think in most cases, we are still using single dose for
most brain tumors, including metastases. But the enhancement that
you see depends on the tumor itself, the dose, the delay after the
injection, and, of course, the specific sequence. Our approach has
been that when it is going to make a clinical difference. For
example, a patient who is found to have one or two metastases is a
candidate for either curative surgery or targeted radiotherapy. So,
we'll go ahead and give the triple dose at the time of their
treatment planning scan, at all the radiotherapy, and all the
surgeries being done with a 3D MR. That is, we are anticipating
that some patients may end up being excluded as surgical
candidates, because we may find additional metastatic disease.
Another approach would be to use, for example, magnetization
transfer in combination with single or double dose to improve the
conspicuity. But in our hands, the key features are really getting
at that triple-dose study, a volumetric acquisition, so we are not
going to lose lesions between slices in inner-slice gaps. To get
good T1 weighting, I see a problem with a lot of people trying to
get better coverage, and letting it creep up toward a proton
looking scan. At that point, you don't know what you are looking
at. So our approach is really two-fold, the standard imaging and
then, at the time of treatment planning, we'll go ahead and give
the triple dose if it is indicated.
Do you think it's better to know that you need a high-dose study to
look for absolutely every metastasis? Is it better to do a staged
injection; or is it better just to give the triple dose right from
Well, that's a great question, because, of course, some tumors will
take up contrast over the several minutes after the injection. In
our shop, we'll usually know if we are going after a triple dose
anyway. It's our approach to just give triple dose and we'll
perhaps get, for example, the routine T1 or a T2 FLAIR, and then
follow that with the 3D SPGR or an NP-RAGE to capture both the time
and the added features of the volumetric acquisition.
Well, I think that that should conclude our panel discussion. I'd
like to thank all of the panelists as well as our coordinator,
Oliver Anderson, from
. I'd also like to thank Amersham Health for their unrestricted
educational grant to
, to support this symposium. Once again, thanks to all the
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