Discussion 17

Acad Radiol 1996;3:$461-$463 �9 1996, Association of University Radiologists

D ~: Dawsou: Dr. Lee, if we had a good safe and effective biliary contrast agent, we could find all kinds of applications for it. It is worth consid-

ering why, with laparoscopic cholecystectomy in particular, there is a need to image the biliary tree. Most surgeons would say that if there is no history to suggest stones, if there is no abnormality of liver enzyme levels to sug-

gest cholestasis, if the sonographic findings are reasonably normal and the duct is not dilated, then you can proceed to surgery. If you are unlucky and find a stone later, they are willing to accept that risk. Other cynics say

that even if there are no stones in the c o m m o n duct, but there are in the gallbladder, the stones are going to end up in the duct during surgery any- way. The real reason that we are being asked to image the biliary tree is because it is considered that duct anomalies increase the danger of injury during surgery. There is some evidence for this, because patients with duct anomalies are considerably overrepresented among patients who suffer

iatrogenic injury during conventional surgery. The problem is that most of these patients have had an intraoperative cholangiogram, which doesn ' t

apparently seem to have prevented the injury, so it is then worth asking why that is. The answer may lie in a recent observation in an operating theater in the United Kingdom. A large number of conventional procedures were observed and cholangiograms were obtained carefully during sur- gery, but the f luoroscopy facilities were not very good. So pictures were taken, but by the time the deve loped films arrived back in the theater, the procedure was finished and the damage was done. It is thus not clear that surgeons actually put knowledge about anomalies of the bile duct into practice. If we are going to detect such anomalies of the duct, why not sug- gest to the surgeons that they do an intraoperative procedure? Their reply is that to do so is difficult during the laparoscopy. Other surgeons convinc- ingly argue that it just requires a little more practice and then you can do it in about 97% of the cases. The question then is, can we radiologists do it? We already have some cholangiographic agents like meglumine iotroxi- nate, and recent studies with them indicated you can get very good pic- tures of the c o m m o n duct, but the studies seem to have revealed very few

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DISCUSSION 17 voL 3, suppl. 2, August 1996

anomalies. We know from surgery that the incidence of anomalies of the duct is actually high, more than 10%, and yet in these studies something like 2% were found.

Even if we apparently have successful intravenous cho- langiograms, they are not successful in the one way that matters. So the bot tom line is, if it is cheap for the

companies to develop such an agent, if that agent is safe, and in itself, rather cheap, and easy to use, and if it shows duct anomalies, then maybe we can let the surgeons give us the job. If we can't be sure about even

any one of those things, then maybe the investment isn't worth tile gamble, and we should tell tile surgeons

to do the job properly themselves. D r Lee: I think you are going to need a large clinical

study to answer all those questions. One point about intraoperative cholangiograms is that by the time you

get tile c holangiogram they've already cut open tile duct to stick the tube in, so if they cut the wrong duct,

you 've already lost it. DI: Weinmann: Dr. Runge, please define your T1-

weighted imaging parameters. Dp: Rzmge: It is a two breath-hold sequence with a

repeti t ion time of 200 msec and an echo time of 10 msec that uses a partial matrix on one side. It is a heavily Tl-weighted sequence.

D~: Weinmann: You probably don' t reach the maxi-

mum signal intensity increase. Dp: Runge: Are you asking if a different Tl -weighted

sequence might have achieved a greater improvement

in signal intensity? D,: Weinmann: No, I think the technique you used

was well selected, and you have also shown on one of

those compounds that if you increase the dose you get a higher contrast enhancement or signal enhancement . Sometimes our people are not using a proper sequence, and they reach a peak level above which

they cannot get a higher signal intensity. D r Runge: Right, but we were not at max imum signal

intensity with that sequence. DI: Weinmann: About 2 years ago, we did a similar

study with rabbits, and we had a sequence similar to yours, using a dose of 250 pmol/kg. We observed, using o u r compound, a curve that had two maxima. The first p e a k in enhancement occurred right after the contrast material was administered from rapid perfu- sion; then the signal intensity decreased as you have shown. If we waited for a sufficiently long time (1-2 hr), the Signal intensity began to increase again. The decrease in signal intensity was caused by the very high

concentration of our contrast medium in the liver, which caused a s t rong T2 effect that competed with the T1 effect. The intermediate decrease in signal intensity

resembles rapid elimination but it was actually caused by excessive accumulation of the contrast medium. The signal intensity increased to a second peak and finally

faded away. Dr. Runge: The point that Dr. Weinmann made is

important. If you have an agent that is continually accu-

mulating in the liver, and also has a very high initial peak concentration, and if you are also saturated in terms of having a T2 effect, then the peak will not be as high as the T1 effect. To some extent, you need to look

at individual curves, because we had only five animals, but there was no evidence in our curves that anything occurred other than an early peak and then diminished

enhancement. Part of the answer might also lie in the gallbladder appearance, because if you are getting very intense uptake by the liver and gallbladder excretion,

then you ought to see that dark rim around the gall- bladder where the agent is being concentrated. The gallbladder removes some water, and you can get that

reduction in signal intensity because of hyperconcen- tration of the agent in the gallbladder. You can look at agents in terms of h o w effective they are by how much artifact you see in the gallbladder, and if we rank our

agents by that effect, Gd-Cy2-DOTA had the greatest

artifact in the gallbladder and gadobenate dimeglum"ine and gadoxetate disodium had about the same artifact in the gallbladder. From that point of view, I don ' t think that we are over the peak in terms of getting a T2 effect that is diminishing our signal intensity. The T2 effect

depends on what pulse sequence you use, but one of the things that confuses this field is that renal excretion in rabbits is very different and much higher than it is in the rhesus moflkey. The monkey also has a much lower hepatic uptake.

DI: Weimnann: I do not have any objection to your study, but I wanted to point out the necessity of taking serial measurements of signal intensity to evaluate the pharmacokinetics of a contrast agent, rather than trust- ing a single measurement taken at an arbitrarily selected time interval after injection of the contrast

agent. Dr. Runge: We do not observe this T2 effect very

commonly in the brain, but it could be more commo n in the liver.

Dp: Lasse,:. Dr. de Haen, some years ago we did a study in rats anesthetized with pentobarbital. We

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injected them with meglumine iodipamide (Chologra- fin; Squibb, New York, Ix,W) and found that we could prolong their sleep time. As a matter of fact, we got a

nice linear response; the more we put in, the longer they slept. It became evident after a while that we were dealing with competitive albumin binding dynamics. Now I don' t know whether your material binds to albu-

min or not, and whether that would play any role in the transit time to bile versus transit time to the kidney.

D,: de Hahn: We tried to measure binding by equilib- rium dialysis, and we have not been able to measure any binding at all. The sensitivity of the assay was such that any binding with a binding constant stronger than about

5 mmol/l would have been detected. The relaxivity of gadobenate in the presence of albumin is definitely increased relative to just plain water. That is only expli-

cable by a fleeting interaction, a weak binding with albu- min, but it is very weak and so far not measurable.

Dl: Lasse,:. So you didn't detect any difference be tween your :anesthetized and nonanesthetized rats

that you might think about in these terms? D,: de Hahn:: I don' t think you could possibly detect

such a small difference. Dr. Laubenberger: Dr. Lee, do you think it is really

necessary to develop intravenous cholangiogmphic techniques? There are well-developed techniques for magnetic resonance (blR) cholangiogmphy that just

exploit T2 effects. D,: Lee: I knew I was going to get that question. For

those of us who do both computed tomogmphy (CT) scanning and MR imaging, it's pretty clear at this point

that the T2 techniques that you are talking about have a large number of motion artifacts that can degrade the

images. There are pretty pictures shown in the posters, but I think that at this point a single-breath-hold spiral CT scan through the liver with or without contrast mate- rial would give you fewer artifacts and more reproduc- ible images than the T2-weighted MR images currently

produced. D*: Laubenberger.. Our recent article in Magnetic Res-

onance ilz Medicine describes a technique we devel- oped that allows 4-sec take breath-holds, a single-shot technique. This js faster than CT scanning, and you can even evaluate papillary motion in the distal portion of the bile duct. I think there are no major restrictions to this technique, which doesn' t take the time usually required by spin-echo techniques, some 10 rain plus

reconstruction time.

Dr. Lee: No, I am not discounting blR imaging,

because there are many new developments that are happening or going to happen in the future. At this point, with your typical hospital and your typical scan- ner, I think that CT scanning is a little bit ahead of MR imaging in terms of artifacts.

Dl: Cavagna: Just a brief comment about the meth- odology of evaluating contrast agents in the liver. Very

powerful methods are available to measure T1 very rapidly. I would propose that the evaluation of the effi- cacy of contrast agents in the liver be simply done by measuring T1. Then there will be no danger of satura-

tion and one gets a clean, neat number, which makes it much easier to compare different agents quantitatively.

DJ: Lee: Dr. Dawson, in terms of cost benefit for non- invasive imaging of the biliary tract, if you take a group

of patients who are going to have laparoscopic chole- cystectomy and who have not had any biliary symp-

toms or pancreatitis, and results of their liver function tests are normal, their f requency of common duct

stones is going to be somewhere less than 2%. On the flip side, almost one third of the patients who go for laparoscopic cholecystectomy have had pancreatitis, abnormalities on liver function tests, ductal dilation seen at sonography, and so on. Their rate of positive findings with endoscopic retrograde cholangiopancre-

atography (ERCP) is going to be somewhere around one third or less, primarily stones in the common duct. The cost benefit that could be attained either with blR imaging or CT would be an elimination of two thirds of the patients without having to do ERCP. So, those are the patients who we may need to focus on at this time. We are still doing many ERCP studies in our hospital for that indication, several a day sometimes.

DJ: Dawso~t: Fine, that may be true, and I am sure we could find other good applications for such an agent. I was suggesting that if we were being primarily driven

by surgeons who didn't want to do their own job prop- erly, then maybe it wasn' t worth the while of the phar- maceutical companies to invest enormous sums of money to develop agents that would do what can already be done more simply if the surgeons made the effort. I 'd love to have such an agent and do spiral CT scanning and get lovely three-dimensional reconstruc- tions and so on. That would be fun, but I 'm just trying to think in terms of using resources effectively.

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