Holly Atkinson MD: In this segment, we'll be discussing issues in post-operative care. And joining me to discuss the topic are Dr. Kim Isaacs, Associate Professor of Medicine in the School of Medicine at the University of North Carolina; Dr. James Marion, Assistant Clinical Professor of Medicine at the Mt. Sinai School of Medicine; and Dr. Gary Lichtenstein, Professor of Medicine at the University of Pennsylvania School of Medicine. Welcome to you all.

Kim, let's start with you. Why is post-operative prophylaxis so important when you're treating inflammatory bowel disease?

Kim Isaacs MD, PhD: We're talking mainly about Crohn's disease here. That would be the most common thing you'd be looking for, recurrent disease after surgery. And the reason it's so important is up to 80-90% of patients will have recurrence of Crohn's disease after surgery. It may be of varying severity; it may be very severe requiring a second or even third operation or it may be an endoscopic appearance of recurrent ulcerations. And right now, we don't know exactly how to predict which of those patients that develop ulcerations after surgery will go on to more severe disease. But it's certainly something if we induce a surgical remission, we would like to prevent recurrence of active disease.

Holly Atkinson MD: Jim, talk to us about the traditional approach. What medications have routinely been used to achieve prophylaxis?

You need to look at the type of the disease, the geography of the disease the patient had before hand and the variety or subvariety of Crohn's disease, whether it's stricturing disease, more mucosal involvement or perforating, fistulizing disease.

The first level of therapy, for study at least, has been the mesalamine-type agents or the 5-ASA agents. And there has been some evidence to show that they are, in fact, effective in maintaining that surgical remission.

The second agent that's been looked at is metronidazole at higher doses; usually doses that are very difficult for patients to tolerate. It appears that it may be helpful in preventing a clinical recurrence in certain cases.

The third would be 6-mercaptopurine or azathioprine. Again, there is some preliminary data that suggests it may be helpful, not as helpful as we would probably like. Other agents, such as the biological agents, hold some theoretical promise, but have not been studied adequately, to use them for prophylaxis, at least.

Holly Atkinson MD: Gary, what about the newer agents? What data do we have at this point?

Gary Lichtenstein MD: Well, the newer agents, we have a new antibiotic that has been looked at, ornidazole. And this is the group in Leuven, Belgium, had presented this at our national meeting, Digestive Disease Week, this past year [2002]. And showed that when administered orally for duration of a year, clinical occurrence can be severed such that it doesn't recur as significantly in those taking medication as compared to those who are on placebo. This was a landmark finding. We had no previous data for one year showing that it was substantial benefit as compared to such.

Infliximab has not been looked at in any controlled fashion. The use of 6-mercaptopurine has been compared with mesalamine and placebo, and was shown to be effective at a low dose at the time the study was done. But the presentation back five years ago by the group did it, and, funded through the Crohn's Colitis Foundation, did show benefit directly.

There are other agents that are being investigated. The probiotics, for example, are being looked at. And these, to date, have not shown benefit, but there is at least one large trial ongoing that will hopefully elucidate if they are or are not beneficial. And when I say "they," there may be multiple probiotics, but this particular probiotic is being looked at.

The type of surgery is sometimes looked at-will that influence the post-operative course? And Robin McCloud is now the principal investigator on a grant through the Crohn's Colitis Foundation of the United States and through Canada in a multicenter trial evaluating: Does this lessen the post-operative course of disease when hooking up the bowel in a specific way? And we'll hopefully have those answers shortly.

Holly Atkinson MD: Well, Gary, you've raised the issue. Is there any way to stratify patients that will identify those who are at higher risk?

Gary Lichtenstein MD: Initially, it was suggested that those individuals that present with perforation as a primary indication for surgery are likelier to have a higher recurrence rate. Mandating re-operation in the future at a shorter duration of time than those did not. We, for example, found a median time to re-operation of three years, compared to eight years in those that had perforating versus nonperforating phenotype.

There are individuals who are smokers, that it's portended that perhaps will have a more rapid recurrence. The group in Italy has shown us that individuals that smoke, if they stop smoking cigarettes, can have a better course for their Crohn's disease overall. This was a controlled trial, but looking again at a retrospective data post-operatively, we have a suggestion of such.

These are the data we have. None of these are prospective randomized trials. They're all retrospective analyses of large center experiences.

Kim Isaacs MD, PhD: And clinically, in my practice, I tend to see some sort of stratification based on where their disease activity was when they started. For example, patients who have colonic-only disease-have always only had colonic disease, but never small-bowel Crohn's disease-their recurrence rate in the small bowel seems to be actually very low and one could argue not using any medications in that population, if you take out the whole colon. On the other hand, if you have isolated, segmental colonic disease and you take out the segment of colon that's involved, that population tends to have a high relapse rate of recurrent disease. Those patients who have isolated terminal ileal disease not involving the colon at all tend to do very well, in terms of their relapse rate.

So I think not only Gary's stratification in terms of trying to isolate fibrostenosing disease and perforating disease, but one also needs to look at disease location and the likelihood of recurrent disease.

Gary Lichtenstein MD: And another factor, Kim, was duration of disease as well. That's been a factor when looked at directly, as well the number of previous surgeries. If someone has had five surgeries, there's a high chance they may need re-operation in the future.

Holly Atkinson MD: Well, let's talk about where we can find a consensus among you in how you approach prophylaxis. Kim?

Kim Isaacs MD, PhD: I try to risk-stratify, to a certain extent, and will take into consideration, is the patient a smoker or a nonsmoker? If they're a smoker, I'd like them to stop smoking, but if they're going to continue to smoke, I would feel more strongly about potentially prophylaxing them.

If a patient has had a very complicated disease course going into the surgery, even if it's their first surgery. If they presented with an abscess, if they presented with fistula to the bladder, that patient I would recommend doing post-operative prophylaxis. If a patient comes in and has had multiple surgeries and really can't afford to lose more small bowel, I feel very strongly about doing the best in terms of preventing a post-operative recurrence.

If I have a patient who comes in-a young patient who's had a short-segment resection of isolated terminal ileal disease - I'll discuss with the patient the possibility of post-operative prophylaxis versus not. And since the strongest post-operative prophylaxis that we have evidence to date are the immunomodulators, such as 6-mercaptopurine and azathioprine, it becomes a discussion of the risk of long-term therapy with these agents versus the risk of a complication of recurrence.

So I think one could argue with isolated, short-segment resection of terminal ileal disease, that one might not want to use an immunomodulator. You might use something like a 5-ASA, although that is going to be less effective. One might choose do to nothing.

So I try to have a dialogue with my patients, going over what the risks are, what the benefits are for post-operative prophylaxis. Again, just to reiterate, I feel very strongly about the recommendation for a patient who had a very complicated disease course going in to the therapy.

James Marion MD: I think the consensus here is really going to involve the patient. The difficult--when you've escorted a patient up to and then through a surgery-is then coming around and saying, "Well, I'm going to put you on mesalamine. It's going to be 12 to 16 tablets a day, despite the fact that you just went through all of that." Some patients simply aren't going to tolerate that kind of a regimen. Or, as Kim said, the long-term risk of being on an agent like 6-MP or azathioprine, albeit a low dose, it's very likely very safe. But patients often will not agree to do that.

I think history tends to repeat itself in Crohn's disease in most patients. And the idea that the complexity of their presentation, I think, is an important one to take into consideration when you're going over a post-operative preventive strategy. The geography of the disease, whether it's a more superficial mucosal involvement versus a fistulizing involvement should help influence how hard you push toward either mesalamine or an azathioprine in post-operative prevention. But ultimately, the final arbiter is going to be the patient and the likelihood that that patient will adhere to your suggestion.

Holly Atkinson MD: Jim, how common is the occurrence of pouchitis?

James Marion MD: Well, pouchitis-which we really only see in patients with ulcerative colitis who have an ileal pouch-anal anastomosis or a continent ileostomy, better known as the "Koch pouch". We don't see so many of those these days, but they're still out there.

The issue is: What is pouchitis? Is it a recurrence of the ulcerative colitis, or is it the product of some bacterial overgrowth? Is it the product of our insisting that the small bowel perform a function that it's really not designed to do, which is to be a colon? There's still a lot of uncertainty and misunderstanding of what pouchitis truly represents.

They present, usually, with symptoms that are frustratingly similar to the symptoms of their ulcerative colitis. So there's always a rather heavy note of discouragement when they call, "I went through all of this surgery and, look, I'm having diarrhea again."

Holly Atkinson MD: Gary, tell us what the differential diagnosis is when someone presents with symptoms that obviously can be a number of things?

Gary Lichtenstein MD: The differential diagnosis you have: Is there cuffitis, which is inflammation of the rectal mucosa that might remain that has not had a mucosal stripping? Is there a stricture? Is there a need to go in and balloon-dilate that stricture at the pouch-rectum anastomosis? Is there ischemia? Sometimes when pulling down the ileum into the pelvis, you tether the vasculature and it can become compromised, changing the angulation and the supply and ischemia can ensue.

The other thing, of course, is: Is this Crohn's disease? And that can sometimes be devastating to patients that have ulcerative colitis, have gone through the surgery for the pouch, now have Crohn's. But they should be treated as though they had Crohn's and they didn't have a pouch. Treat them with aggressive medical therapy as one would do otherwise.

Or, is this an infectious process? Is this salmonella, Campylobacter, to name some of the things that might come about? Or simply, are you treating lactose intolerance that is perhaps not necessarily pouchitis, and hence the need to do an examination episodically in individuals that have such to see: Is the mucosa pristine? Is there inflammation in the pouch directly?

Holly Atkinson MD: Kim, any way to predict before surgery who's at higher risk?

Kim Isaacs MD, PhD: We tend to see a higher incidence of pouchitis in patients who've had other extraintestinal manifestations. For example, if the patient had fairly significant immunologic skin disease-such as pyoderma gangrenosum or erythema nodosum-also, very bad inflammatory joint disease-all of those indicate that the person has increased immunologic reactivity. And those patients are more likely to get pouchitis.

In addition, smoking may play a role in risk of pouchitis. Patients who are smokers, who are active smokers may have increased risk of pouchitis. And you may ask, why is that? Well, one possible reason is that you're increasing the mucosal permeability, increasing the antigenic drive from the bacteria in the pouch and causing this ongoing inflammation. There have been some studies that demonstrated that serologic markers may be helpful in predicting who's at risk for pouchitis. There's some data on p-ANCA. However, this probably reflects the person's underlying immunologic reactivity.

So I think that if you have a patient with fairly significant extraintestinal manifestations, you should counsel them they may be at increased risk for pouchitis. And in general, I've found in my patients, that does not stop them from getting this procedure done. The alternative to the ileal pouch-anal anastomosis would be an end-ileostomy. And most patients want to give it a go and still be able to go to the bathroom through their rectum before they go on to have a permanent appliance.

Holly Atkinson MD: Jim, what's your approach to treatment?

James Marion MD: If a patient presents to me with clear-cut pouchitis, I usually start off with either metronidazole or ciprofloxacin. Usually a course of a week or two will settle the symptoms down quite nicely; most patients will have a response within a day or two.

The next level of therapy really depends on whether or not you've ruled out other possibilities on the differential. However, some people will try reinstituting 5-ASA agents, either mesalamine or sulfasalazine in these patients. Topical therapies can also be tried, such as steroid enemas or 5-ASA enemas or suppositories. My own experience with those, however, is that they're usually rather disappointing and they're difficult for the patients to tolerate, given the smaller size of the reservoir compared to the rectosigmoid.

Beyond that, using immunomodulatory agents or immunosuppressant agents or even biological agents have been tried and sporadically reported in case reports. There's really no large experience with these. It's exceedingly unlikely that a pouch will have to be removed, because of pouchitis. Fewer than 1% of pouches typically fail and require removal; usually, you can control these patients.

And I also want to stress to the practicing gastroenterologist: There is no sin in using symptomatic medicines in these patients, even if they've had pouches for a while. So anti-diarrheal agents should always be considered in these patients, if they're having a difficult time, or if their symptoms are disruptive.

Gary Lichtenstein MD: I think fiber supplementation is another issue. And often we'll put patients on that initially after surgery. About four to five months later, their small bowel will accommodate and take over the function of the colon and the frequency of stools will go down to the mean of approximately five, perhaps as high as eight, as low as three per day. And the individuals will then realize what their baseline will then be at that particular point and realize that an increase in stool frequency may be the heralding onset of pouchitis or other inflammatory conditions, such as an infection.

Kim Isaacs MD, PhD: Two other approaches I've used as well. And one is for the patient who cannot tolerate oral metronidazole due to the nausea-Is that we've used some topical metronidazole, it's available in a vaginal gel, you can formulate it also as a suppository. And the doses that you use are usually much lower than you would use orally and you instill the metronidazole directly into the pouch. And that's been effective in some patients.

In addition, we didn't discuss this as part of the differential, but in a way, an irritable bowel syndrome or spasm of the pouch. There are some patients who may respond to antispasmodics that are typically used for irritable bowel syndrome and that may help decrease frequency. It really won't help with the inflammatory component, but may help symptomatically.

In addition, going into trial, there are several nonabsorbable antibiotics that are going to be looked at in the treatment of pouchitis. And the advantage that they have is that they'll have very little systemic effect, yet we'll be altering the bacterial population of the pouch. And again, when we talk about the pathophysiology of this disease, we probably are again talking about a combination of environment, we're talking about the immunology and we're talking about the bacterial population in the pouch.

Holly Atkinson MD: Well, talking about that, I imagine you have a lot of patients coming in, all of you who are interested in complementary and alternative medicines. What about probiotics?

Kim Isaacs MD, PhD: Probiotics may have a role in pouchitis. Again, we're looking at the interaction between the bacteria in the pouch-the reservoir of the pouch is holding the bacteria in the stool there-and the immunologic interaction of the pouch mucosa. There is one small study out of Italy that demonstrated that patients who were treated with antibiotics and then given probiotics for a year after they were treated for pouchitis, had a marked reduction in their development of pouchitis. These were patients who were having three to four episodes of pouchitis per year. And all of these patients had no episodes of pouchitis while they were on the probiotics.

The unfortunate or maybe fortunate fact is that you have to stay on the probiotic. All of these patients relapsed within two weeks of stopping the probiotic. So what one is doing is changing the population of bacteria in the pouch, maybe to less immunogenic bacteria, with the probiotics. But you have to keep on with that change; you can't just stop it and expect it to maintain remission. And the other thing is that you have to take it all the time; you can't take a couple of doses and really expect that to work in terms of preventing pouchitis.

Holly Atkinson MD: Final thoughts for the practicing physician? Kim?

Kim Isaacs MD, PhD: Treat pouchitis when it occurs. I think that also, as we mentioned earlier, there is a broad differential. One needs to make sure you're treating pouchitis rather than infection, Crohn's disease, the whole list that Gary stated before in terms of the differential of pouchitis. But once it's there, treat it and don't be afraid to use the symptomatic therapy.

James Marion MD: I think it's important that the gastroenterologist pre-operatively, before these patients have their pouches fashioned, that they give the patient a realistic expectation of how these pouches function. I think the surgeons give one side of the story. The gastroenterologist is there really to escort them through this and is most likely going to be the one to follow them up for the long run.

So make it clear that on average it will be anywhere from five to eight bowel movements a day. Some people can have as many as ten to twelve, some as few as three. It will not be the same bowel habits that they had before they ever were diagnosed with ulcerative colitis. And while the ileal pouch-anal anastomosis, or less frequently, the continent ileostomy, are imperfect cures, they're really all we have at this point. But I think the patients need to go into these surgeries with a realistic expectation of the outcome.

Holly Atkinson MD: Well, thank you all for sharing your clinical wisdom with us. And thank you for being with us today. I'm Dr. Holly Atkinson.

Moderated panel discussion: post-operative care