Appendicitis Management & APPY Trial: Update Course 2016

Now he's going to talk to us about what is the evidence tells us, not emotion, but what does the evidence tell us about how we should be managing appendicitis. Thanks, Todd. Um, when, when I was first asked to, to talk about this, uh, we talked about maybe an update on appendicitis and reviewing some of the approaches and those kind of things, but, uh, that debate has, has gone on and on, and the effect sizes are probably too small to, to make a meaningful difference. So where the next big step is gonna be is whether we need to be doing the appendectomy at all, uh, for patients that have non-perforated appendicitis. You have to. Sort of spin the the mouse on the table until you see the arrow and then there you go now push it, yeah. And so we're gonna be talking about a multi-center randomized trial that compares appendectomy to non-operative treatment, the background literature that, that led to this study, and uh where we're gonna go from here. So, uh, the initial working group was Agostino Piero and, uh, Nigel Hall, Simon Eaton, Thomas Wester, and, and several others. Uh, the group grew and we got involved about 2.5 years ago and the, the first round of funding failed and so we took a hard look at how we calculated the sample size and how the study was designed. And then we came up with a bit more of a pragmatic approach and then the next round of funding failed and so um we made some more modifications to the trial and then ultimately this past year we got enrolling and unfortunately uh sick kids saw this as a sponsored drug trial, even though there's nothing that's uh experimental about Augmentin. And as such we're gonna hold the researchers uh legally uh re legally liable, which isn't reasonable. So the only way for these guys to handle it was to, to give up ownership of the study, uh, so that we could continue on with it. But credit to Augustino, Nigel, and Simon for having gotten, having pushed this to where it is now. So this is our logo, um, which you may start seeing this is developed by Eric Skarsgard in Vancouver. And uh the background, we all know that appendectomy is the gold standard, but any operation is going to be associated with complications. Appendicitis can be treated without surgery, and we know that from our literature on complicated appendicitis where we can treat to the end point of, of, uh, getting them. Um, over their appendicitis regardless of, of how badly it's perforated up front, but then there's those patients that have taught us lessons from their experience, um, talking to Bob Parry last night, one of Todd's partners, he was in Ireland, developed appendicitis, and was put on antibiotics and ended up going a full year before he had a recurrent bout of his appendicitis and, and had his appendectomy out. But could we consider that a primary therapy? The justification would be that there's more patients now being reported in the adult literature and emerging pediatric evidence. Some parents definitely want to avoid an operation, as we're finding out now as we try to randomize these patients. And then there's potential cost savings, both medical and societal. Now prior to getting involved in this study, I thought that was a little bit nonsensical, but now we're we're starting to see that that's true. So I've, I've got a picture of one person in, in my office that, that hangs on the wall, and that's Archie Cochrane, and he is sort of a, a father of uh clinical research and evidence-based medicine. And his quote, which I agree with in most circumstances, is that we should support things with comparative evidence. It doesn't have to be a randomized controlled trial, but we should support our emerging procedures and management strategies with comparative evidence so that we we know in fact not necessarily that it's better or that it's worse, but we know by how much and we know how it's different so that we can consult families and we can make educated decisions. So in a review of the studies that have been done in adults, uh, this was, uh, started by Thomas Wester with the help of Nigel Hall and Simon Eaton. Um, what you see there is about what you would expect with 300 versus 500 patients, 300 and some managed non-operatively against the 500 that were managed operatively. The treatment failure, although it was kind of spread around in those series, it trended toward favoring a surgical approach, and that's what you would expect. How can you beat a 100% cure rate when you're talking about an appendectomy? And so the question isn't, can, uh, which one's better at curing appendicitis. Um, one of them is an operation and one of them is not. How, how much of a failure rate would you be willing to accept to avoid an operation? And when we look at the complications, all of the studies, of course, uh, favored non-operative management because it's, it's a little bit more difficult to get a serious complication from a round of Augmentin. I sure did. There it is. And then it just fades away again. So the adult estimates of success revolve around that 80% mark and as I'll explain in a minute, um, this, this was integral in developing our sample size for the randomized trial. The pediatric experience is growing by the minute. If we just wait another month, there's gonna be another paper that comes out in some form with their experience of non-operative management as you see, those dates are mostly contemporary, and most of them are are cohort studies, a few small comparative studies and only one pilot randomized trial, and that was by Thomas Western in Sweden who is part of our group. And here is that study. They randomized 50 patients. 24 ended up with antibiotics. They had a 92% or 22 of the 24 that had initial resolution of symptoms. One patient came back with recurrent appendicitis, but they took out several other appendices in that time because of parental preference. So they, they had resolution of symptoms. They went home, and then kids being kids, belly hurt, acting funny, not sure, and then mom just wanted to get the appendix out, but the other ones were path negative. We decided in this study any appendix that has to come out, even if it's mom preference we have to consider because that's that's real time. I mean that's what's gonna happen in practice if we if we do this and send people home with their appendix we have to be prepared for the fact that their parents could lose their nerve as soon as the kid starts um complaining of really anything. So we all know about the preference trial um that was started at Nationwide with uh Pete Menici and Kate Deans and now they've extended that to the Midwest Pediatric Research Consortium which we're a part of but we had already committed to the randomized trial and and philosophically, um. The reason was because in the preference trial, the parents get to pick which which they're going to get non-operative management or operative management. The concern is naturally that those that are that are that are sicker or looking worse, even if it's subjective and not necessarily objective, two kids can have the same white count, but one of them can stand and walk and the other one can't get out of bed. They may be more likely to choose non-operative management if they're less sick. Non-operative management or antibiotics will be extremely effective for the kids who do not have appendicitis. And and that's that's that's what we would, we would expect um now that we've been trying to enroll these patients, that's exactly what we're finding that the, the people who are a little bit less sick, moving around OK, uh, are the ones that are more likely to sign up for the study. The kid that can't get out of bed and is in severe pain, uh, the parents don't want to hear about it, they want the, the appendix out ASAP. So at the time they last published, and this is, this is a fast moving target because there's now with the consortium involved about 150 patients total, but at 77 they had 30 that chose non-operative treatment and even now that they're closer to 150, it's about a third of the patients that are choosing non-operative treatment. Um, they were extremely effective, about 90% at 30 days, and they had fewer disability days, early return to school, improved quality of life versus surgery. And I had talked to Pete about this um prior to us enrolling patients in in our study, and I thought that didn't feel viscerally right that we can do a si zappy on a non-perf patient and send them home the same day and give them no activity restrictions, no bathing restrictions, no limitations. Even though we give them no restrictions, they restrict themselves. They, they really do for several days. And so now that we're keeping these, these diary cards and the patients come back, the people who respond to antibiotics, they're literally normal the next day. So from the time they go home, we'll discharge them on a Tuesday. They almost all go to school on Wednesday, and, and it could be uh parental preference, but if you send the Api patient home on a Tuesday, a lot of times the parents will wait till Friday or the following Monday to to get them back to school. By the way, um, for those of you in the, the, the audience here, if everyone could use their phone and answer these poll questions that we're putting up so we can get everyone's input on this. Yep, go ahead. Uh, this was a little pilot experience that Andriana put together and she's also part of our working group. Uh, she treated 12 patients non-operatively. 10 of them succeeded. She compared that to 10 patients with operative management and of course there were no differences. So that leads us to where we are now and um this is the the clinical trials.gov registration for it and we officially started enrolling in January and um Stockholm started in in March. And so the question is, can patients be treated non-operatively with enough success to warrant as first line therapy over appendectomy? Again, there's no way it can possibly be superior and so that's why this was designed as a non-inferiority trial. The question is how, how much recurrence can we accept. In order to avoid an operation up front and then potentially choose a group of patients that avoid an operation altogether, so it's a pragmatic parallel group unmasked non-inferiority study. And by pragmatic what that means I'll explain here in a sec, but uh we include patients 5 to 16, those that are under 5, as you know, will frequently be perf regardless of how they present. And then those are suspected of having non-perforated appendicitis. So, um, the nationwide led study was using a bit more strict criteria, white count less than 16, no fecolith. Um, we wanted this to be broad enough that you could just roll it out into any ER tomorrow. Uh, we talked about this a long time. Do we need an Alvarado score, a PAS score of some value? Do we need ultrasound that shows this or that? And we agree that when we're talking about centers all over the world, um, we don't need to be telling surgeons how to diagnose appendicitis. So if you don't use imaging in your hospital but you treat appendicitis every day, then keep doing what you're doing. If you use ultrasound, use it. If you use CT, use it. Whatever it is that you're doing, what you consider going to the operating room with non-perforated appendicitis would be the patient that you want to sign up for this study, expecting that you're gonna be wrong sometimes. And then excluding those with a suspicion of perforation, antibiotic treatment that had been initiated at an outside facility that was in the protocol. Once we started doing this, we realized that that happens universally once they get the diagnosis, they get the drug, so we said two doses, meaning you've pretty much committed to a non-operative management and um those that have had a previous episode of appendicitis treated non-operatively and then those with systemic disease. So what we're doing is taking these patients. That look like they have non-perforated appendicitis and it's a balance. If we enroll more aggressively, we'll have more patients and we'll have more kids that end up with a perf and if we are more conservative, then we're going to end up with fewer perfs but then we're also going to end up with more patients that did not have appendicitis. Either way, what we've tried to get all the groups together and and we had a meeting in January in Toronto um is be consistent so whatever it is, if you're gonna sign up that patient that has a white count of 18 because they've only had one day of symptoms and they have focal pain, then you have to you have to stick with that. So this is what our eligibility checklist looks like with the things that were just mentioned. And we're gonna stare at that for a while. Mark, can you advance? We'll go back to the mouse. So there's always a debate about central versus local randomization. We are using central randomization through a website that you go log in and then put in the next patient, and then it'll give you what the next allocation is. Minimization means that instead of it being stratified um or equal gender duration of symptoms center, minimization means that as it gets tilted in one direction, your odds of getting um the the next therapy get shifted. So if there's more female. In the non-op group and another female comes in, she's more likely to get an appendectomy. If a center starts to get ahead of itself with operation or non-operation, the next one is likely to shift the other direction so that you're more likely to be fifty-fifty in these criteria. Well, we don't know the impact of sex, we thought it was very important. Um, based on center and duration of symptoms, particularly when we look at secondary outcomes like length of stay, um, where it's, it's very hospital-based, not necessarily patient-based. This is what the algorithm looks like. Uh, Simon did a great job with the initial version of it. When we started to put it into practice, we realized that pragmatically there were a lot of things that we just, we couldn't do. So for instance, um, the initial iteration said that we would have an initial evaluation at 24 hours and then another evaluation at 48 hours. The problem with that is that that's not how the workday runs, and a lot of these kids get signed up overnight. So if somebody comes in at 1 o'clock in the morning. And you say if you sign up for the study, then we'll reevaluate you tomorrow night at one o'clock in the morning. No, that would mean if they come in at Sunday night at one o'clock in the morning, they would get reevaluated Tuesday morning on rounds. Well, what if I don't sign up for the study? Well then we'll take out your appendix in the morning and they'll go home, so no one's, no one's gonna sign up for that study. Unless patients have the ability to go home the next day also and so, um, once we started enrolling, we quickly realized that we had to give these kids a clear diet and tell them that if, if you're fine in the morning, we'll feed you breakfast if you do OK you can go home tomorrow and so on Sunday night that that sounds pretty palatable. We do tell them though if they're not better we don't encourage going straight to the OR but give it another day and then we reevaluate Tuesday and then after they've had a full 48 hours of therapy, so by Wednesday morning that's when we would typically say OK it's time to take out the appendix. So, um, One of the questions would be at this point if we're more aggressive, could we raise our success rate in Stockholm they had a 90% success rate with initial IV therapy of at least 48 hours. The answer is of course yes. If we can treat somebody that has a perf and an abscess and no drain through to completion with antibiotics, then we can continue to treat these kids until they're better every single time. But you've got to balance that against the option of sending them home on Monday. And so that's why by Wednesday we, we tell them that that's the end of it because, uh, 3 days in the hospital is, is, is too much already and so at that point then it's time to take out the appendix and, and forego that effort. The primary outcome is treatment failure, which is defined as an intervention for appendicitis requiring a general anesthesia within 1 year in both groups. So if somebody comes back with an abscess, that would be a treatment failure in the in the operating group, and then a negative appendectomy in the OR group. Which basically comes down to negative appendectomy versus recurrent appendicitis. The secondary outcomes, um, important to us, length of stay, number of admissions, and then total healthcare visits, imaging, and costs. So that's gonna be an important issue if, uh, the patients go home and then they're, they're bouncing back to their PCP in the ER every time something happens because they're concerned about the appendicitis. This is a non-inferiority margin of 20%. We saw that, um, you saw the adult data that it was all hinging around that 80% success rate and the, um, time frame that that was measured was highly variable, so some of them were short and some of them were longer. We're looking at this at one year follow up and we, we debated for a long time with, with the numbers and then the, the two things that that came out of the debates that were pretty obvious was. One is what would you consider unacceptable. So just polling the people and we'll, we'll, we'll pull it here. What would people consider unacceptable for treating somebody with antibiotics? A 10% failure rate, would you consider that too high? Hands? Nope. What about 20%? 25% 30%? Yeah, so when we were having this discussion, uh, it became pretty clear that most people would say once we start getting into the twenties, it's, it's too high of a failure rate, um. To consider non-operative management and one of, one of the big things that that I was thinking about as we were talking about this, it really doesn't matter. It's nice to have a randomized trial so that we can compare all the secondary outcomes and really have some fidelity to what the differences are, but this could be a prospective observational study just as easily because all you need to know is what that number is 20%. That only means what it means to mom. And so if it ends up being 24% and we say it's inferior, if it ends up being 16% and we say it's non-inferior, that's irrelevant what the conclusions of the manuscript say. That's just trial design. What's important is when you tell a mom there's a 16% chance that you're going to have to do that again in the next year. Somebody might say absolutely not. Somebody might say that sounds great. Give me the antibiotics and I'll go, even if it's as high as 26%. Some, some parents will say that that's better than an operation, and, and some parents will say, I, I'm not gonna repeat the last 24 hours for anything, so I don't care if it's a 2% chance. I'm not doing that again. Take out the appendix. So what we do, since we have 24 hour dosing, um, it makes the protocol pretty simple. They come in, they get their diagnosis, they get their drug, we reevaluate in the morning, and then they either stay for one more day or they don't, and then they go home with Augmentin or Ciproflagyl to complete 10 days of therapy. They do take home a diary. We follow up in 2 to 4 weeks, and then we're gonna have a telephone follow up at 1 year, and we're planning to follow our cohort, uh, in perpetuity because we need to know exactly what the recurrence rate is at 5 years, 10 years, as, as long as we can keep our hands on them. And that's what the diary card looks like. Really what it comes down to is, um, when did you get back to full activity? When did you get back to, uh, when did you get back to normal activity, then full activity defined as sports and competition, and, uh, when did you get back to school? These are the collaborating centers in trial development. And this is the, the, the enrollment so far, and I should probably check my email because info at randomized.net sends an email every time somebody randomizes. So this is a rapidly moving target. And currently we've enrolled 52 Stockholm 25, Helsinki, 7. Vancouver, Ontario, and Calgary just got their IRB approval last week, and Vancouver and Ontario already have a patient signed up. So hopefully we'll, we'll see this number grow pretty fast. And now that you guys have had a chance to hear the protocol, if you think that your center would be willing and able to participate, uh, we'd be happy to have you. Um, the early results that we've seen so far, and, you know, we're starting to get a feel for it too. Uh, we had in the OR group, uh, 4 that ended up having a perforation, so that shows that we're being fairly aggressive with the diagnosis. And 2 with a negative path. 1 was readmitted for an abscess in the non-op group, 3 failed early. 1 was found to have a perforation. That means they didn't make it out of the hospital. 4 failed after discharge. Most of them were within 2 to 5 days, and they went home and they just continued to have the same nagging pain. Nobody got worse, they just didn't get better. And then um we just before I came here had one that came back after 6 months. It was actually 6 months to the day since they enrolled in the study, and they came back with appendicitis and all of the recurrences have had appendicitis and all the failures have had appendicitis, so we haven't taken out a normal appendix yet. Yes, Mac. The two negative pasts, did they have imaging workup? Uh, did they have positive ultrasounds, or they, they had, um, secondary signs that where you see a little bit of fluid, but you don't see the appendix. And so, um, that right there, if you look at that, you say your, your, your failure rate's pretty darn high, 7 out of 24, um, with that, I think we're we're getting a better feel for it and some of those patients that failed um in the, in the, the 3 of the, of the 3 that failed early, 2 of those were really parental impatients. It was the morning of and uh they were like, OK, we're we're done, and they didn't really give it a chance. So I think we're getting a little bit better with that. So, uh, We feel a randomized comparison is required if we're gonna prove that this is as efficacious as appendectomy and um that should be demonstrated in a realistic population in a in a multi-center setting with a management scheme that's comparable to what whatever you do in daily practice so that regardless of what we find we know that it'll be translatable to to your center and then um. We, we don't think that non-operative management should include protracted inpatient courses, so it, it will work, um, universally, but you, you kind of have to draw the line somewhere if the other option is to send him home immediately. So now we can get to the debate, Steve. Uh, I mean, this is, it's very interesting information, but one of the things that I never hear anybody talk about is for the last 20 years, I've been hearing about not using antibiotics indiscriminately because of creating resistant organisms. And now we're talking about treating a large population of patients who most of have a surgical disease that we can cure with a long-term antibiotic. So is anybody questioning or asking, you know, what are we actually doing? To that population of resistant organisms that we could eradicate and, and what is the risk-benefit ratio of that? That's an interesting, interesting point. The reason for the push of limiting antibiotics is that that same Augmentin is given to kids every day in Peed's offices that have sniffles, and we all know that they're, they're treating the parents and so we're talking about really big populations, so thousands of people on a daily basis that are that are getting Augmentin that they never needed, and this is an active intraabdominal infection, um, that, that, that's being treated and so. We treat all of our perforated appendicitis with antibiotics and then if they end up with a complication, long term antibiotics until they're better but we're treating something and so here I see us treating an intraabdominal bacterial infection which is a little bit different than what the move has been which is limiting unnecessary antibiotics. So we're not. We're not sinning as bad as they are. We're treating, we're treating what we know requires antibiotic treatment with or with, with or without surgery. So they still, they still get a dose of antibiotics, uh, with the operation. So they still get the exposure. Um, so Steve, one of the things I take from this is that we can do it. So I'm not going to offer this to my patients, at least not right now, but I'd like to know that we have pretty substantial evidence that this is an option in a patient that might not be a great surgical candidate, that logistic reasons that they wanna go back home and they're out of town and then, who knows what it is, but I, I am not gonna use this as a treatment protocol. I'm treating this as, uh, that's good to know that this is an option. This is. We know we can do it. The reason for this study is not even so much should we do it. Just to know exactly what it means if we do it, so what are the chances of failure? What's the likelihood of having a protracted stay in the hospital? What, what are the likelihood of, of, of coming back if you make it home and you're doing fine so that if somebody is interested in that option, then they know exactly what they're, what they're signing up for. Sean, what's the adult literature suggest is the real long term outcomes, you know, beyond a year? Has anyone looked at beyond one year recurrence? No. And that's why, particularly in the pediatric population, we are very interested in following these patients as long as we can keep our hands on them. So as many patients as we get enrolled, um, we're, we're gonna keep after them every year. And that's gonna be telephone follow up and we've asked them if they, if they move to let us, let us know what their contact information is and I can tell you straight up from other studies very, very difficult to, to keep these patients in, in a follow up situation, but we're gonna do our best to follow them as long as we can. You know it'll be interesting is, as we, as we all are transitioning to health health information exchanges. If you can get IRB approval, you can actually probably follow them through their medical records going forward, at least if they stay within a state or a region. And back to what we were talking about earlier, um. I think it's really unlikely that this study would show that non-operative management should be first line therapy. And I think there's a distinct possibility that it could end up showing that we really shouldn't use it as first line therapy if that failure rate ends up exceeding 25% over a year, we would have to say it's, it's probably not worth it, but even then we would at least have the numbers to tell a parent who's interested in avoiding an operation or is in a social circumstance that they can't have an operation right now what what they're getting into. Um, I think we're gonna, um. Gonna wrap things up unless there's other comments. There's some couple of comments from the virtual audience. Anyone have comments here? Yeah, do you have a microphone? Thank you, and this is a very nice, interesting, uh, subject. Really, I have a question. Uh, what was the criteria of perforated appendix? In my personal experience, I found most of the perforated appendix are due to fecole. So it could be the appendicitis which is caused by the fecole, not, uh, feasible to give antibiotic at prostitute surgery. It's my question. I mean, we specify. Appendicitis with feli to proceed with surgery without antibiotic. Right, um, that, that was a debate that we had in trial design is whether we should include patients that have a fecal lith. There's always some judgment there, but, um. We have not excluded those patients that have a fecal lith uh because it it is a big chunk of the population. We define perforation as a hole in the appendix or afecolith in the abdomen, so in other words, irrefutable proof of contamination is only an intraoperative diagnosis. It's not a preoperative diagnosis, and we've looked at that extensively both directions trying to predict non-operative, I mean non-perforated and perforated, and you're, you're gonna be wrong both ways as we're seeing here where we're trying to select those that are clearly non-perforated, and we've got a handful that end up that do have a hole at the time of the operation. The presence of a fecolith is actually an exclusion criteria for the study being done through the Midwest Pediatric Surgery Consortium, so we may get some information on that through that study. Yeah, yeah, that's what I'd mentioned earlier is a white count of less than 16 and no fecolith, and one of the, one of the concerns is that you, you could end if, if you're too conservative in your diagnosis, you're going to end up with a larger portion of the patients that, that don't have appendicitis. And you're, you're not gonna know that um if you don't have equal equal levels of sickness going to the operative group with the randomization, we feel like regardless of where we set our criteria, we're gonna know how many non-ops how many non-appendicitises we've managed in the antibiotic group by how many normal appendix we take out in the operative group. And then we're gonna know how many perfs were probably in the antibiotic arm based on how many perfs end up showing up in the OR arm so we've got a window to look at at both arms. I just want to make a comment. I work at Nationwide with Kate and Pete doing the antibiotics, uh, treatment, um, arm, and we actually went back and looked at our exclusion criteria because the appendicolith did exclude a significant number of patients from the study and did a separate, um, small population in which we allowed them to be enrolled in the study with an appendicolith, and we actually stopped that based on the failure rate. So, we'll see what happens, but All right. And then, uh, I do appreciate all the comments in the chat. Uh, the question about, uh, that I don't wanna spend too much time, uh, uh, Daniel, uh, is because, uh, it's not quite on topic, but a question about, there's a lot of questions coming up about management of an abscess post-op if they're, uh, asymptomatic on antibiotics, do you have to drain it. Um, and I appreciate Astrid for answering those questions. Uh, any comments on that? Uh, yeah, so we, we had taken a look at, uh, a large cohort of patients that had an abscess after their appendectomy. These weren't pre-op abscesses and com and, and, and you would say, well, comparing drain to no drain is not a fair comparison because those that had a drain had a drainable abscess and those that didn't get a drain didn't have a drainable abscess. But we went through a period of time where, um, we didn't have the IR support that we have now, so we did have a lot of very straightforward drainable abscesses that were managed without a drain. And um we, we saw that the outcomes were relatively equivalent. The drain didn't offer a huge advantage, but the biggest abscesses, the worst patients got the drains. So then we got rid of the patients so that we had a size match, and that size match brought us down to 17.5 centimeters squared, and that's um AP versus lateral in, in an axial dimension, your, your greatest AP versus lateral area. And there was an advantage to not having a drain in those patients. So, so currently at our center, if they have uh less than a 20 centimeter squared abscess, less than 4 x 5. Um, we, we typically discourage a drain because whatever advantage you're going to get, um, is pretty small and it's an extra anesthetic and it's an extra procedure and, and in some cases it, it increases your length of stay because then once our drains placed in our system, IR manages it. They want to see the drainage get down less than 10, and we'll say pull it and they'll say leave it one more day and, and sometimes they, they, they stay longer than they need to, but that's a study in itself to keep the drains or not. Right, well, and we had enough patients to compare the aspiration alone and in, in all three groups drain, aspiration, antibiotics alone, we didn't see a difference in the total length of antibiotics required, uh, to, to cure. So with, with that being said, um, we're being a lot less aggressive about drains. And, and Robert, I'll have, uh, I'll have Sean because we're out of time. I'll have Sean and others if other people can answer the questions about. Um, setting standards for quality now and, and how we are evaluated on appendicitis and how this may change things now. Uh, it's a very interesting question. Um, so,