Appendicitis has an incidence of 80,000 pediatric cases per year in the United States, and the gold standard for the past 100 years has been to treat children with appendectomy. However, recent research in adults has suggested antibiotics without surgery may be an effective treatment, challenging conventional practice.
Join Dr. St. Peter and Transformational Pediatrics, as we look to learn more about the Children’s Mercy randomized study looking to answer if broad-spectrum antibiotics may be used to successfully to treat acute uncomplicated appendicitis in children, helping these patients avoid surgery all together.
Selected Podcast
Can Acute Uncomplicated Appendicitis Be Successfully Treated with Antibiotics?
Featured Speaker:
Learn more about Shawn D. St. Peter, MD
Shawn D. St. Peter, MD
Shawn D. St. Peter, MD, is a pediatric surgeon with Children’s Mercy Kansas City. He is the Director, Center for Prospective Clinical Trials; Director, Surgical Scholars Program; Professor of Pediatric Surgery, University of Missouri-Kansas City School of Medicine; and Program Director, Pediatric Surgery Fellowship. He completed his medical degree from the University of Washington, Seattle, WA, a surgery residency at Mayo Clinic, Scottsdale, AZ, and fellowships in clinical research from John Radcliff Hospital, Oxford, England and pediatric surgery at Children’s Mercy Kansas City. He is certified in both general and pediatric surgery and specializes in achalasia, anti-reflux surgery (laparoscopic fundoplication and g-tubes), clinical trials, inflammatory bowel disease, minimally invasive surgery, and pectus deformity.Learn more about Shawn D. St. Peter, MD
Transcription:
Can Acute Uncomplicated Appendicitis Be Successfully Treated with Antibiotics?
Dr. Michael Smith (Host): So, our topic today is “Can Acute Uncomplicated Appendicitis Be Successfully Treated with Antibiotics?” My guest is Dr. Shawn St. Peter. He is professor of pediatric surgery at the University of Missouri Kansas City School of Medicine, and is Program Director, Pediatric Surgery Fellowship. Dr. St Peter, welcome to the show.
Dr. Shawn St. Peter (Guest): Thank you.
Dr. Mike: So, I have a couple of little stats here. Appendicitis has an incidence of 80,000 pediatric cases per year and the gold standard for the past 100 years has been to treat children with appendectomy. So, obviously, there’s been a change in thought in this. So, what has happened over the past few years that has brought us to this point looking at antibiotics as a potential treatment?
Dr. St. Peter: Well, it started with the perforated appendicitis. The worst case develops an abscess. That’s a very difficult operation so people realized you could put in a percutaneous drain and then treat them with antibiotics. Then, people started to treat all perforated appendicitis with antibiotics with the idea of being that you make an easier operation for yourself later. We have done a piloted, randomized trials on that topic a few years ago and found that they were fairly equivalent length of stay, but the early operation had higher quality of life and it wasn’t as stressful for the families. And then, a larger study taking all comers showed that there was a benefit to doing an early operation. So, some centers are starting to back away from doing primary antibiotics in patients with perforated appendicitis but the next natural question led to this concept of “Do people who have non-perforated appendicitis transition to perforated appendicitis once they start their antibiotics and can their operation be delayed?” It became pretty obvious that that wasn’t the case and, in fact, once the antibiotics started, you’re treating the disease. And so, frequently people would feel better within a day or two once the antibiotics was started. So, then there was a piloted study done on adults that showed that there were fairly equivalent outcomes, basically, a non-inferior outcome by giving antibiotics up front and, most of the time, you can avoid an operation altogether. And so, the question then goes to children where appendicitis is extremely common and, they have, obviously a lifetime risk as opposed to somebody who’s a little bit older and has medical co-morbidities and you want to avoid an operation regardless because they’re higher risk. These are fairly healthy people who have low risk of an operation. And, if you leave the appendix, then you’re going to be leaving it for life. So, there’s been several centers that have turned their attention to this and we started working with a group in Toronto as well as several groups in Europe about three years ago, on developing a multi-standard prospective randomized trial. And, the idea would be to definitively gather a cohort of patients that will answer the question, “If you treat with antibiotics alone, what are the changes of failure in one year?” And, that is the number that we need. We discussed this for a long time about how we were going to develop the study and what the sample size would be. The study is designed as a non-inferiority trial meaning, at what point would you say this is actually inferior because it obviously can't beat an appendectomy. You got 100% success rate. The appendix is out, that’s done. So, it’s not going to be superior, but it’s also not an operation. So, you’re not shooting to be as good.
Dr. Mike: Right. Right.
Dr. St. Peter: It just means you want to say, “At what point will you say this is no longer acceptable to avoid an operation?” And, my thought was, “I don’t care what we set the non-inferiority limit at. We can set it at 15%, 20%, 30%. It doesn’t matter because the number of failures is what mom’s going to care about. So, if we say it’s a 20% non-inferiority margin and it comes in at 18%, so we declare it non-inferior. Great. It comes in 22%, we declare it inferior. Great. But that 22%, to a mom who’s terrified of an operation sounds great. And, that 18% to somebody who had a horrible night the night before with their appendicitis, that’s going to sound terrible.
Dr. Mike: Right.
Dr. St. Peter: So, we just need to establish what that number is so that we can adequately counsel patients and then they can choose.
Dr. Mike: So, when it comes to this study, where are we at in terms of recruiting for this study? What are the number of children you’re going to try to get into this study? What age groups are you looking at?
Dr. St. Peter: The ultimate end is about 1000 and we’re looking at ages 5 to 16. Most kids under age 5 do have a perforation. Even if they don’t look it, they usually have it because they don’t have enough somatic awareness to tell you when they’re having a problem early on. We started with Toronto as being the primary site and, unfortunately, their center saw this as being a sponsored drug trial, even though there’s nothing experimental about Augmentin and, in fact, we don’t even control what the antibiotic is. So, you can give any antibiotic you want. Our point is just broad spectrum antibiotics versus appendectomy. And, they got into a little bit of a legal snafu and had to give up not only primary but really can't participate in the study. So, we became the primary site. So now, we’re the organizing site. We’ve enrolled 60 patients here. Stockholm has enrolled 30 and there are a handful of other sites that are up and running although they’ve all just had small numbers so far. Helsinki has enrolled close to 10 and Winnipeg, Ottawa, Calgary, Vancouver and London, Ontario, have all gotten IRB approval, but none of them have had more than five yet. So we sitting at about 110 patients total right now. And, that’s--
Dr. Mike: Tell us about the patients in the…Go ahead.
Dr. St. Peter: I was just going to say, that’s with enrollments starting in January. So, we’re about a half year into it.
Dr. Mike: So, tell us about the patients in the non-operative group. What exactly is going to be their course of treatment?
Dr. St. Peter: So, that’s another interesting evolution. Initially, we were talking about 24 hours of IV antibiotics but the fact that in the United States and in our institution, we send patients home immediately after their operation. If you see somebody on Sunday night and you say, “Well, if you’re randomized to operation, you’ll have your operation in the morning and then you’ll go home. If you’re randomized to antibiotics, then we’ll reevaluate you Tuesday morning,” no one’s going to buy that. So, we had to give the patients the opportunity or the ability to go home that first day. So, what that looks like is…
Dr. Mike: Oh, I see.
Dr. St. Peter: …they come in at 10 o’clock at night and you randomize to non-operative management, then you’re going to be allowed clear liquid diet. And in the morning, if you feel good after drinking some clear liquids, you can have breakfast. If you can eat and keep your food down, then we’re going to switch you over to oral antibiotics and send you home with a 10-day course of Augmentin. Everybody gets Rocephin and Flagyl, we use once a day dosing for both which is kind of unique, the 30 per kilo dosing of Flagyl. But, that way you’ve got a 24-hour dose onboard to begin with and that’s going to cover them throughout their next day. It allows them to get out of the hospital and transition over to oral antibiotics. Initially, I think we were a little bit more jumpy and now when somebody is still in pain post-admission day one, we usually encourage them to give it one more day because most of the time, they will transition between day one and day two and then feel better and be ready to go home.
Dr. Mike: Okay. So, just a recap. So, that’s 12 hours of IV antibiotics. If they can eat in the morning and they’re feeling better, you switch them over to oral and then they go home. As far as when you really look at this and with your experience with using antibiotics and your experience with appendectomy, I mean, what do you think are going to be the results from this study?
Dr. St. Peter: I think that we are going to replicate where some of the meta-analysis are in adults. That it’s going to be around 80% successful and it may end up having a little bit of a higher failure rate than that because of parental-driven reasons, which is okay because that’s real world. If we roll this out tomorrow and say, “This is our standard of care,” you’re going to have people that are going to continue to come back and be anxious, and you’re going to have to take out the appendix.
Dr. Mike: Right.
Dr. St. Peter: So, that’s not a false failure. I think that’s a real failure. And then, from there, it’s going to be interesting to see what the recurrence is over time. I would like to see at Mercy to get a very large cohort of patients that we could follow in perpetuity. So, I think it’s going to be difficult to do that in a multi-center fashion but if we can establish a large cohort here, then we can check it at two years and then three years and then five years and that should be the real important thing. If you start to see many failures there, then I think people are going to lose enthusiasm for this.
Dr. Mike: Right.
Dr. St. Peter: There are centers that have picked up enthusiasm for this and I can understand why now that I can see these patients back in clinic. It’s there--when they leave the hospital--they’re normal. So, even though we can do a nice, slick single incision, laparoscopic appendectomy through the umbilicus. There’s no visible scar, there’s no activity restrictions. There won't be any restrictions when you go home after a surgery. That sounds great. But, at the same time, they’re taking a little bit to recover. Sudden start/stop motions are going to hurt at the belly button for a little while. When these kids go home, they’re fine. So, if they go home on Monday, they invariably go to school on Tuesday. They go home on Tuesday, they go to school on Wednesday. And, you can't say the same for an appendectomy. You frankly can't.
Dr. Mike: Right.
Dr. St. Peter: So, when people randomize to antibiotics and they’ve got some big thing coming up, some big athletic event coming up this weekend and they come in on Thursday and we put them on antibiotics, they’re going to be fine to play.
Dr. Mike: So, the one year follow-up in the non-operative group looking for appendicitis, where did that number--was that simply just an easier follow-up timeframe to deal with in a multi-center situation? Because it does seem that the follow-up should be at some longer points here--year and a half, two years. Why was the one year chosen here?
Dr. St. Peter: Because of the multi-center randomized nature of the study. We realized that you wouldn’t be able to keep your hands around that cohort for a long time and, for the sake of the study, you’ve got to wrap it up. And so, this, of course, started with funding applications and so, we went through several rounds of funding efforts which we’ve so far not succeeded. But, just the same, as a study design, your primary outcome is established at what point and one year is about realistic for a feasible study.
Dr. Mike: So, Dr. St. Peter, you are also the Director for the Center for the Prospective Clinical Trials. Tell us a little bit about that department that you direct.
Dr. St. Peter: Yes, that started as an effort to answer questions in our field and there was just a tremendous amount of heterogeneity for the management of common conditions and so we started focusing on randomized trials in common conditions. So, when I started on staff and there was this idea of calling this effort “The Center for Prospective Trials,” my goal was to have five studies randomizing by that first summer which we ended up accomplishing. And so, since then, there’s been sort of a frame shift within the way the entire department of surgery thinks and we no longer talk about opinion very often. We talk about evidence. For instance, we just had a fellow start, and he didn’t like the idea that we use Foley catheters on our patients with perforated appendicitis. So, I said, “We don’t hypothesize here. Go ahead and write up a prospective protocol and make some very strict criteria for who does get a Foley. Everybody else doesn’t and we’ll look at the failure rate and answer your question.” And so, we have completed 15 randomized trials that have gone to print and we’re currently conducting four at the moment, and this is our flagship study at the moment--the antibiotic trial.
Dr. Mike: Well, Dr. St. Peter, I want to thank you for coming on the show today. Thank you for the work that you’re doing at Children’s Mercy. You’re listening to Transformational Pediatrics with Children’s Mercy, Kansas City. For more information, you can go to www.childrensmercy.org. That’s www.childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.
Can Acute Uncomplicated Appendicitis Be Successfully Treated with Antibiotics?
Dr. Michael Smith (Host): So, our topic today is “Can Acute Uncomplicated Appendicitis Be Successfully Treated with Antibiotics?” My guest is Dr. Shawn St. Peter. He is professor of pediatric surgery at the University of Missouri Kansas City School of Medicine, and is Program Director, Pediatric Surgery Fellowship. Dr. St Peter, welcome to the show.
Dr. Shawn St. Peter (Guest): Thank you.
Dr. Mike: So, I have a couple of little stats here. Appendicitis has an incidence of 80,000 pediatric cases per year and the gold standard for the past 100 years has been to treat children with appendectomy. So, obviously, there’s been a change in thought in this. So, what has happened over the past few years that has brought us to this point looking at antibiotics as a potential treatment?
Dr. St. Peter: Well, it started with the perforated appendicitis. The worst case develops an abscess. That’s a very difficult operation so people realized you could put in a percutaneous drain and then treat them with antibiotics. Then, people started to treat all perforated appendicitis with antibiotics with the idea of being that you make an easier operation for yourself later. We have done a piloted, randomized trials on that topic a few years ago and found that they were fairly equivalent length of stay, but the early operation had higher quality of life and it wasn’t as stressful for the families. And then, a larger study taking all comers showed that there was a benefit to doing an early operation. So, some centers are starting to back away from doing primary antibiotics in patients with perforated appendicitis but the next natural question led to this concept of “Do people who have non-perforated appendicitis transition to perforated appendicitis once they start their antibiotics and can their operation be delayed?” It became pretty obvious that that wasn’t the case and, in fact, once the antibiotics started, you’re treating the disease. And so, frequently people would feel better within a day or two once the antibiotics was started. So, then there was a piloted study done on adults that showed that there were fairly equivalent outcomes, basically, a non-inferior outcome by giving antibiotics up front and, most of the time, you can avoid an operation altogether. And so, the question then goes to children where appendicitis is extremely common and, they have, obviously a lifetime risk as opposed to somebody who’s a little bit older and has medical co-morbidities and you want to avoid an operation regardless because they’re higher risk. These are fairly healthy people who have low risk of an operation. And, if you leave the appendix, then you’re going to be leaving it for life. So, there’s been several centers that have turned their attention to this and we started working with a group in Toronto as well as several groups in Europe about three years ago, on developing a multi-standard prospective randomized trial. And, the idea would be to definitively gather a cohort of patients that will answer the question, “If you treat with antibiotics alone, what are the changes of failure in one year?” And, that is the number that we need. We discussed this for a long time about how we were going to develop the study and what the sample size would be. The study is designed as a non-inferiority trial meaning, at what point would you say this is actually inferior because it obviously can't beat an appendectomy. You got 100% success rate. The appendix is out, that’s done. So, it’s not going to be superior, but it’s also not an operation. So, you’re not shooting to be as good.
Dr. Mike: Right. Right.
Dr. St. Peter: It just means you want to say, “At what point will you say this is no longer acceptable to avoid an operation?” And, my thought was, “I don’t care what we set the non-inferiority limit at. We can set it at 15%, 20%, 30%. It doesn’t matter because the number of failures is what mom’s going to care about. So, if we say it’s a 20% non-inferiority margin and it comes in at 18%, so we declare it non-inferior. Great. It comes in 22%, we declare it inferior. Great. But that 22%, to a mom who’s terrified of an operation sounds great. And, that 18% to somebody who had a horrible night the night before with their appendicitis, that’s going to sound terrible.
Dr. Mike: Right.
Dr. St. Peter: So, we just need to establish what that number is so that we can adequately counsel patients and then they can choose.
Dr. Mike: So, when it comes to this study, where are we at in terms of recruiting for this study? What are the number of children you’re going to try to get into this study? What age groups are you looking at?
Dr. St. Peter: The ultimate end is about 1000 and we’re looking at ages 5 to 16. Most kids under age 5 do have a perforation. Even if they don’t look it, they usually have it because they don’t have enough somatic awareness to tell you when they’re having a problem early on. We started with Toronto as being the primary site and, unfortunately, their center saw this as being a sponsored drug trial, even though there’s nothing experimental about Augmentin and, in fact, we don’t even control what the antibiotic is. So, you can give any antibiotic you want. Our point is just broad spectrum antibiotics versus appendectomy. And, they got into a little bit of a legal snafu and had to give up not only primary but really can't participate in the study. So, we became the primary site. So now, we’re the organizing site. We’ve enrolled 60 patients here. Stockholm has enrolled 30 and there are a handful of other sites that are up and running although they’ve all just had small numbers so far. Helsinki has enrolled close to 10 and Winnipeg, Ottawa, Calgary, Vancouver and London, Ontario, have all gotten IRB approval, but none of them have had more than five yet. So we sitting at about 110 patients total right now. And, that’s--
Dr. Mike: Tell us about the patients in the…Go ahead.
Dr. St. Peter: I was just going to say, that’s with enrollments starting in January. So, we’re about a half year into it.
Dr. Mike: So, tell us about the patients in the non-operative group. What exactly is going to be their course of treatment?
Dr. St. Peter: So, that’s another interesting evolution. Initially, we were talking about 24 hours of IV antibiotics but the fact that in the United States and in our institution, we send patients home immediately after their operation. If you see somebody on Sunday night and you say, “Well, if you’re randomized to operation, you’ll have your operation in the morning and then you’ll go home. If you’re randomized to antibiotics, then we’ll reevaluate you Tuesday morning,” no one’s going to buy that. So, we had to give the patients the opportunity or the ability to go home that first day. So, what that looks like is…
Dr. Mike: Oh, I see.
Dr. St. Peter: …they come in at 10 o’clock at night and you randomize to non-operative management, then you’re going to be allowed clear liquid diet. And in the morning, if you feel good after drinking some clear liquids, you can have breakfast. If you can eat and keep your food down, then we’re going to switch you over to oral antibiotics and send you home with a 10-day course of Augmentin. Everybody gets Rocephin and Flagyl, we use once a day dosing for both which is kind of unique, the 30 per kilo dosing of Flagyl. But, that way you’ve got a 24-hour dose onboard to begin with and that’s going to cover them throughout their next day. It allows them to get out of the hospital and transition over to oral antibiotics. Initially, I think we were a little bit more jumpy and now when somebody is still in pain post-admission day one, we usually encourage them to give it one more day because most of the time, they will transition between day one and day two and then feel better and be ready to go home.
Dr. Mike: Okay. So, just a recap. So, that’s 12 hours of IV antibiotics. If they can eat in the morning and they’re feeling better, you switch them over to oral and then they go home. As far as when you really look at this and with your experience with using antibiotics and your experience with appendectomy, I mean, what do you think are going to be the results from this study?
Dr. St. Peter: I think that we are going to replicate where some of the meta-analysis are in adults. That it’s going to be around 80% successful and it may end up having a little bit of a higher failure rate than that because of parental-driven reasons, which is okay because that’s real world. If we roll this out tomorrow and say, “This is our standard of care,” you’re going to have people that are going to continue to come back and be anxious, and you’re going to have to take out the appendix.
Dr. Mike: Right.
Dr. St. Peter: So, that’s not a false failure. I think that’s a real failure. And then, from there, it’s going to be interesting to see what the recurrence is over time. I would like to see at Mercy to get a very large cohort of patients that we could follow in perpetuity. So, I think it’s going to be difficult to do that in a multi-center fashion but if we can establish a large cohort here, then we can check it at two years and then three years and then five years and that should be the real important thing. If you start to see many failures there, then I think people are going to lose enthusiasm for this.
Dr. Mike: Right.
Dr. St. Peter: There are centers that have picked up enthusiasm for this and I can understand why now that I can see these patients back in clinic. It’s there--when they leave the hospital--they’re normal. So, even though we can do a nice, slick single incision, laparoscopic appendectomy through the umbilicus. There’s no visible scar, there’s no activity restrictions. There won't be any restrictions when you go home after a surgery. That sounds great. But, at the same time, they’re taking a little bit to recover. Sudden start/stop motions are going to hurt at the belly button for a little while. When these kids go home, they’re fine. So, if they go home on Monday, they invariably go to school on Tuesday. They go home on Tuesday, they go to school on Wednesday. And, you can't say the same for an appendectomy. You frankly can't.
Dr. Mike: Right.
Dr. St. Peter: So, when people randomize to antibiotics and they’ve got some big thing coming up, some big athletic event coming up this weekend and they come in on Thursday and we put them on antibiotics, they’re going to be fine to play.
Dr. Mike: So, the one year follow-up in the non-operative group looking for appendicitis, where did that number--was that simply just an easier follow-up timeframe to deal with in a multi-center situation? Because it does seem that the follow-up should be at some longer points here--year and a half, two years. Why was the one year chosen here?
Dr. St. Peter: Because of the multi-center randomized nature of the study. We realized that you wouldn’t be able to keep your hands around that cohort for a long time and, for the sake of the study, you’ve got to wrap it up. And so, this, of course, started with funding applications and so, we went through several rounds of funding efforts which we’ve so far not succeeded. But, just the same, as a study design, your primary outcome is established at what point and one year is about realistic for a feasible study.
Dr. Mike: So, Dr. St. Peter, you are also the Director for the Center for the Prospective Clinical Trials. Tell us a little bit about that department that you direct.
Dr. St. Peter: Yes, that started as an effort to answer questions in our field and there was just a tremendous amount of heterogeneity for the management of common conditions and so we started focusing on randomized trials in common conditions. So, when I started on staff and there was this idea of calling this effort “The Center for Prospective Trials,” my goal was to have five studies randomizing by that first summer which we ended up accomplishing. And so, since then, there’s been sort of a frame shift within the way the entire department of surgery thinks and we no longer talk about opinion very often. We talk about evidence. For instance, we just had a fellow start, and he didn’t like the idea that we use Foley catheters on our patients with perforated appendicitis. So, I said, “We don’t hypothesize here. Go ahead and write up a prospective protocol and make some very strict criteria for who does get a Foley. Everybody else doesn’t and we’ll look at the failure rate and answer your question.” And so, we have completed 15 randomized trials that have gone to print and we’re currently conducting four at the moment, and this is our flagship study at the moment--the antibiotic trial.
Dr. Mike: Well, Dr. St. Peter, I want to thank you for coming on the show today. Thank you for the work that you’re doing at Children’s Mercy. You’re listening to Transformational Pediatrics with Children’s Mercy, Kansas City. For more information, you can go to www.childrensmercy.org. That’s www.childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.