SCCM Pod-489: The AIMS Trial: Battle of the Bundles, Hour-1 Versus 3-Hour

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The Assessment of Implementation of Methods in Sepsis and Respiratory Failure (AIMS) Study seeks to determine the safest and most effective approach to sepsis intervention using the evidence-based Surviving Sepsis Campaign guidelines. Marilyn N. Bulloch, PharmD, BCPS, FCCM, was joined by Mitchell M. Levy, MD, MCCM, at the 2023 Critical Care Congress to discuss the goal of the AIMS Study and the elements of both the Hour-1 and 3-Hour bundles. Dr. Levy is chief of the Division of Critical Care, Pulmonary, and Sleep Medicine and professor of medicine at the Warren Alpert Medical School of Brown University. He is also the medical director of the medical ICU at Rhode Island Hospital in Providence, Rhode Island, USA.

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Transcript:

Dr. Bulloch: Hello and welcome to the 2023 Critical Care Congress edition of the Society of Critical Care Medicine podcast. I’m your host, Marilyn Bulloch. Today, I’m honored to be joined by Dr. Mitchell Levy, MD, MCCM, to discuss the AIMS Trial, Hour-1 versus 3-Hour bundle. Which bundle will win? Dr. Levy is chief in the Division of Critical Care, Pulmonary and Sleep Medicine at the Warren Alpert Medical School at Brown University, where he’s a professor of medicine. He’s also, in his abundant free time, the medical director of the medical intensive care unit at Rhode Island Hospital in Providence, Rhode Island. Welcome, Dr. Levy. Before we start, do you have any disclosures to report?

Dr. Levy: I have some NIH funding from a T32 and my recent R01 that we’re about to talk about, and I’m on the advisory board of Inotrem and Endpoint.

Dr. Bulloch: Thank you for letting us know that. I read the AIMS trial overview on clinicaltrials.gov. It looks fascinating. I think it’ll provide us a lot of good information. It’s got a little bit of a different design to it. It’s a hybrid type 2 implementation setting. What is that, for people who may not be familiar with that design?

Dr. Levy: It’s a great question. A hybrid type 2 implementation effectiveness trial is a combination of the implementation science aspect and effectiveness aspect. The three aims, if you will, of the study: The first aim is to improve implementation in general of the SEP-1 bundle, that’s the 3-Hour Sepsis Bundle.

The second aim is to compare the effectiveness of the Hour-1 Bundle versus the 3-Hour Bundle. The Hour-1 Bundle we published in 2018 in Critical Care Medicine; it was founded on the idea that antibiotics are already recommended within the first hour. We already recommend, if patients are hypotensive, that we start fluids within the first hour. We recommend that you get lactate as soon as you see a patient. We realized in the Surviving Sepsis Campaign Steering Committee, “Gee, why aren’t we just making this, as soon as you see a patient and you suspect sepsis, just give them all of the elements of the bundle?” That was the genesis of the Hour-1 Bundle.

The final aim of the study is, Chris Seymour is one of the co-investigators on the trial, and we’re going to use Chris’s data that he published in JAMA to generate phenotypes because the idea would be, Okay, let’s see, first and most important is Hour-1 versus 3-Hour bundle. Second is improving compliance overall with the 3-Hour Bundle. Third is, what if there are a couple of phenotypes that specifically respond to bundles more than the others? So it seems like that would be hypothesis-generating, so that the next trial would be, Okay, maybe it’s not Hour-1, maybe generate the phenotypes first, and then that will put us in the ballpark of perhaps 1) phenotype or 2) respond preferentially more than the others.

Dr. Bulloch: That’s fascinating to me. I remember back when I was a resident, one of the first things I heard at a critical care congress like where we’re at is that, in the ICU, we have to not only practice evidence-based medicine, but we have to practice evidence-based individualized medicine. That’s something I’ve tried to share with my medical and my pharmacy students since then. So the fact that some of that data may come out of this trial I think is really beneficial to us in our world.

Dr. Levy: Yeah, I think that’s exactly right and I think this idea that one size fits all, none of us really believe that one size fits all, right? But the idea behind the campaign and behind SEP-1 is, how about a minimal dataset? Now, if we can find that that minimal dataset works better in certain populations, that’s even better.

Dr. Bulloch: Let me ask you this. The 3-Hour Bundle has been adopted by lots of regulators. Before the current version of the guidelines came out, we were all teaching and at least clinically going, “I know this is what the regulations say, but use the 1-Hour anyway for outpatient outcomes.” Where did the idea come practically in terms of comparing the two now?

Dr. Levy: That’s a great question. Honestly, there was a huge uproar from the emergency department community. If this were not a podcast, I would show some of the slides, there are a couple of ED bloggers; we’ve been compared to the Death Star, what is it, less fake news, more real news.

Dr. Bulloch: I’ve seen some of those blogs.

Dr. Levy: It’s kind of funny, right? I mean, I’m flattered in a certain way. But the ED community, and I think, understandably so, because the ED community, because the 3-Hour Bundle was adopted by CMS as national mandated metrics for SEP-1, they rightfully worried, “Oh, boy, so now is the Hour-1 bundle going to be adopted by CMS? Are we just on a slippery slope so that we’re never going to be compliant?” I think that’s what empowered us to write the grant. I also think, honestly, that’s the case we made in the grant to NHLBI that this answer is really needed, because, is Hour-1 Bundle better? Is it 3 hours? Can we achieve Hour-1? I think it’s a really important question.

Dr. Bulloch: You bring up a good point in terms of emergency medicine. Sometimes I feel like they’re stuck with the core measures and they’re just trying to help the hospital survive. We’ve seen other core measures, pneumonia, an antibiotic one where everybody got antibiotics. You got heart failure, but you had shortness of breath, you’re going to get an antibiotic. So these could have very big downstream effects, which I want to talk to you about in just a little bit. But first, you’re studying in the AIMS trial specific to the emergency department, you’re not studying people who get septic on the floor or anywhere else. How did you decide, let’s just focus on the emergency department?

Dr. Levy: Yes. We published in the New England Journal, Chris Seymour was the lead author, I was the senior author, just emergency department patients in the New York State database. I think it was like 70,000 patients, we used that. These are patients who had the 3-Hour Bundle and we looked at those patients. We said, “Okay, what happens when they are compliant with all the elements of the bundle within 1 hour?” We were able to demonstrate a pretty significant survival benefit. We felt it is much more challenging to identify time zero, the moment someone gets sepsis. Now it’s sepsis; it used to be severe sepsis. When does that happen on the wards? And is it really just based on a chart? Especially because there are alerts that key in on two out of four SIRS, we thought it would be easier to identify the patients in the emergency department rather than in the wards or in the ICU.

Dr. Bulloch: Do you think the data will still be able to be extrapolated to those patient populations? Or do you think we’re going to have to do an AIMS 2 trial or something?

Dr. Levy: That’s a great question. No, I think they’ll be able to be extracted. The challenge is, as I just said, identifying those patients. I do think, if we can demonstrate that when someone walks in the door of the emergency department, if you give them all of the bundle elements in 1 hour versus 3 hours, and it’s more efficacious, statistically significant, then I think a lot of people would make the case, “Well, then we should be doing this on the wards and in the intensive care unit.” There’s nothing specific to ED patients versus wards versus ICU other than they just don’t get recognized as quickly. But I do think that the impetus would then be to identify these patients more quickly.

Dr. Bulloch: I think that’s going to be a good conversation to have once the trial is over because sometimes people get so focused on the study environment and the exact patient population that they forget how to extrapolate data to other avenues. But you did make a very good point, that there’s really not that much difference in terms of when they develop sepsis and the pathophysiology behind it. One of the things that we struggle with where I live, I’m sure you probably do too, is compliance. Compliance nationally when CMS reports is, what, around 60%? It’s not great, and that’s probably much better than before CMS said you had to do it. So I imagine there’s going to be some research challenges, particularly with the individual study sites. What kind of challenges do you anticipate and how are you going to overcome those?

Dr. Levy: It’s a great question and, honestly, even in my own hospital right now, we’re trying to figure out, how do we get clinicians to just accept the SEP-1 bundle? There’s always a reason not to give it. “Oh, this patient has end-stage renal disease.” “Oh, this patient has cardiomyopathy and I’m not really sure that they have sepsis.” Whereas a lot of the third-party payers, like Blue Cross Blue Shield and others, are actually now making the SEP-1 bundle part of their performance measures so that there will be a holdback for hospitals that are not in compliance. We also know that SEP-1 is being incorporated into the value-based purchasing arm of CMS, which means, before they were just doing mandated reporting but now they’re going to do pay for performance. So people are going to have to figure out how to improve compliance.

Part of the problem is, look, if you really think this bundle, these fluids, these antibiotics, are going to hurt your patient, don’t give them. But if you’re doing it routinely and, there’s always an excuse not to give fluids and there’s always an excuse not to give antibiotics, you have to second-guess yourself because the question is, I think the data really support the use of the bundles and that’s why CMS has adopted the bundles. So if you’re constantly making an excuse why you don’t want to give fluids or antibiotics, you have to question yourself a little bit.

Dr. Bulloch: Obviously, somebody who doesn’t passionately believe in fluids or something like that probably won’t participate. But the ICU’s a big team, there are a lot of people involved. How are you going to overcome that at the individual sites?

Dr. Levy: I will tell you that, just using my site as an example, and we’re one of the sites in the trial, we track our compliance on a regular basis. In my division, pulmonary critical care and sleep, we have a certain amount of support that comes from the hospital and $100,000 of that support is held back and we have to apply quality indicators to that $100,000 holdback every year. We’re now talking about doing the same thing for every division, whether it’s pulmonary critical care or surgery, because the failure modes, they’re in the neurocritical care unit, they’re on the ward, so we are about to embark on holdbacks for physicians so that they don’t really have a choice but to comply, and their salaries could depend on it. I honestly feel like the data strongly suggest that if your compliance is higher, more people survive. Therefore, I think we have to hold physicians accountable for their performance.

Dr. Bulloch: What about the other disciplines? I’m a pharmacist, for example, and I passionately believe in timely administration and stuff. But I know that sometimes I train physicians and sometimes it’s not their fault. Sometimes they write the orders and it doesn’t get done or it’s hard to get other disciplines to give the fluids in time or to get the antibiotics in or to get the lab to get the lactate reported. How do you overcome that kind of stuff?

Dr. Levy: That’s a really great question because what we can do is start to track, where are the failure modes? That’s a pretty traditional implementation science aspect, which is, “Okay, we’re trying to achieve five elements, let’s say, and where are the failures?” You have to write the order, then the nurse has to administer the antibiotic, then the nurse has to administer the fluids. Where are the failure modes? What’s the time between writing the order and administering it? Those are the kind of things that we’ll start to study during the trial.

After the baseline data collection phase, there is the implementation phase, which is, each arm will be randomized to either Hour-1 or 3-Hour and there’ll be two collaborative phone calls per month. We will then give each site information on their performance, and that will be the subject of these calls, which is, Okay, you’re failing the antibiotics. Where are the failure modes? Let’s look at how long it takes from writing the order to getting the antibiotics administered. If it turns out that it’s really the time it takes from after the order is written to it being started, that’s completely different than not writing it. Same thing for fluids. If it turns out that you just don’t have the right fluids in your emergency department, you write the order, but they’re not available, then that’s what needs to be addressed. We’re hoping to target where the failure modes are and then move to improve it.

Dr. Bulloch: That’s such an important piece. I feel like sometimes it’s missing when the people who have to report this to CMS and extrapolate it, they don’t get that. They just say, “Well, we’re not doing this and we never go back and look at the why.” I think that piece to me sounds like not only just a research part, but good quality assurance and background, so I’m happy to hear that.

Now we’ve talked a little bit about this, but I’m hoping maybe you can take it one step further. CMS adopted this, almost around the time that we initially got rid of SIRS when we went to qSOFA or new guidelines came out, and CMS is a lot slower to change than we are. Then, of course, a lot of us know about New York and the making it part of the wall. What do you think and, again, this is kind of speculation, the potential regulatory implications could be from research like your study?

Dr. Levy: If it turns out that Hour-1 is more efficacious than 3-Hour, I mean, it’s too soon to say, but I would imagine that if it turns out there’s no difference, then SEP-1 will stay the same. I think that if it it does turn out that administering all of these things within 1 hour makes a difference in terms of mortality and respiratory failure, then we’re going to be hard-pressed not to change the SEP-1 to 1-Hour. I say that with trepidation just because I know how nervous it makes people. But remember it’s two out of four SIRS, organ dysfunction, and a physician noting that there’s sepsis. That’s what creates time zero in CMS. In a lot of places that have Epic, when you write the order for antibiotics, it says, “Where do you suspect the infection?” That will count as a physician notation of suspected sepsis. So if I write amoxicillin and it comes up and I write skin, that’s a note already. I think this process is going to encourage people to be more compliant with identifying time zero more rapidly.

Dr. Bulloch: We’ve talked about the quality assurance piece with it, which maybe as a practical standpoint, I think if that were to happen in SEP-1, we’re going to have to move to the 1-Hour Bundle. The data that you’re collecting on, where were the holes, where did things fail, I think it’s going to be even more valuable to the everyday hospital out there that’s just struggling to do the 3-Hour Bundle right now. Now, let me ask you this: What if there is no difference? I know we have a lot of data on the 3-Hour, but I can hear critics saying, “Well, does it really have to be 3 hours? Could we push it back a little bit?” Is there any thought about that down the road?

Dr. Levy: I think that’s a fascinating question. If the Hour-1 versus 3-Hour trial is negative, will people now say, “Well, then we should wait until 6 hours?” Honestly, the data are pretty clear in the literature that the sooner you do compliance, the better. I just showed it in this talk that I just gave here, which is, the odds ratio of dying goes up in a linear fashion for every hour delay. Just think about it from a practical point of view, what would you want for your loved one? You would want to know that we’re going to give you the antibiotics, fluids, get a blood culture as soon as possible. That’s what the origin of the Hour-1 is. So I think people are going to be hard-pressed to say, “Well, since 1 versus 3 didn’t make a difference, let’s wait until 6.”

Dr. Bulloch: Now, I know this is going to be a little bit hard and this may not be an aim at the current moment. But again, assuming that maybe there’s no difference, I have always felt, and the literature supports it, the sooner you get antimicrobials in, the better. I say antimicrobials because I like viruses and I say that, so not just antibiotics. But the patient is more likely to get better, their mortality goes down. But if there’s no difference between the two, is there any plan to look at the individual components to see if maybe there is a difference among those?

Dr. Levy: Yeah, inevitably we will. We have them as secondary outcomes so certainly we will look at that and also bacterial versus viral, right? There’ll be a lot of papers that will come out of this that will look at subpopulations of patients. I will tell you that when we looked in the past and tried to say, “Well, what about four out of six,” we’ve never been able to find a combination that has a louder signal than all-or-nothing compliance. It’s hard to get all-or-nothing compliance because you’ve got to do all the things in the right order. But we’ve never been able to find, “Oh, well, if you give antibiotics and fluids, it doesn’t matter what you do otherwise.” We’ve not been able to find that.

Dr. Bulloch: That is very interesting. All right, my final question for you. This is something that obviously is on everybody’s mind, not only just because we like sepsis, we’re critical care practitioners. Even those who don’t love sepsis, the government is telling us we have to think about this. When are we going to know more? When will we have these data?

Dr. Levy: When will we have the data? We finish the baseline data collection, June 30, 2023, then we’ll start a 30-month implementation phase, then we’ll do another six months of data collection. So, 30 months, it’s going to be probably 2025 before we get the results of this trial.

Dr. Bulloch: We’ve got a little bit of time to wait. Maybe we’ll hear some trickles between there, I don’t know, you may have it locked up pretty good.

Dr. Levy: I think so. I hope so. It’s a randomized control trial.

Dr. Bulloch: All right. That’s my last question for you. But before we go, I just want to give you an opportunity. Is there anything else you want to say about this trial for our listeners?

Dr. Levy: I’m very excited that the NHLBI funded the trial. I think a lot of us, just as you’ve said, Marilyn, really want to know the answer to this. I’m excited to be able to answer it. We’ll see.

Dr. Bulloch: That’s great. Well, thank you so much for being here.

Dr. Levy: My pleasure.

Dr. Bulloch: This concludes another edition of the Society of Critical Care Medicine Podcast. For the Society of Critical Care Medicine Podcast, I’m Marilyn Bulloch. Thank you for joining us.

Maryland N. Bulloch, PharmD, BCPS, FCCM, is an associate clinical professor and director of strategic operations at Auburn University Harrison School of Pharmacy. She is also an adjunct associate professor in the Department of Family, Internal and Rural Medicine at the University of Alabama in Tuscaloosa, Alabama, USA, and the University of Alabama Birmingham School of Medicine.

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