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Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
Communicable_E058_HAPPEN_trial
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[00:00:00]
Angela: Hello and welcome back to Communicable, the podcast brought to you by CMI Communications, ESCMID's open access journal covering infectious diseases and clinical microbiology. My name is Angela Huttner, and I'm the editor-in-chief of CMI Communications.
And an infectious diseases physician and clinical trialist based at the Geneva University Hospital in Switzerland. I'm joined by my co-host, Josh Davis, infectious diseases physician and clinical trialist based at John Hunter Hospital and the University of Newcastle in Newcastle, Australia.
Josh, hello.
Josh: Hi. Hi, everybody. glad to be back. Today, we're excited to be joined by three guests who are experts in an area we've not really covered on this podcast before, and that's clinical trials in infection prevention and control. I guess also cluster trial designs. I'm not sure if we've talked about them before.
But we'll be discussing two recent trials on [00:01:00] prevention of hospital-acquired pneumonia, and we may be referring to it just as HAP from here on. So if you hear someone say HAP, we're talking about hospital-acquired pneumonia. So the trials are the HAPPEN trial, which was presented at ESCMID Global in Munich in April this year and just published in Lancet ID.
and then also a hybrid implementation effectiveness trial, which was performed at a hospital in Zurich. And if we wanna refer to that one for short, we'll call it the Zurich trial. that one was published in twenty twenty-three, also in Lancet ID.
Angela: First, I'd like to introduce Aline Wolfensberger, an infectious diseases physician and hospital epidemiologist at the University Hospital of Zurich, with a second affiliation at the Institute for Implementation Science in Healthcare, also at the University of Zurich. she's also a member of Swissnoso, the Swiss National Center for Infection Prevention, where she is the lead for national NV-HAP surveillance and prevention projects. And just [00:02:00] a note, NV-HAP stands for non-ventilator associated hospital-acquired pneumonia. Welcome, Aline.
Hello.
We're also joined by Aline's colleague from University of Zurich, Lauren Clack, Who is an assistant professor of implementation science in healthcare and director of the Institute for Implementation Science at the medical faculty.
Angela: She's also affiliated with the Division of Infectious Diseases and Hospital Epidemiology at the university hospital. Welcome, Lauren.
Lauren: Hello. Thank you for having us. It's a pleasure to be here.
And then finally, we're joined by my friend and colleague and fellow Aussie, Brett Mitchell.
Josh: Brett's a professor of infection control and a clinical trialist from Avondale University and the University of Newcastle, which are both in New South Wales in Australia.
Well, good day everyone. Thanks for having me.
So as our listeners know, we start these episodes with a get to know you question. I was scraping the bottom of the barrel for the question this time, 'cause we've talked about books, movies, and other stuff, but today the question is: what would [00:03:00] your 20-year-old self be most surprised to learn about you today?
Josh: and I'm going to ask Brett to answer that one first.
I think, for me it's probably that I'm a reasonably sensible adult and that there is other drinks other than lager that exist.
Angela: Nice. Now we have an image, Brett.
Aline
Aline: Yeah. At that time when I was 20, I was just starting medical school, and probably I thought I'm gonna be a physician who do the spectacular things like saving lives in dramatic situations or treating rare diseases.
And now I'm 25 years later, I'm would be probably surprised to learn that I have become a physician who is most passionate about prevention, and I end up promoting seemingly simple things like hand hygiene, toothbrushing, or getting patients out of the bed.
Yeah, but this is still literally being a hero and saving lives.
Angela: Come on. That's what we're here to talk about today. you just didn't know a toothbrush was [00:04:00] actually, the killer weapon ...
Aline: it doesn't sound so spectacular anymore.
Angela: But see, that's why we're here. We're a bunch of, like, medical science nerds, like, to explain to people that this is actually how you do amazing things, right?
Lauren, you're up next.
All right. So, you know, I was thinking growing up, my dad was a little bit of a germ freak
And so I was taught from a very early age to, , use the, tissue paper to open doors and things like that. And so probably it would not be a surprise then that, that I ended up working in the field of infection prevention, that a lot of our projects are infection prevention.
Lauren: But surprisingly, that is limited to my professional life. So at home, actually today, I'm not at all a germ freak. quite the contrary, I don't believe in the five-second rule. It's the, you know, five-hour rule. And I'm really am not concerned with, germs in general outside of the hospital setting
Angela: Nice. A total [00:05:00] rebellion. You're such a wild child, Lauren.
Josh, you're up.
Yeah. Okay. mine's not really work-related. The one that sprung to mind is when I was that age, when I was 20, I hated running. I thought running is the dumbest thing. I didn't know why people would do it, and I also wasn't that into sport, like watching it or playing it. and I, hated football.
Josh: Anyway, now I love running, and I love Australian football, AFL, Sydney Swans. I'm obsessed with both of those things now. So I would've absolutely not believed you if you had traveled back in time and told me that when I was 20.
Angela: wow. I wouldn't believe that that was your 20-year-old self because I see you on Strava, and you've been running again. Yeah. You're the baseline. You know
Josh: what they say, late converts are the worst zealots, right?
Angela: Mm-hmm. Mm-hmm.
Josh: okay, Angela, what about you?
Angela: Oh, yeah, Josh, you've picked the toughest questions. I think my answer has to be literally everything. Like, everything about me now is not what I thought would have happened when I was 20.
Like Being a doctor, living in Geneva, this [00:06:00] isn't what I had thought at 20.
At 20, I was more, history and literature and, just after 20, I made a big change.
Josh: the message to all our 20-year-old listeners out there, of whom I'm sure there's heaps, you never know- Yeah ... what your, what direction your life's gonna go in, so get excited about the future.
Angela: So we've got three lovely guests today.
Brett, first question is for you. how did you end up working with Lauren and Aline?
Had you all already worked together before? What's sort of the origin story of the HAPPEN trial?
Brett: we haven't really formally worked together, on any project yet, but we've spoken. So I guess the origins for the HAPPEN trial were at conferences for the last 10 years, point prevalence studies have been presented showing that pneumonias are the most common infections.
It gets repeated time and time again in point prevalence studies in Europe, the US, and Australia, and they always ask the question, "So what are we actually doing about it?" It's like collecting data and doing nothing about it, and it's like beating your head up against a wall. I [00:07:00] would get up and ask the question at times, "So we found this again, what are we doing about it?"
And, I think there were similar voices by similar people asking similar questions to this. and so I think it was just coincidental. I actually heard Victoria Ewan talk at a conference a few years ago. She gave a great talk about the biological plausibility of, microaspirations as it relates to NV-HAP, and also argued the point we need to be doing something about it.
And so the HAPPEN trial came about after I think 10 or 12 grant applications, unsuccessful grant applications, to try and get funding to do this trial. Eventually, we did, and coincidentally, Lauren and Aline's trial happened concurrently, just it was probably about 18 months ahead of us. And so ours was planned and developed and funded by the time their trial, I think, was just getting published.
So, and then we started the conversation, particularly Aline and, myself and Martin Keenan and others about, what we could learn. so I guess that's the origins of this. For me, it was common infection. We've got to do something about it. I can't believe we're not doing things about [00:08:00] it.
and we just gotta try some things.
Angela: Wow. Hats off. And listeners, please note, 10 to 12 attempts at funding, failed attempts, and yet you're still here. You did it. Thank you so much. It is so hard. Thank you. but you stuck it out.
Aline. Can you just tell us what is HAP and why should we care about it?
Yes. so HAP is pneumonia that develops during a hospital stay and was not present when a patient was admitted.
Aline: So by definition, first symptoms start two days after admission earliest. When people talk about HAP, most people probably immediately think about ventilator-associated pneumonia and intensive care. but actually the larger burden comes from pneumonia that affects non-ventilated patients. So these, NV-HAP or non-ventilator hospital-acquired pneumonia occur in patients mostly on regular hospital wards, but of course also on ICUs or intermediate care units.
Why we should care is, because HAP is one of the most common and most [00:09:00] serious healthcare-associated infections. It's associated with increased morbidity, with increased mortality. It prolongs hospital stay, and it, is associated with substantial healthcare costs. and there is a great, European burden of disease analysis by Cassini and colleagues that identified HAP, so both ventilator and non-ventilator-associated pneumonia, together as the healthcare-associated infection that is associated with the greatest disease burden, from all HAIs, measured in disability-adjusted life years.
Aline: still HAP has historically received little attention. Prevention efforts of us IPC people usually focused, on device or procedure-associated infections. So patients at increased risk of, HAP are typically older, frail, multi-morbid people, with impaired mobility, poor oral hygiene, dysphagia, or aspiration risk.
great answer, [00:10:00] Aline. So it sets the picture nicely to why we are thinking about prevention and what we can do to prevent it. So, Brett, can you summarize for us the HAPPEN trial design, please first- Yeah ... and then I'll ask you about the results later on.
Brett: Yeah. Okay. and just as a, follow-up from, Aline's commentary there
there's still a lot to do in this space. it's amazing that not much has been done given the burden and given the frequency and impact of this infection.
So that was a real driver for why we wanted to do something about that and, what we did in the HAPPEN study was a multi-center stepped wedge randomized controlled trial. conducted in three Australian hospitals, two publicly funded hospitals, one privately funded hospital.
Bed ranges from sort of four hundred to nearly a thousand in those, across those three hospitals. the trial was conducted over 12 months, and the trial starts with, all the clusters in those, hospitals commencing in the control phase. So we had nine clusters across the three hospitals, so three [00:11:00] clusters in each hospital.
and sequentially, three each, so every ward or a ward would transition from a control to an intervention phase every three months. So as the study progresses, you end up with more people, the more clusters in the intervention phase, and by the end of the study, all of the wards or clusters in this instance were, in the intervention phase.
The clusters in the study were, wards that were typically at high risk of patients who would acquire NVHAP, so general medicine, elderly stroke units, and those that, have those risk factors that Aline identified, earlier. and our intervention was to try and improve, the frequency and quality of oral care.
and we achieved that through, all patients who were admitted to the ward being given a pack, and in that pack was a toothbrush, toothpaste, and information about, resources, so this is part, uh, patient-focused. that was developed in this part of our preliminary work where we identified barriers to performing oral care with both nursing groups and with patients themselves.[00:12:00]
Brett: The toothbrush had a little prompt on it to prompt, patients to brush their teeth, and that was an idea that came up with from patients themselves. and then on the clinician side of it, we also provided education to the nursing staff on the ward about the importance, provided them with, just-in-time resources, so a website that allowed them to, find out how to do certain procedures in certain tricky situations when it came to oral care.
to refresh their knowledge on certain things. and that was the main intervention that we undertook for the trial.
Josh: And Brett, so just to clarify with this stepped wedge design, it's still randomized, right? But what is randomized is the order in which each ward starts the intervention and the time when they do it.
Brett: that's correct. And most stepped wedge designs, they're generally, used in, I guess, when you're introducing a new model of care or health services-based research. And so it's very difficult to blind, participants in that kind of environment, and we were unable, for obvious reasons, to blind participants to this study.
what we were able to achieve is, blinding the person who was collecting, [00:13:00] or persons collecting data, on the outcomes of interest, NVhap and others, because when they were reviewing medical records, they were unaware of, that allocation of whether the person was in a ward that was either an intervention or a control.
so we were single-blinded in that sense, but, very difficult to undertake a double-blind, design in a stepped wedge randomized control trial
Angela: Yeah. You have a great figure in the article. That nice layout of how these clusters were randomized, in a sequential fashion.
I just think we need to stop and behold the stepped wedge trial. It's just such a great design. It's so practical and yet gives good, reliable information. It's still randomized. It's so pragmatic, maybe you have limited resources, it's such a great thing to be able to do as you're gonna implement something anyway, right?
Yeah. I think that the advantage, of course, with the stepped wedge is obviously everybody ends up in the intervention. Mm-hmm. So it aids the implementation of something for ongoing use. Right. Like, [00:14:00] there are some, other limitations. You know, contamination's always something to have to try and manage in stepped wedge designs when you think about are there gonna be contamination, of the intervention between the clusters.
Brett: And so that can- be minimized if there's not much patient movement, or if the intervention's gonna be very targeted, or if the clusters are at a larger level, like a hospital, sort of level, I guess. the other challenges are around secular-related, issues with data and trying to account for those in analysis.
So those are some of the challenges and some of the limitations that, stepped wedge designs have and probably why some people feel, in some instances, a little bit less willing to accept stepped wedge designs as opposed to parallel, RCTs.
Angela: Yeah. I think the gold, gold standard would be indivi- individualizing at the patient level every time. and then of course, cluster randomize But I think stepped wedge is sort of the link between theory and real life. It's right there in the middle between the two.
It's just a clever way of, capturing really important information when you're gonna do something probably [00:15:00] anyway, right? And I think people do need to accept a bit of imperfection. You know, we don't live in a laboratory, right? No. Patients don't. You can't always control circumstances, and it's a lovely way, I think, to study while doing,
Brett: And infection prevention control, it's very difficult to, in most instances, to do individual patient randomization. think about the things like hand hygiene or environmental cleaning. you can't randomize at an individual patient level quite often for those things. So , the cluster design more broadly lends itself nicely to infection prevention control research when you need to do something in a randomized way.
Angela: So Brett, what was the primary outcome, and what were some, you know, highlighted secondary, tertiary outcomes?
Brett: Our primary outcome was NV-HAPS, so non-ventilator associated hospital acquired pneumonia.
and we measured that at both the cluster level and at the individual patient level. and our secondary outcomes were a composite outcome of lower and upper respiratory tract infections combined.
we also had, ear, nose, and [00:16:00] throat, oral cavity infections as a secondary outcome. And in addition to that, the proportion of oral care provided on any given day to a patient was another outcome. We had a tertiary outcome combining NV-HAP, ear, nose, and throat infections, upper and lo- lower respiratory tract infections as well, but, that wasn't, as part of our primary outcomes or secondary outcome.
Josh: So you said, Brett, the primary outcome's HAP. What do you mean, the incidence of it? how do you express that?
Brett: Yeah, we expressed it, in two different ways. and it was interesting that we want to do that because, when you're thinking about a cluster RCT, you can express it, as a hazard ratio, and I guess as an incident rate ratio.
And so, we wanted to express it both at the cluster level, so if you were to introduce this to a cluster, what would be the risk, and also at the individual, patient level. So essentially a hazard ratio and an incident rate ratio.
Josh: Okay. now we know what the trial was.
Drum roll. Did it work? Did your [00:17:00] intervention work? What did the results show?
Brett: Yeah. So what we found was that improvements in oral care were associated with reductions in our primary outcome, NVHAP, and, the hazard ratio was 0.4, with the 95% confidence intervals from around 0.2 to around 0.8.
and the incident rate ratio, it's massive, massive reduction. the incident rate ratio, was 0.41 per 100 at-risk admission days and, the 95% confidence intervals were similar, 0.2 to 0.85 essentially. so again, regardless of whether you look at the cluster or the individual patient level, there was really huge reductions in the primary outcome, for this study.
what we didn't see was reductions in our secondary outcomes, so lower or upper respiratory tract infections and EENT or those ear, nose, throat cavity infections. there were non-significant changes, to those types of infections.
Josh: Great. Yeah, that's a, huge effect size, isn't it?
and I guess with even using frequentist, you know, p-value of 0.05 type [00:18:00] cutoffs, it's significant, right? 'Cause those 95% confidence intervals don't cross one.
Brett: Yeah. And look, those sort of reductions, we have been seeing in aged care, with some of the RCTs that have been done in aged care for improving oral care.
Some of the outcomes are slightly different. They're looking at different types of pneumonia, or cause, fatal pneumonia admission to hospitals, performing pneumonia. but essentially those, reductions were similar in some of the RCTs that have been conducted in, nursing homes.
There was also one other, cluster randomized control trial done in a, single site in the US and, it was a smaller study. and they also saw similar reductions in their trial as well, and their, primary focus was oral care in that study as well.
Josh: let's park the HAPPEN trial for a bit, and we'll come back to it, and talk about it in the context of, the other trial and, what they both mean.
So Aline and Lauren, the main paper reporting your trial is titled A Type 2 Hybrid Effectiveness Implementation Trial. So what does that title mean? What does that, trial design mean?
Lauren: [00:19:00] Right. So hybrid effectiveness implementation trials, mean that essentially we are asking questions about the effectiveness of a clinical intervention, but also questions around how to implement it and what are the most effective implementation strategies in order to support the introduction of the clinical intervention.
And when you think about the way that we, you know, traditionally tend to do research, first, we want to know, does something work? And then only once we've demonstrated that it works, then we think about, okay, well, how do we do this? You know, how do we then introduce this in practice? How do we scale it up?
And questions around this. And one of the challenges that the field of implementation science tries to address is that this leads to really long legs between knowing that something is effective and actually seeing that implemented into practice. And so these hybrid trials [00:20:00] that ask questions about the effectiveness and implementation in a parallel process, the idea is that by doing that, we're trying to improve but also accelerate research translation.
So hopefully by the end of a hybrid trial, we have insights about is the clinical intervention effective, but also why and how, and in doing so, hopefully generate some insights that will help others to also implement those kinds of interventions. And I think a really nice example that we often cite is the group of studies from the Pronovost trial, the bundle of interventions to prevent catheter-related bloodstream infections, which was a huge success in Michigan.
Yeah.
Josh: It's, uh, we don't think about enough as clinical trialists, the implementation side of things. and for listeners who are interested to learn more about the trial design, we'll put a link in the show notes to, a recent article that, I think you wrote, Lauren, right, explaining these trial [00:21:00] designs.
so can you tell us about the, design of your trial now?
So together with colleagues from the University Hospital of Zurich, we wanted to address that there's not a lot of evidence around the clinical measures to prevent healthcare-acquired pneumonia, and specifically the non-ventilator-associated healthcare-acquired pneumonia.
So on one hand, we wanted develop and test the clinical bundle, which was composed of oral care, dysphagia screening and management, mobilization, discontinuation of non-indicated protein pump inhibitors, and respiratory therapy. And at the same time, we wanted to develop and evaluate an implementation strategy, which is around how do we make sure that those clinical interventions are making their way into practice.
Lauren: And the approach that we took, was to identify, in each participating department, people that we called delegates. They were local implementation teams, and they were really responsible for guiding the [00:22:00] implementation in each of their wards. And the idea was that they had kind of a tailored approach, we knew that there needed to be elements of education and training and changing the infrastructure to support the implementation, but we really wanted them to take the lead.
We didn't want the perception to be that this is kind of an infection prevention project and it's somebody else's business, but we wanted them to take really local ownership around how do they want to go about approaching the implementation in their wards. And so from the study design on the effectiveness side, we had this quasi-experimental, non-randomized stepped wedge design.
And from the implementation side, we used a longitudinal mixed methods approach where we were using interviews and observations and also some surveys to understand what was happening, from the implementation side of things. one last element that I think was really important for the methods in this trial is that we had a formative evaluation, [00:23:00] meaning that even as the trial was ongoing, we were continuing to do observations and, talk to people about how the implementation was progressing.
in doing so, we were able to identify some things that we needed to adapt on the go from the implementations perspective.
Angela: You're laughing, Lauren. What were those things?
Well, Brett mentioned the role of patients. and we had already identified at the very early stages of the project that patients play a really important role.
Lauren: But in, the implementation strategy that we had planned, we did not, for example, have patient-facing implementation strategies. And so that was one thing that we needed to go back and adapt. And another important group that we had forgotten was housekeeping, who were delivering straws to patients or delivering food to patients laying flat in bed, and of course, increasing the risk of aspiration.
And so even though we thought we had a really complete, approach to implementation, we had the physiotherapists on boards, the nurses on boards, the physicians from [00:24:00] each participating department. Even so, we had kind of overlooked some important groups. And so through this formative evaluation, we were able to capture some of those things and then course-correct from the implementation side.
Wow, that's brilliant. Yeah, now it sounds so obvious, but housekeeping, of course. we don't usually include them in our designs.
Lauren: Yeah.
And that's what's kind of so delightful, I think, about the hybrid effectiveness implementation studies is that it's inherently part of the study to capture those things and also to report them. Because I think, , when you look at the New England Journal or The Lancet publications, often , you have a limited number of words, and you- Yeah
really focus mainly on the clinical aspects of things. and we're laughing about it, seemingly obvious, things can make such a difference to the actual implementation success. So that's why I really enjoy this kind of study.
Angela: It sounds like some humility makes you go a lot farther too.
Josh: what was the primary and secondary outcome measures for the [00:25:00] trial?
Aline: our primary outcome measure was NVHAP incidence rates. We defined that according to the ECDC Surveillance definition criteria.
In our hospital we have a semi-automated surveillance for NVHAP, so we applied the surveillance. and secondary outcomes from the clinical side was in-hospital mortality. I maybe can also already tell the results of, these, clinical effectiveness, arm. So the main finding was very encouraging.
We also found a significant reduction in NVHAP, incidence rates. So from the baseline incidence, rate of one point four cases per thousand patient days, we decreased to zero point nine cases per one thousand patient days during the intervention period. And, the adjusted incidence rate ratio was zero point six nine.
So we basically were able to reduce approximately one-third of the NVHAP rates. We were not able to see a [00:26:00] significant results when we analyzed, the mortality, probably also because we were underpowered for this, endpoint. as Lauren said, there was also the implementation arm of the study.
There we measured implementation success, so this was a, a score, that we came up, composed of four implementation outcomes that are often measured in implementation, directed studies, and we chose the acceptability of the intervention, so the acceptability of our prevention bundle, the perceived appropriateness of our bundle for the setting or for the patients, fidelity, towards the bundle, and sustainment of the bundle.
in this composite score, implementation success score, we interestingly found that a greater implementation success is associated with an increased reduction in pneumonia. So this is, of course, very intuitive, but it's rarely shown, in studies that, there is this link and it shows us that it's [00:27:00] important not only have the right prevention measures, but also to these measures can successfully be introduced and integrated into daily practice.
you saw a dose response curve really, which greatly- Kind of ... strengthens the association, right, between the- Exactly ... the intervention and the outcome.
Aline: Mm-hmm. That was great to see. And, last but not least, we also tried to identify factors that were associated with this increased implementation success.
We did this by qualitative data analysis. We collected a lot of qualitative data from interviews, from action plan meetings. We regularly met those implementation teams from the department and collected data from these meetings and also from focus groups, discussion at the end of the project. And there, we found, some factors that were associated with increased implementation success, and these were, for example, if the healthcare workers perceived that the risk for NVHAP of the [00:28:00] patients from their departments is high, implementation success was higher.
Aline: So there apparently was, a higher motivation to work on the implementation, of our bundle. Also, physical proximity of the inter-interdisciplinary teams was important, so that physicians, nurses, therapists work close to each other, have their offices also close to each other because it's a very interprofessional, bundle, and it helps if people are in contact to each other.
And then well known from other trials, is that it matters who is responsible to implement, the bundle. So if you have motivated people, people with charisma, people who have also the authority to make certain decisions, these are the people who can drive, an implementation and can make the difference if things get, difficult.
super interesting. How do you measure charisma? No. We could go down a lot of rabbit holes, I think. it's all so clever, and I, totally understand how Brett would want to come to you guys.
Angela: How did [00:29:00] you measure this compliance with the bundle? There were lots of elements to it.
Aline: Yeah, we, tried to measure compliance, but it was very challenging, I have to say. also quality improvement, we had the challenge that, healthcare workers were not always documenting what they did do. So oral care is something they often don't document, or it's hidden into patient care, documentation. it's also the fact that often patients can contribute to prevention measures.
That's also not documented. But still, we try to measure, compliance. We did that in two ways. We measured the application rates of prevention measures, so how frequently were prevention measures still documented in the electronic medical health system, and we e- just extracted this data and, measured the application rates for months and looked if, there were changes over the study phases.
And second, we tried to, measure adherence, by manual chart review and patient interviews of repeated samples of fifty patients per [00:30:00] department at three time points. So there we were able to also measure the contribution of patients to prevention measures. we're able to control for if there is an indication for the prevention measure at all for this specific patient.
Aline: So yeah, both approaches had strengths and limitations. we were able to see clear improvements for this stage of screening and for reduction of non-indicated PPI, but we were not able to see statistically significant changes in oral care, mobilization, or respiratory therapy Although we believe that and also know a bit from qualitative data collection that there must have been an improvement in oral care because people invested a lot, and they told us, "Hey, we are doing it.
We just don't document it. It takes us too much time." and there we really think for oral care, there probably also was an improvement, maybe also from, quality of care.
And so Brett, in the HAPPEN trial, how did you guys measure compliance [00:31:00] with oral care intervention?
Yeah. Well, we measured that through documentation of oral care, which as Aline alluded to, comes with some limitations of course.
So we assumed if someone had documented that they'd done oral care, that it was done. we chose that because if we were doing direct observation, we thought there'd be the Hawthorne effect. if we were going to ask people, either patients themselves or healthcare workers, "Did you perform oral care?"
Brett: It's gonna be that social desirability bias that's introduced. and we didn't feed back the results of oral care audits to the nurses on the ward. So we didn't do that deliberately, it's because we didn't want them just to document better, so we tried to account for some of those things by doing it that way, but it's a real trick.
We also have done interviews with, nurses on the ward. We haven't published that yet. We're just in the process of writing that up and we'll have that in due course, as well as patients. So we've done both those sides. And whilst our study did not focus on implementation as Lauren and Aline's study [00:32:00] did, we tried to measure some other, process measures.
So we looked at hits to the website, that were only provided to patients and to staff, so there was no one else who actually had access to that website. So we could look to see were people actually using the resources and what were they using, and that increased with time. We found that was, well used.
And similarly, we could look at how many bags were distributed to patients that contained the resources and information. So, we're pretty bit more con-constrained in the sense of looking at some of those other things that, Lauren and Aline looked at in their study.
So yeah, what you've just said, Brett, leads nicely into what I was gonna bring up next, which, don't shout me down, Lauren.
Josh: I may be coming from the completely the wrong angle here, but both the trials put effort into education, of staff in the intervention, and then also implementation of the interventions. And they both included some process measures as well as efficacy outcomes. So was the HAPPEN trial actually a hybrid effectiveness [00:33:00] implementation trial, just less explicitly kind of called that or not?
And if not, why not? So, maybe I'll ask Lauren to comment on this first from a sort of external angle, and then Brett, what do you think?
Lauren: So I think that's a, really nice question and, Josh, you mentioned at the beginning of the discussion that our team just recently published a review in CMI about looking at hybrid effectiveness implementation trials in infection prevention and, infectious diseases.
And what we found of the 26 studies that we ended up including, about only half of them actually use this terminology of labeling them as hybrid effectiveness implementation trials. the publication kind of introducing this terminology was only introduced in 2012. So I think that there is inherent in the infection prevention and, infectious diseases community an interest in implementation, so a lot of the studies that we do have these elements in them.
it's not necessarily new to explore implementation [00:34:00] and effectiveness together, but the, terminology is perhaps not consistently applied yet. That's one of the messages that we gave. And you know, Brett, I think your, HAPPEN trial was published in 2025 and our review was published just before.
Lauren: So I think, unfortunately we didn't capture your study, but I think that what we were looking at in classification of hybrid trials is does the study have an intentional focus on one hand on the effectiveness, evaluating effectiveness, gathering information about is a clinical intervention effective?
And does it also collect data or ask questions around the implementation? So for example, is the way in which we're introducing the trial, for example, through education or through provision of toothbrushes are another example of an implementation, strategy. And then do they collect data that tells us not just if the intervention is effective, but why or how it is effective?
Then we would consider it a hybrid approach.
Okay, that is [00:35:00] quite a politician answer there. Yeah,
Lauren: Lauren. I think Lauren's
Brett: being, I think Lauren's being very
Lauren: polite. I actually, actually want ... I wanted Brett to answer the question
Brett: first. I think Lauren's being polite. Uh, my answer is no, it's not. because, as Lauren just beautifully articulated, using implementation science and a framework to help deliver and evaluate that formally is something we didn't do.
so I, I don't think personally that, that ours is what you would classify as a hybrid implementation trial. There was attempts to look at that. I think that's probably just should be standard practice. It wasn't a deliberate planned evaluation of the how when it came to implementation.
Angela: however, what I think is really lovely about the HAPPEN trial is that it doesn't exist on its own.
It is phase two, right, of a three-phase project, a larger project, that will be looking at implementation, in the next phase. Yeah. If you want to elaborate on
Brett: the HAPPEN study broadly was three phases. The first [00:36:00] phase was identifying, barriers and, facilitators to improving oral care.
So we did, focus groups, we did national surveys of nurses' practice, we engaged with consumers, and that helped us, modify some of the intervention components for the RCT, which was phase two. as other elements of phase two that I alluded to, which, you know, the interview components which, for patients and for healthcare workers, cost-effectiveness evaluations, those things are also underway and under review with journals at the moment.
the third element, which is phase three, is really preparing based on what we've learnt from the trial, those interviews. we're looking to, modify all the resources that we developed in the trials. So what did we see the patients use and didn't use and accessed? what was the feedback on those?
what do we find useful in the way we communicated to nursing staff on the wards in terms of presentations being whatever that, in different formats that they might be? And so we're evaluating those through the other processes at the moment, not through a formal framework, but just [00:37:00] through our experience using those things.
And we're going to make those freely available and adaptable. And so in, Word formats and things like that where people can then download those and adapt them to their own hospital context and setting. but at least have a starting point to say, "This was used in the context of this trial.
It was evaluated. It might be a useful starting point in your hospital." So that's phase three, which is sort of latter end of this year and early into next year.
Angela: Lauren, what do you think of phase three? Would that pass muster as a hybrid effectiveness?
Lauren: Absolutely. , These things are on a spectrum, right? And There have been three types of hybrid trials classified. Type one, where you have a primary focus on effectiveness, but you collect a little bit of information perhaps about the implementation, for example, through a process evaluation.
And then you have on the other side of the spectrum, you have a primary focus on the implementation. Maybe you already have strong evidence that your clinical intervention is effective, but you want to really focus on how to make it work, and you can even randomize them to different implementation [00:38:00] approaches.
so that's type three. And then you have type two, where you have a co-primary focus on the implementation and the effectiveness. that's what we did in Zurich, but I think it sounds then, Brett, like you're kind of, moving across the spectrum in terms of having more focus in the next steps on really the implementation side of things, which is very exciting.
Angela: Just as an aside, like I think it's so cool. Lauren, when you said the word randomize, I think if someone did a functional MRI on my brain, I think it would light up. Like that just makes me so happy. The word randomize. Josh, I bet you have this too. And Brett and Aline. Yeah. And Lauren, you are working in a world where obviously randomization is not that easy to do, and yet you're still finding a way where, okay, but we could randomize.
I think that's awesome. Anyway, total aside,
Brett: I agree because randomization in IPC is inherently difficult to do. we've got a review coming out shortly in the next, month or so, which has tried to look very crudely at all the RCTs that have been done in the IPC field and what areas they've been done on, and see where there's been growth [00:39:00] in randomized controlled trials in, IPC.
The short answer to that is there is growth in that area, and we need to make sure though that the areas of growth do match the needs, of the questions that need answering clinically and from a guideline perspective. but in a separate review, also looked in the context of Australia, how IPC research is going, and the growth is there, but the growth is really, observational-based studies and single-centered being a large, contribution to that.
And so we don't want to, for want of a better word, waste resources by doing research that isn't gonna advance, our knowledge or practice. And whilst RCTs are difficult to do, I think that we've should always think about can we do them first. Is there a way to do them in some way, shape, or form? because it just adds so much value to the evidence base.
Which is why I love the stepped wedge design. Because it's still, you know, you're, you're being practical, but you're still saying, "Hey, I need that randomization. That eliminates bias. I have to do that."
Lauren: on the topic of randomization, [00:40:00] our team is involved together in a, project where Walter Zingg is the PI. It's a European trial where across 24 hospitals that are implementing infection prevention and stewardship, It was step wedge, so they, they started their implementation of the IPC and the stewardship activities over time, but then they were also randomized to different implementation arms. So some of the hospitals got facilitated implementation support from our team locally in Zurich, and supported them to tailor their local implementation activities, and others got the standard trial approach.
And so that's really a kind of cool but very complex design where we have the randomized implementation, but also the step wedged IPC and stewardship interventions.
Angela: Very cool.
The degree of reduction in HAP is really similar in both your trials. Why do you think this is? Oral care, of course, was the link between your two trials. is it all due to [00:41:00] improved oral care? What do you think, Brett?
well, I guess I can only comment because our focus was oral care, in our trial, and I guess probably the other differentiating factor is Our clusters were, patients that were probably at high risk of NV-HAP, and I won't speak for the other trial, but, I guess might be different if you included clusters or wards that were a little bit more diverse.
I think that's, possibly one of the reasons why we saw, the reductions in oral care. and, I guess we couldn't evaluate and we didn't evaluate some of those other, approaches such as mobilization, dysphagia screening, and other, o-other things that were evaluated in, in the other trial
Aline: So we implemented a bundle composed of five prevention measures, and I think it's not possible to retrospectively say what element of the bundle was most effective to reduce nvHAP. I have gut feelings. I think that oral care is probably a strong candidate [00:42:00] because it's, very much biologically plausible, the relationship between, colonization in mouth, pharynx, and the aspiration risk, and whatever you aspirate can cause pneumonia.
So I think, oral care played a role. but because pneumonia is multifactorial and, there are, for example, in patients with certain risk factors for dysphagia, the detection and management of dysphagia is also a very strong candidate for a highly effective prevention measure.
So- Okay ... I can't say yet.
Josh: Yeah.
Aline: Mm-hmm.
Angela: I have a question there for Lauren, or for Aline, Devil's advocate. I have always struggled with the idea of bundle interventions. I know they're a really big deal in infection control. I get it. but it has always bothered me that, okay, at the end, you may have five, nine, 10 components to your bundle, and you don't really know which one was the most effective, you know.
And it's great if your hospital has the resources to always implement those nine, 10 components, but what about settings [00:43:00] where they don't have that level of resources? So provocative question perhaps. Should there be a prerequisite? If you're gonna do a bundle intervention, should you not also be including in your trial design, a continuous, analysis, or even a postmortem, , analysis of which component was the most effective?
Should we not be sort of required to do that? Because yes, we're giving something new to the world, but with all these caveats and with all these question marks, what do you think?
Lauren: My mind goes to two places when you ask this question.
One is about the feasibility, and so that's why I think that having something like this formative evaluation or doing something like a feasibility assessment, are really important. When you look at, for example, the Medical Research Council recommendations for developing and evaluating complex interventions, before they go to effectiveness, they start with this feasibility where you work with, the individuals that are going to be implementing this to assess [00:44:00] is the intervention itself or the implementation approach going to be feasible in practice.
And so this initial feasibility evaluation can be really important. That's kind of one direction that my head goes in when you ask this question. The other is in terms of what are the statistical methods that we have to evaluate which of the specific components are contributing most of the outcomes that we see.
In the space of implementation, there's a group of statistical methods called, configurational methods that look at what factors are necessary or sufficient in order for a certain outcome to be observed. And so it's a very interesting group of statistical methods, and we have done a study looking at, coincidence analysis.
It's one specific, statistical method where we can look at, for example, if many different implementation strategies have been used, which of the implementation strategies are most important to lead to the observed [00:45:00] implementation outcomes. So it's a kind of, yeah, niche statistical method that we're exploring now in implementation science.
But I- I'm not sure how much that really answers your question. so we've, talked about what parts of the bundle might be effective, and Brett, in your trial, part of the intervention, of oral care was the patients were given a toothbrush, and there was a message printed on the toothbrush.
Josh: It said something like, "Brushing your teeth prevents pneumonia," or something.
Brett: Yeah. Yeah.
Josh: What did it say?
Brett: well, there's two different messages. One said, "Brush away pneumonia," and then on the other side of the toothbrush, it said, Toothbrushing helps prevent pneumonia."
Josh: Okay. So the toothbrush had a message written on it, and then they were given QR links to some videos.
How much of the observed benefit do you think was just due to the toothbrushes as opposed to all the other parts, the videos and the training and all that? Like, It's pretty cheap, right? Should we just give every patient a toothbrush with a message on it?
Brett: It would help a bit, but I think you've gotta have the other component, because otherwise it just becomes another thing that someone's [00:46:00] given in hospital.
and this is the, trick of like, what is the contributing factor here? When we talk about infection control practice change, It's not like prescribing a drug, you know it's gonna be given, and you're gonna be given at a certain time or hopefully it is, but when you're changing a practice, you can't just go say to someone, "You need to change this."
They're not gonna know about it unless you educate them to start with. So then to try and delineate between the education and the provision of something, the change, you're trying to change, it's, in really difficult in the sense of IPC related research.
So I think it's the same here. you can give someone something, but you do need to do something else to help say, "Why is this important?" And so I don't think you could just do one thing, and that is give a toothbrush and expect that kind of change. You might get a little bit more buy-in with it, but you're not gonna get the same level of buy-in.
Lauren: I love that, Brett, and we often say that education is necessary but insufficient to- to support behaviors. And so I think that the, people often know, what it is that [00:47:00] they need to do, but maybe the environment doesn't support them to do it. or in some cases, like you said, they don't know in the first place, but knowing is not necessarily enough to actually do it.
So I think really nice example
Josh: so Aline, the results of your trial were published a bit over two years ago now, I think. Have your findings been translated into routine care in Zurich or further afield?
Aline: yes. So one important thing I did not mention yet is that our project had to be terminated prematurely due to the COVID pandemic back in twenty twenty, and so we did not put at that, time a lot of emphasis into sustainment. but still some components, were proven to be quite durable. So, several of the implementation strategies focused more on standardization or changing the environment, and those changes are still in place.
We also have a toothbrush that we, introduced in our hospital accompanied by informational leaflet. We have a sticker for patient on mirrors in bathrooms that informs about the, [00:48:00] relationship of, toothbrushing and pneumonia. These stickers are still there. we have some, dysphagia screening, for example, was institutionalized and is still performed currently.
Aline: And what Lauren, mentioned is that on a national basis, Swissnoso, that's the Swiss National Center for Infection Control, is working on a national and we have prevention guideline and also on an implementation support, like providing implementation resources to Swiss hospital that not every hospital has to invent the wheel itself and, we can translate our learnings from our single center study to more Swiss acute care hospitals.
Josh: Yeah. Fantastic. So it'll be in your hospital too, Angela, soon, I guess.
Angela: Yes, indeed, and we look forward to it
Josh: So Brett, in the, editorial that came out with the HAPPEN trial, there was discussion about seasonality and whether that may have, influenced your outcomes given that the wards started at different times and they all ended up getting the intervention by the [00:49:00] end.
Do you think seasonality was important in your trial or might have explained some of the findings?
Brett: One of the challenges with stepped wedge designs is , to think about seasonality and , secular changes and, trends. I don't think it is in our trial, and the reason for that is that the start point was June, which is the beginning of winter in Australia.
And so I can see the point being made that perhaps at the end of the trial were were there some hospitals that were exposed perhaps not to the main flu season. but not all hospitals started at the same time. So one of the hospitals in the trial actually had three months, their last three months of the trial was purely during the winter season.
So arguably, if you're trying to make a link between seasonality, then VAP, and, seasonality and NVHAP, then that probably doesn't wash because one of the hospitals had their entire intervention phase where all three clusters were mainly in the intervention phase during winter.
so I don't think that quite washes. I'm also not sure of the evidence base linking seasonality to NVHAP. I mean, it makes- Yeah ... some kind of [00:50:00] sense, but, and I guess when we think about the intervention of oral care, probably it's gonna focus more on bacterial rather than viral pathogens, in terms of its effects.
So again, it's a possibility, but I probably wouldn't hold too much credence to that.
Josh: And probably would be much more important if it was a community-acquired pneumonia trial than a HAP one, potentially- Yeah ... seasonality.
Brett: Yeah.
Angela: Before we wrap up, is there any last message you wanna give our audience? Brett,
Brett: so I think our trial showed that improving oral care is possible through a relatively simple intervention. It didn't require any new technology, nothing fancy, low cost, and that sometimes these simple interventions, can work.
And so for me, it was a take home message. It was doing something perhaps we should already be doing. It's part of our fundamentals of care, providing good oral care to patients in hospital. but by just doing something simple, engaging patients and clinicians in that, process, we can improve oral care, and we can see [00:51:00] reductions in NV-HaP.
So, for me, it's one of those interventions that low cost, not glamorous, but probably has a , pretty powerful impact.
Angela: And totally antibiotic sparing. That's right. I mean, it's so much easier to brush your teeth than get a dose of ceftriaxone, right?
Brett: Yeah. Yeah,
Josh: absolutely. That's the message. Brush your teeth.
Yeah. Three words. Yeah. Brush your teeth. Yeah. Um, brush your teeth. Like
Angela: you were taught when you were little. .
Alain, how about you? Sorry. Aline, what's your, takeaway?
Aline: So one of the most important things for me is that, HaP prevention is very interprofessional, and it's important to include all healthcare professionals that are implicated, but also to include patients and their families. And I think Brett did that beautifully in his study.
It's so important that you inform patients, and if they know why measures are important, I think for many of the, HaP prevention measures, also for mobilization, for example, they can contribute. So my final message is, HaP prevention is a team effort. Patients and families are also very important to be included.
Josh: Great. and Lauren, finally, a-any takeaways from you?
Lauren: Sure. So I guess I [00:52:00] have a message that's a bit, biased by my perspective as coming from the implementation world. I have said before and, and I continue to promote that I think all effectiveness trials should be hybrid trials. And what I mean by that is not that, , you have to do a full-fledged implementation trial and randomize the implementation approach, but I think that these efforts that we take to understand not just if something works, but how it works, can be so important for the messages that we give on about our studies.
So understanding-- the interprofessional approach, that was really critical. and most studies are not reporting on those aspects, and so I think having this hybrid mindset can really help us to improve the, research translation
Angela: Yeah. You've totally sold me, Lauren.
I'll be calling you for the next grant submission. Oh my goodness. it's so true. We do so much [00:53:00] work to start a trial, run it, and then we think we're done when we've published the results, and no, not at all. Not at all. I think, Josh, you're the one who told me that, the interval of time between publishing your results and getting those results integrated into clinical practice, I think it's-- there's like a seven to 10 year interval.
Angela: No? Yeah.
Josh: Yeah, clinical practice there's seven years is- There's
Angela: even
Josh: more, right? ... often quoted. Yeah, yeah.
Angela: Yeah. Yeah.
thank you all so much for the conversation. It's been really great talking about things I don't think about that much usually, like implementation science, cluster designs, infection prevention, and so on. And I hope the listeners have enjoyed that as well. thank you to the listeners for listening to Communicable, the CI- CMI Comms podcast.
Josh: This episode was edited by Katie Hostettler-Oi. The theme music was composed and conducted by Joseph McDade. Any published literature we've discussed today can be found in the show notes, and you can subscribe to [00:54:00] Communicable on Spotify, Apple, or wherever you get your podcasts, and you can also find it on ESCMID's website, for the CMI Comms Journal.
thank you for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.