Transcript
Speaker: Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: And now, your host, Dr. Sergio Zanotti.
Speaker: For the last 15 years, an enormous emphasis has been placed on improving the outcomes of patients with sepsis and septic shock.
Speaker: There has been a big push for early identification of sepsis and implementation of time-sensitive therapies, including broad-spectrum antibiotics and fluids.
Speaker: At the same time, growing concerns for increasing antibiotic resistance have led to calls for rationalization of antibiotics and efforts to decrease unneeded exposure to antibiotics in patients who do not have proven infections.
Speaker: In 2017, the FDA approved the use of a procalcitonin assay to help guide the starting and stopping of antibiotic treatment in patients with suspected low respiratory tract infections in the emergency department or hospital.
Speaker: In this episode of Critical Matters, we will discuss this topic.
Speaker: Our guest is Dr. David Wong.
Speaker: Dr. Wong is an associate professor, Departments of Critical Care Medicine, Emergency Medicine, and Clinical and Translational Science at the University of Pittsburgh Medical School.
Speaker: He is the director of the multidisciplinary acute care research organization, MACRO, the administrative core director of CRISMA Center, and also serves as the associate medical director for the transplant intensive care unit at UPMC Montefiore.
Speaker: Dr. Wang has extensive research experience, and his research focuses on multicenter clinical trials that span the ED and ICU.
Speaker: He served as medical monitor of the PROCESS trial, a leader for the ROSE trial, and was the principal investigator of the Procalcitonin Antibiotic Consensus Trial, PROACT, that was recently published this year and that will be the focus of our discussion.
Speaker: David, welcome to Critical Matters.
Speaker: Thank you, Pedro.
Speaker: So I think that maybe we could start with a very basic kind of approach.
Speaker: explanation of procalcitonin, what happens in health, what happens in acute illness and infection, and how it became of interest for a potential biomarker for infections.
Speaker: Sure.
Speaker: So ordinarily in healthy people, procalcitonin, it's a precursor of the hormone calcitonin, and it's made by the thyroid,
Speaker: and then certain other organs.
Speaker: But when you get sick, forget everything about endocrinology.
Speaker: You shouldn't think of calcitonin or anything.
Speaker: Beat Mueller, arguably the
Speaker: the foremost leader in procalcitonin research sometimes describes it, he's written, he's described it as a hormone kind, like a hormone cytokine in the sense that when somebody gets septic or infected with a bacterial infection, amazingly, procalcitonin seems to be constitutively expressed by almost every tissue type in the body.
Speaker: So I think the first, I think one of the first
Speaker: observations of procalcitonin was around in the early 90s or late 80s, where those authors noticed that, hey, procalcitonin seems to go sky high in general with bacterial infection, but very weirdly is actually low in viral infection.
Speaker: And then the implications for patient care became obvious,
Speaker: with such an observation.
Speaker: And then actually after that, there's relatively few basic science type papers with an extensive record though of human research.
Speaker: And the reason why we think it goes up so acutely and so prominently
Speaker: bacterial infections is because it sounds like LPS or endotoxin is a very potent precursor of the messenger RNA that actually stimulates the production of proclastotonin, is that correct?
Speaker: Yeah, that's one of the main mechanisms at least.
Speaker: And again, it's apparently released by almost every type of tissue in the body, which is quite interesting.
Speaker: And then further basic science papers have noted that, at least in general, viral infections actually suppress the release of procalcitonin.
Speaker: And I think that that's a good starting point to have an understanding of how what we mostly learned in medical school as a hormone, like you said, also has a cytokine aspect or almost like a dual personality.
Speaker: And in infections, specifically in bacterial infections, has been seen to be secreted in large amounts throughout the body in multiple types of tissue.
Speaker: So for many years, it sounds like procalcitonin has been an
Speaker: heavily studied and utilized in Europe mostly.
Speaker: Obviously, we'll talk about how it came, I mean, to be approved and what led to the PROACT study.
Speaker: But could you give us a little bit of what the literature, I mean, just broad strokes of what the literature has shown in Europe and kind of what served for the basis of your thought process in designing the PROACT study in the last couple of years?
Speaker: Yeah, sure.
Speaker: So, so,
Speaker: A couple years ago I got curious as to how troponin came to replace CKMB.
Speaker: I was a second year resident when I was told, okay, start ordering tropes now.
Speaker: But nobody actually explained to me why.
Speaker: So the history of how troponin replaced CKMB is somewhat analogous.
Speaker: Actually, it's quite analogous to
Speaker: to procalcitonin in the sense that initially it started with a lot of observational studies, both Troponin research and procalcitonin.
Speaker: And so there's a ton of observational studies looking at PCT.
Speaker: And to summarize all of them, although the overall signal is that procalcitonin
Speaker: outperforms in terms of sensitivity, specificity, whatever performance characteristic you choose, generally seems to outperform other markers such as white blood cell count, IL-6, lactate, CRP, in terms of differentiating bacterial versus viral infection, sepsis versus sterile inflammation, et cetera.
Speaker: Now, not every paper
Speaker: There are certainly papers looking at, for example, aspiration where procalcitrant doesn't do very well in differentiating sterile inflammation versus microbial infection.
Speaker: But if you looked at the last, gosh, there's probably like 1,000 observational studies, in general, that's what the overall findings are.
Speaker: for the observational studies.
Speaker: So then the RCT started.
Speaker: Oh, I shouldn't make one sidebar is that the big advantage that troponin research had was that they had an objective gold standard, which was echo finding.
Speaker: The huge issue with infection and septic research is that there is no gold standard to define infection.
Speaker: So, for example, as we all know, even in rip-roaring septic shock, a third to half of patients are culture negative.
Speaker: And then for regular old community-acquired pneumonia, there was a New England paper just two or three years ago
Speaker: where even with research-level molecular diagnostics, a significant minority of patients were still microbe negative.
Speaker: So that's a huge, huge problem with infection and sepsis research.
Speaker: And so studies have done stuff like having a clinical adjudication committee of an ID doc, an ED doc, a critical care doc, et cetera,
Speaker: retrospectively look at the entire patient's record and then decide but that's obviously subjective and when you're making a decision on a sick patient right in front of you obviously obviously you don't have you know all the future data so what the swiss pioneers did led by beat mueller who is i thought really clever they did they decided to do an rct
Speaker: where half the patients got pro-calculated care and the other half did not.
Speaker: And then they just looked at the patient outcomes.
Speaker: So then the patient outcome became the gold standard rather than an endless circular debate as to what's the gold standard.
Speaker: And I think that, sorry to interrupt, but I think that's an important point, right?
Speaker: Because one of the challenges we have with sepsis is that it's a syndrome, right?
Speaker: And I like to think about it, infection, with or without organ failure, infection, with or without shock.
Speaker: But ultimately, what we really care as clinicians is does whatever we apply help us not define the syndrome, but improve outcomes?
Speaker: So that, I mean, like you said, is an important distinction and quite a smart move by Mueller and his group of investigators.
Speaker: Yeah, it was really great.
Speaker: It was really great.
Speaker: So then what they, so then they did a series of trials.
Speaker: Most of them centered around emergency department patients with lower respiratory tract infection.
Speaker: So, and in general, actually all of them found reduction in antibiotics
Speaker: And the larger study, ProHAS, published in JAMA in 2009, showed that it was safe in the sense that adverse events in the Brookhouse Stone arm were not higher in the care arm.
Speaker: So those trials were
Speaker: were pretty impressive and really caught the world's attention.
Speaker: And then there were also other trials, of course, like in clinics, a number in the ICU as well.
Speaker: And in terms of what they were showing, I mean, like you said, basically a growing number of trials were showing that if you used procalcitonin-guided therapy and lower tract infections, you could reduce the use of antibiotics and you could safely do it without any increased outcomes in those patients who were in the procalcitonin-guided therapy.
Speaker: And if I'm correct, some of these studies also showed that it was procalcitonin levels, serial levels,
Speaker: were also correlated with prognosis and outcomes, so higher levels associated with either higher progressions to organ failure or shock mortality.
Speaker: So that was also a prognostic value in procalcitonin.
Speaker: And ultimately, I think there were a growing number of European studies that suggested that once you start antibiotics, if you followed a series of percussotonins, and once they went below certain thresholds or a decrease of greater than 80%, you could also start stopping antibiotics without causing any harm.
Speaker: So that was what basically the European experience was showing.
Speaker: Is that correct?
Speaker: Yes.
Speaker: Overall, with just a couple of caveats in the sense that
Speaker: So the ICU trials were really pretty much focused on, so the ED trials were focused both on stopping initiation, like completely, as well as decreasing a number of days.
Speaker: The ICU trials were very understandably mainly focused on just decreasing duration as
Speaker: If you just intubate somebody and they're febrile and on two pressers, 100 out of 100 doctors are going to start antibiotics no matter what.
Speaker: And then the other caveat is that only a couple of the ED and ICU trials were large enough to really be powered for safety.
Speaker: So I think as is common in a lot of what we study and with randomized studies and small trials, even though there was a growing body of literature and you look at different meta-analysis, they were not all necessarily on the same page.
Speaker: And like you said, we didn't have all the answers.
Speaker: So clearly there was also clinical echopoison specific populations.
Speaker: And even though the approval we'll talk about by the FDA came in 2017 for the expanded indications, I presume since PROACT was published last this year, you started it before the FDA had approved it.
Speaker: Can we maybe, before we talk about the FDA approval,
Speaker: dive into the trial.
Speaker: I'm just curious in terms of what was the rationale, how you were thinking about when you said we're going to study this and maybe we can go step by step into what you actually did with your team.
Speaker: Sure.
Speaker: Yeah.
Speaker: So when I and my colleagues at Pitt and elsewhere started really digging into the
Speaker: ED LRTIR trials, you know, it was extremely impressive, very exciting from a patient care point of view.
Speaker: Like, so, you know, I did a residency in emergency medicine, and, you know, it was just exhausting to, you know, hand out antibiotics when in your gut you wonder, do I really need to?
Speaker: Like, I'm...
Speaker: I wonder if there's a test that could sort of help me and help the patients safely decrease antibiotic exposure.
Speaker: But as we started digging into it, we thought there were two key residual questions from the Swiss trials related to the ED-LRTI population.
Speaker: First is, will it work in the United States?
Speaker: So ProHosp, the largest trial, they very forthrightly state in the paper that they use enforcement methods in order to enforce physician adherence to the protocol.
Speaker: So what that meant was that if the physician wanted to overrule the ProCalcitonin guideline, so for example, give antibiotics even though the ProCalcitonin was low, then they had to call
Speaker: the research center and asked for permission.
Speaker: In addition, the treating doctors in the middle of their ED shift actually enrolled the patients into the study, as they forthrightly state in their method section.
Speaker: So, you know, I just didn't, I think even my
Speaker: best friends from my emergency medicine residency, I don't think that they would do either one for me in the middle of a really busy shift.
Speaker: So that basic question, will it work with a different design that at least I feel is more realistic to you as practice
Speaker: really, really popped out.
Speaker: And I think, David, that's an important point because we often...
Speaker: translate results of clinical trials, right, to clinical practice very quickly, at least clinicians like to, and we extrapolate.
Speaker: But you're very, very, very, very on point there where this was basically almost a protocol that was dictated and enforced, right?
Speaker: Whereas, I mean, it's a lot harder to do that in the outside of the confines of a very controlled clinical trial and practice, right?
Speaker: Physicians ultimately have the authority and autonomy to order or not order the antibiotics.
Speaker: And I think that's what you were trying to capture in your clinical trial, correct?
Speaker: Yes, yes.
Speaker: And besides the autonomy issues, there were differences in background care.
Speaker: So the length of stay was really long.
Speaker: So, for example, in pro-hosp for community-acquired pneumonia, it was...
Speaker: 10 to 12 days, versus on average it's about five to six in the United States.
Speaker: And their antibacterial was also really long.
Speaker: It was about 11 days.
Speaker: Now, in their defense, their reference was the 2001 IDSA and ATS CAP guidelines, which were much bigger about antibacterial than the most current one, the 2008 ones, which are
Speaker: which really pushed trying to use a shorter course.
Speaker: So that was the first question.
Speaker: Will it work in contemporary care in the U.S. and elsewhere?
Speaker: And honestly, elsewhere where you don't have such enforcement and you don't have such long antibiotic duration.
Speaker: And the second question was, is it safe?
Speaker: you know, anytime you don't give antibiotics, at least I always worry, you know, is that the right call?
Speaker: And they used a somewhat wide, it's called a non-inferiority margin, and their point estimate for mortality was, it wasn't stats significant, but it was numerically a bit higher.
Speaker: So I felt like the,
Speaker: the safety issue wasn't entirely wrapped up.
Speaker: So for those two reasons, does it work and is it safe, those are really the two core reasons why we wanted to do PRO-X.
Speaker: So tell us a little bit, I mean, just in a summary, kind of what did you actually do?
Speaker: I mean, obviously, the PROAC study was published earlier this year in the Journal of Medicine.
Speaker: There will be a link attached to the show notes.
Speaker: But tell us, I mean, how you set it up, I mean, with these two questions and, I mean, main questions in mind.
Speaker: And it is the largest study that's been done in North America, for sure.
Speaker: I don't know if it's larger than the European studies, but it is the most recent and largest clinical trial that has looked at this problem, right?
Speaker: Yeah, sure.
Speaker: So you want me to just sort of summarize the overall in a few minutes?
Speaker: Yeah, that'd be great.
Speaker: Okay.
Speaker: So just conceptually, PRO-ARCT was designed to answer a basic clinical question.
Speaker: Can procalcitonin help clinicians safely decrease antibiotic use in lower respiratory tract infection?
Speaker: So it was a two-arm trial, usual care versus procalcitonin, 14 US hospitals, mostly urban tertiary care academic centers.
Speaker: All of them had done very well with the old Joint Commission pneumonia core measures, and none of them routinely used procalcitonin.
Speaker: And we had two aims, which basically mirrored the two questions.
Speaker: Will it work?
Speaker: Is it safe?
Speaker: So we enrolled adult patients with a primary clinical diagnosis of acute LRTI.
Speaker: And then really importantly, where there was diagnostic and decision-making uncertainty, in the sense that the clinician was willing to consider procalcitonin in their antibiotic thinking and decision-making.
Speaker: And the rationale there was because if a patient has purulence coming out of multiple orifices, why would you order procalcitonin?
Speaker: Waste of money.
Speaker: Obviously, you're giving them lots of antibiotics.
Speaker: And conversely, if the, oh, here's Mr. Jones again, well-known as manic, he comes in every two months, especially when he's gardening, okay, obviously, you're not going to give that person
Speaker: Obviously, you're not giving that person antibiotics either.
Speaker: So we wanted to capture patients where an additional test might actually help guide management as opposed to just be a waste of money.
Speaker: We enrolled them in the ED, and then we excluded really sick patients because we felt that, such as endotracheal intubator or impressors, because we felt that
Speaker: basically nobody is going to stop initiation of antibiotics on a patient who's really sick.
Speaker: So these were non-critically ill emergency department LRTI patients.
Speaker: And then we also worked hard to disseminate national antibiotic guidelines, such as CDC and pretty much
Speaker: that for acute bronchitis, you shouldn't give antibiotics for uncomfortable bronchitis.
Speaker: Because past procalcitonin papers trials have been criticized by saying, oh, well, sure, you reduced antibiotic use.
Speaker: That's because in usual care, patients were getting Z-packs like M&Ms.
Speaker: So we wanted to at least do our best to constrain that type of gross antibiotic abuse.
Speaker: So then the intervention was just making sure that the doctors in the ED and the hospital looked at the ProCalcetotin value and recommendation, and then they could do whatever they wanted to do.
Speaker: And we worked pretty hard at implementing the protocol.
Speaker: I had pre-launch education during the trial.
Speaker: There was a lot of live education by the coordinators, then at faculty meetings.
Speaker: And then I reviewed every instance of ProCal Stone and guideline non-adherence and then reviewed each instance with each site PI for each site, trying to try and do
Speaker: a feedback boost.
Speaker: So before we go further, I just want to share with our listeners, I mean, and I have it here from your publication, the actual guideline.
Speaker: So I think that gives a frame of reference, right?
Speaker: So basically, like you said, you shared with all the clinicians the current guidelines for community-acquired pneumonia, COPD, asthma, cuprochitis, educated everybody.
Speaker: And like you said at the beginning, these are already high-performing institutions.
Speaker: that had very good data based on CMS and JCO compliance with pneumonia bundles.
Speaker: So in terms of the guideline that you offered, you had three columns, procalcitonin level, the likelihood of bacterial etiology, and then a recommendation that was linked to a clinical behavior.
Speaker: So if the procal level was below 0.1 micrograms per liter,
Speaker: you thought the guideline would say that it was very unlikely to be bacterial and that antibiotics were strongly discouraged.
Speaker: If it was between 0.1 and 0.25 micrograms per liter, the likelihood of bacterial etiology was unlikely and the antibiotics were discouraged.
Speaker: If it was between 0.25 and 0.5, the likelihood of bacterial etiology was thought as likely, and at that point, antibiotics were recommended.
Speaker: And if it was above 0.5 micro-rounds per liter, it was very likely to be bacterial, and the recommendation was that antibiotics be strongly recommended.
Speaker: So that is basically the instructions that the clinicians had paired to the levels, correct?
Speaker: Yes, and we didn't make up this guideline.
Speaker: It's the same guideline used in the Swiss trials and the same guideline that was approved by FDA last year.
Speaker: Okay.
Speaker: So this is kind of like what's considered the standard from that perspective.
Speaker: Yeah.
Speaker: Okay.
Speaker: Yep.
Speaker: So tell us what you found.
Speaker: Yeah.
Speaker: So...
Speaker: So I'll preface by saying that as a doctor, I was very disappointed because I really hoped that it would be a so-called positive trial.
Speaker: But as an investigator, the data are what the data are.
Speaker: That's how we do a study, right?
Speaker: Yeah.
Speaker: That's why we do the study.
Speaker: Yeah.
Speaker: So what we found?
Speaker: So unfortunately, what we found, as I'm sure you already know, is that there really was no overall difference.
Speaker: If you look at... So first of all, we implemented the protocol well in the sense that almost every time
Speaker: the intervention was done correctly, and that the ProCalS-Totent level was drawn, measured, and quickly made available to the treating doctors, versus in usual care where only 2% had any testing.
Speaker: So there was definitely a separation in terms of administered treatments between arms.
Speaker: there was no difference in the overall primary outcome of number of antibiotic days by day 30.
Speaker: 4.2 versus 4.3 mean antibiotic days, with very similar results no matter how you analyze, whether intention to treat, per protocol, sensitivity analysis, et cetera.
Speaker: And then similarly, there were no differences in adverse outcomes by day 30.
Speaker: So in other words,
Speaker: It didn't work, and unsurprisingly, it appeared safe.
Speaker: In secondary outcomes, though, there was a possible signal in the sense that antibiotic prescription in the eMERGE department for acute bronchitis was cut in half, 32% in usual care, 17% in the ED.
Speaker: And this was
Speaker: And this finding was robust to a very strict, what's called a Bonferroni correction, which is when you correct for what's called multiple comparisons.
Speaker: So basically, if you look at 30 outcomes, the possibility of you finding something with the magic P less than 0.05 is much higher than if you just look at one outcome.
Speaker: But this finding for acute bronchitis, even though it survived
Speaker: rigorous bonferonic correction is a secondary outcome of a subgroup.
Speaker: So hard to call it necessarily truth, per se.
Speaker: And I think that, David, I mean, and I know that there's been follow-up letters to the editor not too long ago, I mean, and you've answered those.
Speaker: And one of the letters actually pointed out about the Q bronchitis population, which is a population that has been more heavily
Speaker: present in some of the European studies, right?
Speaker: And which maybe, like you said, is an area where there's more overprescribing of antibiotics.
Speaker: So that's one question.
Speaker: But the other question that I also had was what happened specifically with the people who we thought had pneumonia?
Speaker: Was there any differences there?
Speaker: Any comments you can make on the pneumonia population?
Speaker: No, there was no signal for pneumonia.
Speaker: antibiotic reduction in pneumonia.
Speaker: And one of the things that I think are important is, in general, people will read an abstract or take a quick look at a study, okay, say it's a negative study, right?
Speaker: But I think that, like you said, it is negative in terms that it didn't show a positive decrease in the use.
Speaker: But also, I think that what it actually tells us
Speaker: a bit more nuanced than just somebody saying, well, I don't believe in precocitonin, and David's study shows it doesn't really work.
Speaker: Can you comment on that a little bit more?
Speaker: Yeah, absolutely.
Speaker: So in October 2017 was when we finally unblinded.
Speaker: And after basically a decade of planning and thinking about PROACT, I finally saw
Speaker: the results.
Speaker: So after going through the seven stages of grief, I completely deleted and trashed my blank tables and figures, which I had drawn up for expecting a so-called positive trial.
Speaker: And then I really went to work on
Speaker: try and understand this surprise finding.
Speaker: You know, this might amuse you and your listeners, but prior to unblinding, I surveyed the entire team, including all the site PIs, and everybody except one expected to find antibiotic reduction.
Speaker: So this was a huge surprise to everybody.
Speaker: But so then we went to work very hard to try and understand.
Speaker: And I think we understand it now.
Speaker: And yes, this stuff is in the manuscript text, but it's not in the abstract in much detail because of word limitations.
Speaker: So I think the first interesting thing was, so we measured procalcitonin in the usual care group.
Speaker: We just didn't show it.
Speaker: So the first most compelling thing is that procalcitonin levels were associated with emergency department antibiotic prescription rates in both groups.
Speaker: So nothing like
Speaker: about three-quarters of the patients presented with really low procalcitonin levels.
Speaker: So there was ample opportunity in the patient cohort for procalcitonin to work, so to speak.
Speaker: But in those three-quarters of patients, whether or not the doctors saw the procalcitonin level, antibiotic prescription was basically the same.
Speaker: It was basically only about one-third in each arm.
Speaker: And then if you go on the other extreme, you look at the patients with really high procalcitonin levels, you saw the exact same phenomenon.
Speaker: Whether or not the doctors saw the procalcitonin level, three-quarters of them in each arm got antibiotics.
Speaker: And in the middle, with the middle two tiers, yeah, maybe you start to see some differences.
Speaker: But the vast, some differences in antibiotic prescription between arms, but the vast majority of patients presented in either the lowest or the highest tier.
Speaker: So to me, that was sort of suggestive that good doctors can sort of almost sense what the procalcitonin value is.
Speaker: And then
Speaker: And then once we saw that, I decided to look at clinical signs and outcomes and correlate them with procalcitonin level.
Speaker: So in 2008, we did an observational study of procalcitonin and community-acquired pneumonia, and I found that in general, as procalcitonin level rose, so too did
Speaker: severity scores, and outcomes.
Speaker: And we found the exact same signal here.
Speaker: So for example, in the lowest procalcitonin tier, number of service criteria was one, actually 0.9, but then as you rose to the highest tier, it doubled to 1.7.
Speaker: So I think in that context where procalcitonin is associated with how the patient looks and how the patient ultimately does, procalcitonin probably only provided
Speaker: modest incremental information to guide clinician decisions.
Speaker: And that's why we saw that for emergency-partum antibiotic prescription, whether or not you saw the procalcitonin, your actions were pretty similar.
Speaker: So that's, I think, an important point, right?
Speaker: I mean, and I think that it also speaks to the evolution of care.
Speaker: And you were involved with the process trial as well, right?
Speaker: But I think that's another example of when you compare a trial that was done a decade earlier, right?
Speaker: right, like the Swiss trials with some different design issues.
Speaker: And then you do a different study like PROACT almost 10 years later.
Speaker: Not only, I mean, the design is different, but also the clinical behavior has changed, right?
Speaker: I mean, people have molded their practices in different ways.
Speaker: And it seems that at least in the two extremes of those groups, it seems like the doctors were doing a better job and being congruent in terms of being coherent in their approach to either give or not give antibiotics.
Speaker: Yeah, I think so.
Speaker: At least in these 14 academic, there's like, yeah, at least in these 14 tertiary care centers.
Speaker: But exactly.
Speaker: So if you look at the control groups of ProAct and ProHosp, we had much less antibiotic use.
Speaker: Now ProHosp did have a sicker population with more pneumonia than we did.
Speaker: But that said, it's pretty dramatic.
Speaker: So ProAct control,
Speaker: Antibiotic duration was 4.3 days and pro hosp was double 8.7.
Speaker: Yeah, but you know Pro hosp finished enrolling 10 years ago and then since then as we all know, this is huge movement towards shorter courses Yeah, so clinical practice is changing.
Speaker: I mean is evolving as we go along Absolutely.
Speaker: Yeah, and then also, you know, so These these emerge departments were not handing out the packs like candies
Speaker: which is a common criticism of not only EDs, but PCPs and everybody for acute bronchitis.
Speaker: So in PROACT, less than a third of patients with acute bronchitis got antibiotics, but nationally, it's more like 70%.
Speaker: So these 14 hospitals were relatively judicious in their antibiotic use.
Speaker: And I think that a lot of the issues that we discussed also speak to the limitations that these large randomized trials have.
Speaker: I mean, running these trials are not easy.
Speaker: Designing them is not easy.
Speaker: And everything you decide to include, it means that you exclude something else and everything has...
Speaker: probably unintended consequences.
Speaker: So it's very difficult to foresee all of this.
Speaker: But I mean, like you said, I mean, the design, I think the design was phenomenal.
Speaker: I mean, you're trying to address important questions and our listeners can look at the study themselves, but the compliance with what was intended to be done and the follow-up was phenomenal.
Speaker: So I think that, like you said, at the end of the day, whether you were hoping for something positive and dramatic or not,
Speaker: the data is the data, right?
Speaker: And you have to kind of report that and kind of try to understand that.
Speaker: Yeah, exactly.
Speaker: Exactly.
Speaker: So I think that, David, and I know that a lot of the emphasis was on, like you said, LRTIs and the ED, but still very important for our critical care audience and for obviously our ED audience.
Speaker: But I do think that just to kind of bring together
Speaker: what your experience with the trial is just to remind, I mean, our listeners that at kind of the same time that you were finishing your trial in 2017, what the FDA really did is expand the approval of the procalcitonin assay to include an
Speaker: to be utilized as a clinical tool in conjunction with clinical findings for decisions regarding starting and stopping of lower respiratory tract infections and for
Speaker: for the stopping of antibiotics or antibiotics in patients with sepsis, which is not the same, right?
Speaker: So there's no really FDA approval to decide, like you said, on a patient that comes in and is in multi-organ failure, is this high lactic acid, maybe a vasopressor, and you don't have a source, you think, oh, should I give or not antibiotics?
Speaker: That's not what we're talking about.
Speaker: We're talking about basically the population you studied, right, which is basically lower respiratory tract infections, and that includes COPD, asthma, acute bronchitis, and pneumonia.
Speaker: Or in those who are start antibiotics with sepsis, there are protocols that over time can
Speaker: If the ProCal drops below a certain level, usually below 0.3 or 0.25, you can safely stop the antibiotic.
Speaker: Or if there's a drastic reduction of greater than 80%, also can help you shorten the duration.
Speaker: Any comments from that perspective and how you see the use today?
Speaker: Yeah, so when FDA approved it in 2017, I...
Speaker: I thought that was quite interesting.
Speaker: And I read the transcript of the meeting, which was very helpful.
Speaker: So they approved procalcitonin.
Speaker: The FDA approved procalcitonin based on a meta-analysis submitted by the manufacturer of procalcitonin.
Speaker: And the FDA did forthrightly state that the primary limitation associated with the meta-analysis was the lack of US trial sites.
Speaker: But the overall feel was that antibiotic resistance is such a huge problem.
Speaker: And they stated that although there's two US trials running,
Speaker: PROACT and then a different one, they're not finished yet and they needed to make a decision.
Speaker: So I think it was understandable given the enormous worldwide problem of antibiotic resistance as to why FDA approved PCT.
Speaker: What was your second question, Serge?
Speaker: In order for us to say we're going to do this on 100,000 ICU patients or a large number of patients, the evidence has to be top-notch, right?
Speaker: I mean, you really have to, in order to mandate something, you have to feel very comfortable.
Speaker: I think there's still, I mean, there's a lot of good signals and good evidence, but I still, we're not there yet with patients.
Speaker: mandating procrastinate on everybody.
Speaker: And I think that current guidelines like the Surviving Sepsis Campaign and other institutions are moving along those lines and saying that there is evidence, this is what the evidence shows, if you're going to be an early adopter, there are certain things that you should consider, right?
Speaker: So they're not saying that everybody should do it, but I also think a lot of people are measuring their institutions procrastinate.
Speaker: I think it's important for them
Speaker: to understand how to utilize it best if they choose to utilize it.
Speaker: So from your perspective, David, are there any specific recommendations you can give our clinicians in terms of if they're gonna use prospective patent, when and how to use it?
Speaker: Yeah, sure.
Speaker: So why don't we talk just a little bit about the ICU trials.
Speaker: Excellent, yep, yep, yep.
Speaker: Yeah, so there's been a large number of ICU trials
Speaker: But a lot of them were single center, you know, like less than 100 patients.
Speaker: Two of the largest ones were ProRata, about 600 odd patients in France, and SAPS in the Netherlands, that was about 1,600 patients.
Speaker: And there are other decently large studies as well.
Speaker: So first of all, yeah, so most of them were relatively small studies, except for Prorata, Saps, and one or two others.
Speaker: Most of the ICU trials were in medical patients.
Speaker: They did have logical exclusions, such as immunosuppression, endocarditis, et cetera.
Speaker: And then they all used different
Speaker: cutoffs.
Speaker: So the ED-LRTI trials pretty much all use the same guidelines that PROACT used.
Speaker: But all the ICU ones are all over the place.
Speaker: So some of them use less than one microgram per liter.
Speaker: Some of them use less than 0.25.
Speaker: Some of them use the decrease from the baseline peak.
Speaker: It's really sort of a mixed bag.
Speaker: And then
Speaker: And then the overall, so there was a couple of meta-analyses, but one of them basically said, both actually, all of them basically said that if you look at them all together, the average effect size is something like saving one to do antibiotic days, which is great.
Speaker: Well, no, I would say it's good.
Speaker: But what really matters is decreasing antibiotic resistance.
Speaker: That's really the societal goal.
Speaker: So if you take somebody from, say, an eight-day course to a six-day course, certainly you're saving money.
Speaker: And certainly that's a good thing, assuming it's safe, which it probably is.
Speaker: But it's actually unknown if saving two days will actually reduce antibiotic resistance, as opposed to an ED where what I and I assume every other ED trialist was after was if you can convert somebody from a five-day Z-PAC to nothing, then you can take it as a matter of faith that, yes, you reduced antibiotic resistance.
Speaker: So I think that's probably my overall concern with procalcitonin's true utility in the ICU.
Speaker: Are you really going to move the needle on resistance?
Speaker: And I think it's a very fair point.
Speaker: I mean, the difference between decreasing the number of days versus a binary exposure, yes or no, right?
Speaker: That might be a big difference.
Speaker: And it might take maybe a much bigger effect if it is the case that it doesn't make a difference.
Speaker: But we have no proof that that is the case, which is, I think, a very good point.
Speaker: Yeah.
Speaker: So I think –
Speaker: So that's my interpretation, at least, of the ICU evidence.
Speaker: So overall, I kind of agree with what the current SSC guidelines say, which it was something like we suggest that PCT can be used to shorten duration.
Speaker: It was one of those weak recommendations, but it wouldn't be crazy to use it.
Speaker: Yeah, so I have them here, so I'll just share them with the audience.
Speaker: So they had two recommendations on PCT and PCT.
Speaker: One, like you said, David, we suggest that measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients.
Speaker: And as you stated, it's a weak recommendation with low quality of evidence.
Speaker: And the second one, number 15, says we suggest that procalcitonin levels can be used to support discontinuation of empiric antibiotics in patients who initially appear to have sepsis but subsequently have limited clinical evidence of infection.
Speaker: weak recommendation, low quality of evidence.
Speaker: So again, like they're saying is you could use it, but we're not saying that everybody should use it and there are some caveats to it.
Speaker: Yeah, exactly.
Speaker: So if you ask me what should somebody do right now in the ICU, first of all, as an academic, I have to
Speaker: state that now I'm switching hats and speaking as a doctor because everything I'm saying now is speculation of course but I think I think first of all you shouldn't order it like all the time it shouldn't be done routinely and but I could imagine a strong doctor who's already done the basics the history the physical I've looked at everything else and
Speaker: and it's still kind of uncertain.
Speaker: You could imagine that in certain situations, it's sort of like swans.
Speaker: So there's been now, what, 10 negative trials of swans, but we still swan some people.
Speaker: And it's kind of hard to quantify exactly when a good doctor will swan, but certainly nobody is saying we should just throw swans in the garbage.
Speaker: So I think there are situations where a strong doctor could reasonably, as an early adopter, as you said, Sergio, order a procalcitonin.
Speaker: But then also, you have to be ready to act on it.
Speaker: So it's a bit like the Choosing Wisey campaign.
Speaker: And I saw an editorial on viscoelastic testing, so TEGs, and the title was something like
Speaker: It's not the test, it's the action.
Speaker: Which again, immediately reminded me of the great swan debates from about 15 years ago.
Speaker: What changes with the information?
Speaker: That's the real question, right?
Speaker: Yeah, exactly.
Speaker: So if on a select non-routine patient you decide to order it, then you have to be, yeah, like with anything.
Speaker: Like, is it worth sending this intubated patient
Speaker: an 80% antenna peep down the hall to the CT scan.
Speaker: Well, it is if you're going to change management, but if you're not going to change management, you better not get that scan.
Speaker: Yeah, I agree.
Speaker: And, and what about incorporating your PCT use into a antibiotic stewardship program?
Speaker: There's been a lot of discussion and some of the letters to the editor also talked about that.
Speaker: Any comments on that?
Speaker: Yeah, so I remember when the stewardship program was first introduced at Pitt.
Speaker: And at first, I mean, I'll just speak personally, at first I was like, what?
Speaker: What is this hoop that we have to jump through?
Speaker: But then gradually I saw that this is a wonderful thing.
Speaker: It really is.
Speaker: First of all, it's almost like a curbside consult for ID.
Speaker: But overall, yeah, I think we need to be restricted.
Speaker: So one of the letters to the editor basically said, how come you didn't combine it with a stewardship program?
Speaker: And I basically said, because that would be testing two interventions, which is
Speaker: completely different design and a really heavy... So number one, it's a completely different design and doing two interventions is much bigger in scope than one.
Speaker: But if you already have an antibiotic stewardship program, then you might imagine that folding ProCalStone into it might be more effective.
Speaker: And there's some papers
Speaker: that suggests that that's true.
Speaker: So one thing that we didn't touch on, but I guess would be valuable since we're talking about
Speaker: potential clinical application based on the evidence and what you learned from the trial.
Speaker: There are certain conditions that are associated with elevations in the baseline procalcitonin that are not related to infection, right?
Speaker: And those, I think, were exclusions in your study.
Speaker: Can you mention some of those, David?
Speaker: Sure.
Speaker: So this is not an exhaustive list, but in the study, I chose to exclude relatively common conditions
Speaker: where PCT can be high without infection.
Speaker: So, for example, chronic dialysis.
Speaker: And again, not every paper says this, but certainly at least the time when I designed the trial with my colleagues, there was enough to make me nervous enough to exclude them.
Speaker: So, I'm sorry, what I mean by high is greater than 0.25.
Speaker: microgram.
Speaker: So they would compromise the lower extreme which is the one that's useful in saying don't give antibiotics.
Speaker: That's right.
Speaker: High in the ED may be low in the ICU.
Speaker: Correct.
Speaker: So chronic dialysis, metastatic cancer and then recent surgery.
Speaker: So if you were being an early adopter
Speaker: and you nonetheless decide to order procalcitonin in these conditions, particularly surgical patients, you have to recognize that their baseline level is going to be higher than somebody else's.
Speaker: And then there's also certain types of thyroid cancer where procalcitonin is high.
Speaker: Not every type of thyroid cancer, though.
Speaker: Well, I think that this is obviously still an unsettled topic.
Speaker: I think that because it's already available and people use it or misuse it, maybe we're going to probably hear more about it.
Speaker: But I think that, like, one of the first, I mean, thank you for your time, but also for the effort of trying to study this in a very...
Speaker: scientific way and even though the the sometimes the findings are not what we expect or what we hope for like you said I mean understanding the data is the key of really doing evidence-based medicine so that was very very useful but one of the things that we like to do in our podcast David is at the end kind of ask some questions that are not related to a specific topic and just tapping into the wisdom of our of our guests would that be okay
Speaker: So the first question is, what book has influenced you the most or what book have you gifted most often to others?
Speaker: I think there's two books that stand out.
Speaker: The first is The Seven Habits of Highly Effective People.
Speaker: I think from that book, the single most important message is that we don't spend enough time in what the
Speaker: what Dr. Covey calls the type two quadrant of activities, which is important but non-urgent.
Speaker: So here's an exercise in the book where he says, write down three activities that you know if you did consistently for the next year, so like a New Year's resolution perhaps, given that it's December 6 right now, you know would improve your life.
Speaker: And it's always stuff like,
Speaker: exercising more, flossing more, spend more time with my family.
Speaker: So all those things are important, but they're not urgent, like a cardiac arrest or a grant deadline or whatever.
Speaker: So it's very easy to not do important things.
Speaker: but not urgent things.
Speaker: And I think that this is super applicable to medicine and healthcare in general today.
Speaker: So we work with a lot of hospital partners throughout the country.
Speaker: And I think that one of the problems with a lot of our hospital administrations, and that occurs in academic centers too, is that there is a tremendous emphasis on what's urgent.
Speaker: the last state can't visit or Jayco's coming next week.
Speaker: And I think that sometimes we undervalue or undermine what's important, which is building quality programs that are going to be everlasting and really move care forward.
Speaker: So I think that we do both, I mean, in general, but I think sometimes the emphasis switches too much to what's urgent.
Speaker: And I think that's a great lesson.
Speaker: And we'll definitely link this book at the end of the show notes.
Speaker: What's the second one?
Speaker: The second one, it's called
Speaker: Partners of the Heart, written by Dr. Vivian Thomas.
Speaker: So very briefly, the famous Blalock-Talzig shunt, so the world's first heart operation, in this case, was for the famous, they call them the Blue Babies, for Tetralogy of Fellow.
Speaker: It should be called the Blalock-Talzig-Thomas shunt.
Speaker: So Blalock was the surgeon.
Speaker: Talzig was the pediatrician, female pediatrician.
Speaker: And Vivian Thomas was the Noel College education, African-American lab technician who did little minor things like create the dog model for Tetralogy of Fallot.
Speaker: And
Speaker: And when Blalock became chair, he actually, it was Thomas who did all the operations in the lab, such that when Dr. Blalock did the world's first heart operation, he literally told Thomas to stand on a step stool behind his right shoulder and told him to walk him through the operation.
Speaker: Yeah, interesting, right?
Speaker: And it's amazing.
Speaker: So HBO did a docudrama on it called Something the Lord Made, based off of a quote where when Dr. Blalock felt the vascular anastomosis that Thomas had made in the dog, it was so smooth that he was like, my God, this anastomosis is like something God made.
Speaker: Wow.
Speaker: And when I saw the docudrama, I was like,
Speaker: this is too crazy to be true.
Speaker: So I heavily researched it, I got biography, and it is 100% true.
Speaker: They changed one little minor historical detail at the end, but the rest is completely true.
Speaker: And yeah, 100% it should be called the Blalock-Towcyk-Thomas shunt.
Speaker: Which is interesting, like how every story has so many layers that we don't necessarily know.
Speaker: And I think that's also something that we learn when we talk with the investigators who run these trials.
Speaker: We read them, but there's a lot of things that go behind scenes, thought process into the whole design that I think it's interesting to understand.
Speaker: So these two will be referenced at the show notes.
Speaker: I mean, I have not read Partners of the Heart, but definitely have an interest in that.
Speaker: So definitely we'll look it up.
Speaker: The second question, David, is what do you believe to be true in medicine or in life that most other people don't believe?
Speaker: Give me a minute here, Sergio.
Speaker: Most other people...
Speaker: Well, and I think that one of the things that you mentioned that would be an extension of the seven habits of highly effective people is the importance of focusing on what is important versus urgent.
Speaker: Right.
Speaker: So figuring out, I guess, a lot of people don't see that.
Speaker: Everybody's always busy with what's urgent, the next emergency.
Speaker: But ultimately, the more energy we spend in that quadrant, probably the better for ourselves and also for the people we're trying to help.
Speaker: But I think that that would be kind of an example, I think, of what I consider things that are true, but most people don't believe or they believe it, they don't act on it.
Speaker: Yeah, fair enough.
Speaker: Yep.
Speaker: So what would you want every intensivist who's listening to this podcast to know in closing?
Speaker: Anything in particular could be related to PCT or anything else that is important for you?
Speaker: I think the... Well, I guess related to PCT, I think the Choosing Wisely campaign is probably one of the best things to come out of organized medicine in the last 10, 20 years.
Speaker: It's not another controversial...
Speaker: maintenance of certification exam, but actually something that really is a strong clinical use.
Speaker: And I think choosing when to order Procalcitonin wisely is just a – it fits very well into the overall Choosing Wisely campaign.
Speaker: I agree.
Speaker: And I think in terms of when you choose it, when you order a test, I mean, using that to make meaningful impact on the patient.
Speaker: So I think there are so many data points that we order that cost money, can cause problems that we don't utilize or we're not going to utilize.
Speaker: And I think it's just, I mean, wasteful and low value care for our patients.
Speaker: Yeah.
Speaker: And, you know, one last thing, like I don't want to be nihilistic about procalciton.
Speaker: And like, if you think about it,
Speaker: You know, so like, you know, we have such an intense troponin envy, but like cardiologists, everybody's still arguing over how to best use troponin in 2018.
Speaker: And heck, we still don't know exactly when and who and how to order mammograms.
Speaker: So the whole area of testing research and how to test the test
Speaker: Procalcitonin is just one small part of that overall clinical and academic struggle of how do you test the test and when should you actually order that test and on who and how often.
Speaker: So it's going to take a lot more both research and clinical experience to figure out when to order prostate-specific antigen, when to SWAN, when to order mammogram, and when to order procalcitonin.
Speaker: And I think that that's a perfect place to stop.
Speaker: I really want to thank you, David, for your time, for being so generous with all your knowledge and walking us through, I mean, a wonderful trial that, even though it's negative, I think taught us a lot about implementation of change in clinical practice.
Speaker: And hope to have you again on the podcast soon.
Speaker: Great.
Speaker: Thanks a lot, Sergio.
Speaker: Thanks again for listening to Critical Matters.
Speaker: Make sure to subscribe to this podcast on iTunes or Google Play.
