Hi, everybody. I'm Guillaume Das, and I'll be taking the very, very tall task of following Dr. Siegel and Dr. Dixon. I am very honored to follow them, and I'm much earlier in my career actually having just graduated Critical Care Fellowship just this last academic year, and I'm currently a Cardiac Anesthesia Fellow. And so I'll be speaking more about some of the clinical data that has come out and some of the emerging themes in ARDS management as well. There's my introduction slide. And I have no disclosures. So some of the objectives that I'll be talking about today is kind of reviewing the historical approach to ARDS management, which Dr. Siegel talked a little bit about the previous thought process that the lung was a sterile environment, and as we now know, that is not true. Discussing the impact of the microbiome on ARDS, identifying methods of alteration. There's some big studies and some analyses that have come out very, very recently, and I'll try to address those as well. And then understanding some of the emerging themes in ARDS management with regards to not only microbial management, but identifying different subphenotypes of ARDS as well. So I know Dr. Siegel had put up here the Grand Prismatic Spring in Yellowstone, and I wanted to lead with this as well. You know, the bacteria and the diversity of bacteria on Earth is just amazing, and that is no less in the human body as well. And you know, we are just kind of getting into the, with the culture-independent methods of bacterial identification and pathologic identification, we are just kind of scratching the surface of understanding how the microbiome interacts with the human body. In the normal lung, the lung microbiome closely resembles the oropharyngeal flora. And some ideas and thought processes behind this is, you know, just due to normal levels of microaspiration and kind of the proximity of those two organ systems. Bronchoscopic samples in the healthy volunteers demonstrated that the density of bacterial DNA was the highest at the crina, but as they collected bacterial samples and bronchoscopy samples further down with each division, they noticed that there were still bacteria, but at a lower density as well. And there's two studies of mechanically ventilated patients with, and they looked at patients who ended up developing VAP and patients who did not. And they noted that there were not significant differences in the diversity of the pulmonary microbiome in those patients that went on to develop VAP and those patients that did not. After the development of VAP, certainly the microbiome changed. So the promotion of pathogenesis, of pathogenic bacteria in the lung, why does this happen? So the blunting of the cough reflex, impairment of mucociliary clearance, disruption of the alveolar surfactant proteins, which, you know, relating to ARDS specifically, and flooding of alveolus with protein-rich edema as well. Lung injury in all its forms, specifically in ARDS, really provides a nutrient-rich environment that supports the pathogenic populations. I think any talk about ARDS, you cannot really discount the historical aspect of it. And this is ASHBA's initial description of ARDS. And as you see, there's multiple patients who had traumatic injury, traumatic thoracic injury, and then there's multiple patients that had infectious complications, which led to ARDS as well. And this has kind of continued and continued. And we are now just understanding that we can't treat all ARDS the same. And I'll address that a little bit later in my talk as well. So similar, actually the same image that Dr. Siegel placed, I think, is very important. And this is kind of, although he ended his talk with this, so this, you know, I'll start my talk with this. And I think this is the baseline for understanding where we're at. In patients without lung injury, there's separate and distinct communities of microbiota in the GI tract, in the lungs, and the oropharyngeal and nasopharyngeal, in those areas, in the nasopharynx. With the start of pathogenesis, and specifically in ARDS, there's a significant dysbiosis that happens where there's migration of, or appearance at least, of bacteria, which are normally found in the GI tract, and they colonize and take hold in different parts of the lung. And this dysbiosis, I think we're starting to figure out that there is a causal link in the progression of pathogenesis as well. From that same paper, where I took the previous graphic from, they talk about the dysregulated response and kind of how this is a positive feedback cycle that leads to further injury and further pathogenesis as well. So alteration of the microbiome. Some of the studies that have looked at this going back decades look at this concept of selective digestive decontamination. And so these studies have looked at multiple methods of doing this. Some have looked at specifically using oral antibiotic agents. Some have looked at oral plus IV antibiotic agents. And there have been several RCTs over the last decades as well, especially one that was published in 2022 in JAMA. The reason why, there's been non-equivalence, and some studies have shown that there is benefit to this. One of the big reasons why it's postulated that this is not taking greater hold in clinical practice is the concern for antimicrobial resistance. And all of these studies, especially the most recent ones in the meta-analysis that I'll cover, I think demonstrate that there is very minimal concern for antimicrobial resistance when using this strategy. So the selective digestive decontamination in the ICU, this was an Australian and New Zealand-based trial which looked at almost 6,000 patients. And they used 90-day mortality as their primary outcome. Their secondary outcomes included ventilator-free days and antimicrobial resistance. And they conducted an ecological assessment as well to look at antimicrobial resistance across their entire ICU. There was no significant difference that they found in their outcomes, although they state that there was a clinically important benefit. And I think the most important part of this study was that there was a reduction in positive blood cultures and no significant increase in antibiotic-resistant organisms. And I think this kind of reiterates the previous data that is there. This is the Kaplan-Meier curve from that study demonstrating no difference in 90-day mortality. In the same issue of JAMA, there was a meta-analysis that was published looking at all the RCTs that have addressed this topic, 32 RCTs with 24,400 patients. They did notice that there are significant decreases in mortality with a relative risk of 0.91, significantly decreased risk of ventilator-associated pneumonia with digestive decontamination. And ICU-acquired bacteremia as well. The thing I think that was most important with this meta-analysis was that they noted that there was only a benefit when these studies looked at utilization of an IV antimicrobial agent in addition to the oral decontamination strategies as well. I will note that, especially the last study that I referenced, this most recent RCT, they utilized a very potent combination of antibiotics. Colistin, tobramycin, nystatin were just some of the major big hitters that they were using. And so I think it's important to keep that in mind, and I think it's important to understand that there was no significant increase in antimicrobial resistance. This is the results table from that paper. And looking at the incidence of ICU-acquired bacteremia and incidence of VAP was significantly less significant, although they did show a decrease in mortality, but it was less significant. So one of the things I wanted to discuss is this new and emerging theme in ARDS. You know, I showed Ashbaugh's paper from 1967, and since then, we have kind of treated ARDS as a single pathology, and we treat a lot of pathologies this way in critical care. I think the new paradigm that we need to start thinking about is subclassifying these patients and, you know, looking at subphenotypes of these patients. There are significant body of literature that shows no significant difference with different treatment strategies. We have looked at drugs such as ketoconazole, statins, all sorts of pharmacologic treatments for ARDS, and almost all of these studies have shown no significant difference in outcomes. What I'll show is that some of these studies, when looked at in a different light, perhaps there is a difference in outcomes with these patients. So the alveoli trial, which is one of the, you know, initial ARDS-Net trials, and there are many that these investigators have looked at, was this multicenter trial and the high PEEP versus low PEEP arms. When they looked at ventilator-free days and overall mortality, there was no significant difference, you know, as noted in this survival curve. But what happens when we look at this in a new light and try to subclassify these patients into different subphenotypes? Well, you know, Kalfi and her colleagues did exactly this, and they used this method called latent class analysis to create, to re-look at the data set and see what provided the best fit. And they noted that there were two phenotypes that they were able to identify, and this has been a common theme in different studies that have looked at, that re-looked at studies since 2014. That phenotype one was more likely to have trauma, pneumonia, and aspiration, and equal likely to have sepsis-related ARDS. And phenotype two was noted to have increased inflammatory biomarkers, IL-6, IL-8, TNFR-1, PI-1, and lower bicarbonate protein C levels as well, and increased pressure use. And this curve, these two curves of the phenotype shows which inflammatory biomarkers and which clinical signs were higher in each subphenotype. When they looked at the cohorts of the ARMA study and the alveoli study, they did notice that when they broke down these subphenotypes, there was actually a difference in mortality with the high PEEP and low PEEP arms. If you look at phenotype one versus phenotype two, and remember phenotype two was the inflammatory subgroup with increased inflammatory biomarkers, the mortality was significantly less with low PEEP in the subphenotype one group. And there have been multiple studies that have looked at this and re-looked at statin therapy, which there was a difference in mortality, and multiple studies that composed the initial ARDSNet trials. And how can we translate and bring this back to the microbiome? This is a case report of a patient that was enrolled in the ASPIRE ICU trial in Europe, and they did a 30-day phylogenetic study of the bacterial microbiota of this patient and looked at kind of how the translation progressed. Single patient who was initially admitted with aspiration pneumonia and developed ARDS, and for urinary tract infection, they treated with meropenem, and they noted that there were different populations and phylogenetic populations that evolved and were noted to translocate with this one patient. And then as I demonstrated with these multiple inflammatory biomarkers, these inflammatory biomarkers were actually elevated during the time that the meropenem-resistant organism, the pseudomonas organism, translocated to the lung. This is the curve showing the different inflammatory biomarkers, IL-4, IL-33, fractal kinase, and IL-22. And during the yellow bar in the middle there is the time frame of the meropenem treatment and the appearance of the meropenem-resistant pseudomonas. And the elevation in the inflammatory biomarker coincides with the time period of reinfection and this appearance of this meropenem-resistant pathogen in the lung. And I think there's a lot of work still to be done in this realm, and I think this one case report obviously is not going to change our management, but I think it's important to start looking at these biomarkers and the management of our ARDS patients. The key points that I'd like to wrap up with are that the normal microbiome appears to be altered in critical illness, especially ARDS. And the main source of these pathologic species is one of the main sources is from the intestinal tract, and there's significant translocation by multiple mechanisms. Selective digestive decontamination, especially with a combination of enteric and IV intramacrobials appears to have some efficacy. And I think more importantly, there's low risk of generating antimacrobial resistance. And these subphenotypes of ARDS, especially this hyperinflammatory and hypoinflammatory subgroups or these subphenotypes, I think is something that needs to be further explored and addressed clinically as we go forward to identify these patients and hopefully re-look at these different studies and different treatment methods that have shown no difference. But when we look at them in a different light and break down these patients into different phenotypes actually shows a significant clinical difference. So with that, I appreciate your time.

microbiome

ARDS

lung injury

treatment strategies

subphenotypes