Good afternoon, everyone. My name is George Onisi from the University of Pennsylvania. I'm a medical intensivist and a clinical epidemiology and health services researcher. And I'll be talking today about an update on ARDS involving management and definition. And first, I'll just thank the organizers for the invitation to speak and thank my co-panelists. I appreciate their great talks. And for anyone interested, I'll announce that the Detroit Lions are currently leading 3117 against the Tampa Bay Bucks. My eagles are already playing golf somewhere. But to anyone invested, I appreciate you being here rather than in front of a TV and sneak some looks on your phone. I won't be offended. All right. Let's see. Sorry. What are we doing? Left? Oh, there we go. Thank you so much. OK. All set now. So a few disclosures. All my research is federally foundation funded. I have a couple of financial relationships, none of which I think pose a conflict for today's talk. And I should say that my wife is employed by the FDA. Since she was sworn in, we've decided to stop talking about candidate ARDS therapeutics at the dinner table. So I think we're OK for today. But in full disclosure, I point that out. All right. So in 2017, the ATS, European Society of Intensive Care Medicine, and SECM put out a joint clinical practice guideline addressing mechanical ventilation in adult patients with ARDS. And over the past year, actually really over the past few months, independently the ESICM and ATS have both issued independent updates to this guideline document. And so I'll be going through those two documents as part of the talk today. And then we'll finish with a look at the proposed new global definition of ARDS, which I think follows nicely from some of the discussions in those two guideline documents and was also published just over the last few months or so. My objectives are to talk about what's new and updated and why, to point out where there is agreement between the two different guidelines and where there is potential disagreement and how that arose, where there is new and remaining questions for future work. And a few additional disclaimers. One is that, in contrast to my colleagues, this is not going to be a traditional kind of year-in-review deep dive into a few randomized trials. In fact, it's going to be much more of a high-level summary by necessity based on the scope of these. In fact, I'll have to leave out certain things which I'm happy to address as part of questions later on. But for the sake of time, I'll focus on a select group of what was addressed in those documents. And then the last disclaimer is that I'm not an author on any of these. So I, one, thank the authors and the consensus groups for their efforts, hard work, and putting this forward for our field. And I come at it as a reader. So I'll give you my interpretations. I certainly welcome others as we open it up for discussion later on. All right. So both of these documents address adult patients with ARDS. We'll talk about definitions as we move forward. They did include COVID-19 patients as part of that, which is obviously new compared to the 2017 guidelines. Both documents address respiratory support strategies and a small number of pharmacologic adjuncts. And we'll focus on just one of them today. And they use PICO questions, which have been already addressed today, but so-called patients, intervention, comparison, and outcome questions to guide the individual topics they wanted to address. They did literature reviews and either examined existing meta-analyses or performed new meta-analyses based on those literature reviews. And then provided some combination of votes and expert opinion to come up with their recommendations and the grading of the evidence. They took slightly different kind of conceptual approaches to these tasks. The ESICM document took probably a broader scope, addressed 21 different questions. We'll go through a subset of those. And in addition to those specific management questions, they also had narrative sections that addressed evolving questions about how ARDS is defined and phenotyping of ARDS. And we'll touch on each of those briefly. The ATS document was a lot more focused. They addressed a much more finite list of questions that were specifically chosen based on having not been previously addressed in the 2017 documents and or with substantial new evidence and potentially practice-changing evidence that should be addressed as part of the new documents. And so we'll go forward with looking at each of those. So we'll start out with what's easy, with what stayed the same, which is that in 2017, the 2017 joint document endorsed low tidal volume ventilation and prone positioning, which continue to be endorsed by ESICM. In particular, they recommend the use of 4 to 8 cc's per kilogram of predicted body weight compared to larger tidal volumes. And they recommend the use of prone positioning in moderate to severe ARDS, defined as a PDF ratio of less than 150. And they do this with a high degree of evidence for both recommendations for all comers and with a moderate degree of evidence with the addition of COVID-19 patients that were not previously addressed in the prior guidelines. ATS agrees with this essentially entirely. They offer a strong recommendation in favor of those strategies. And in addition to highlight the important lung protective ventilation goal of maintaining a plateau pressure of less than or equal to 30 centimeters of water as part of lung protective ventilation. All right. So the harder questions is what changed and where there are potentially some disagreements. So we'll start out with PEEP management strategies. The 2017 document suggested that adult patients with moderate and severe ARDS should receive a higher rather than a lower level of PEEP. ESICM in 2023 deviates from that to some extent. And they essentially downgrade that recommendation to an inability to make a recommendation against routine PEEP titration with a higher PEEP strategy. And they do this on the basis not of new evidence that's emerged since the 2017 guidelines, but kind of a conceptual refocusing on what they viewed as the most impactful studies that have been performed. And in particular, the ones that had a combination of being the most direct comparisons of the question that was being asked, the intervention question that was being asked, and also that were of the highest quality, the lowest degree of bias. So they focused on three large, reasonably large, randomized trials. But from the mid-2000s, EXPRESS, Alveoli, and LOVES, all of which individually and then when put together as a part of a meta-analysis showed no benefit of a higher PEEP versus a lower PEEP strategy. And that was the basis for them downgrading the recommendation from a yes, use higher PEEP strategy to an inability to make a current recommendation. They extended that also to patients with ARDS from COVID-19 with a moderate degree of evidence. Perhaps in contrast, ATS offers a conditional recommendation, continue to be in favor of a high PEEP strategy for moderate to severe ARDS. And they arrived at that by taking essentially a different approach to looking at the totality of the evidence that exists to date on this question. So instead of focusing in on a few of the perceived to be most kind of impactful or purest trials answering this question, they took perhaps even the opposite approach and looked at a fairly recently published network meta-analysis. I think we're all familiar with meta-analyses. Network meta-analyses are kind of an additionally innovative strategy for looking at evidence for complex management questions that allow you to look at three or more interventions together, compare them together using data from multiple different prior research studies which have varying degrees of crossover of intervention. So it allows you to take kind of a broader look at what's been done that may impact the answer to that question. And in doing so, they found a signal looking at over 1,100 patients where they found that a higher PEEP strategy in the absence of recruitment maneuvers, which we'll come back to in just a moment. So high PEEP strategy with no recruitment maneuvers showed a mortality benefit compared to a low PEEP strategy. And so as a result of that, they offer a conditional recommendation in favor of that. They do caution that this should be used in parallel with close monitoring of respiratory mechanics and hemodynamics. And using caution, patients who have severe hemodynamic instability and increased risk of barotrauma. And so while these recommendations may appear to deviate some, I'll just point out that the language in the ESICM recommendation was against routine use. So it still allows for patient-selected use in specific cases where you feel like there may be a benefit. And so I would say these recommendations are closer together than perhaps at first glance, but certainly not the same, and based on a difference in how they approach the underlying literature. Next we'll address recruitment maneuvers. This was in 2017, there was a suggestion that adult patients with ARDS should receive lung recruitment maneuvers. ESICM changes that recommendation in 2023 to recommend explicitly against prolonged high-pressure recruitment maneuvers and against the routine use of brief high-pressure recruitment maneuvers. And they do this on the basis of new trials of varying quality, but put together that show no benefit and a suggestion of increased risk for barotrauma and other secondary injury. ATS agrees with this recommendation and offers a strong recommendation against prolonged recruitment maneuvers. And interestingly, here they're relying on the same 2022 network meta-analysis that allowed them to find a signal in favor of high PEEP without lung recruitment maneuvers. Here as lung recruitment maneuvers are added to a high PEEP strategy, either compared to a low PEEP strategy, or compared to a high PEEP strategy with no recruitment maneuvers, the benefit of high PEEP that they found prior disappears. And there's a sequentially shifting risk profile towards increased mortality with the addition of prolonged lung recruitment maneuvers. So different strategies of interpreting the evidence bring them to kind of a similar final conclusion recommending against recruitment maneuvers in patients with ARDS. And now let's look at what's new. We'll start with neuromuscular blockade, which was not examined at all in the 2017 guidelines. And I'll note is viewed in this case as, while it's a pharmacologic therapy, it's viewed as an adjunct to mechanical ventilation. And ESICM in 2023 recommends against the use, again, of routine use of continuous neuromuscular blockade. And again, they do this with a similar approach of zooming in on what they viewed as the most impactful kind of purest comparison trials. And so they included two primary trials, a 2010 Papazian AcuraCys, or however you want to pronounce that. I've heard a couple different interpretations. And then the most recent ROSE trial in the New England Journal in 2019, which, again, separately and in a combination in a meta-analysis showed no benefit in mortality of neuromuscular blockade. So they recommend against routine use. And we'll come back to that routine again in a moment. And then ATS, again, appears to deviate a bit from this. They offer conditional recommendation in favor of neuromuscular blockade for patients with severe ARDS. And they do this, again, you're seeing a theme here of looking at a broader pooled analysis of multiple trials of varying quality, but that together in a network meta-analysis show a suggestion of decreased mortality. However, they definitely approach this with an eye towards a carefully selected patient population. So this is patients certainly with only severe ARDS, a PDF ratio of less than or equal to 100. And noting that there is a potential increased risk of neuromuscular weakness with prolonged use of neuromuscular blockade, they suggest this is only to be used in early ARDS in the first 48 hours of mechanical ventilation, and to use it in caution for any duration longer, and to use it in caution in patients with any prior neuromuscular conditions. So again, while these recommendations between ESICM and ATS appear to be different, they're probably closer than we may think. ESICM allows for, again, they don't want routine use, but they allow for it in certain selected patients. And ATS kind of tells us who those selected patients may be, severe ARDS in the very early parts of disease, who are not at higher risk than perhaps average for other neuromuscular weakness or conditions. Additionally what's new in the 2023 document is a recommendation for ECMO. It actually was discussed in the 2017 document, but simply with the statement that additional evidence is necessary. And fast forward to 2023 and 2024, and we have more evidence. And so ESICM recommends that patients with severe ARDS are considered for ECMO. And this is on the basis of the pooling of two trials, with one being the most recent EOLIA trial, 2018, which in and of itself did not meet a primary endpoint. But when pooled together with a prior 2009 trial, which had its own limitations, showed a mortality benefit, again in carefully selected patients, and I'll show you who those are. ATS agrees with this recommendation and offers us additional details. This is a conditional recommendation in favor of using VVECMO in patients with very severe ARDS. They do this based on the EOLIA trial inclusion criteria, which is a PDF ratio actually of less than 80, so even more than just severe ARDS, what we might call very severe ARDS, or acidemia with a PCO2 of greater than or equal to 60. And they're very clear about potential contraindications where this therapy may be futile. So a longer duration ARDS and mechanical ventilation, so late initiation, and severe acute and chronic comorbidities that may prevent this therapy from being efficacious. And they're also very, very clear that a less invasive but mortality-reducing therapy should be used first, as to say things like lung protective ventilation, prone positioning, and neuromuscular blockade, depending on where you are on that evaluation, should be used first and prior to initiation for ECMO. So everything else should be done first. And then if and only if you still meet those criteria would you be evaluated as a candidate. And then the last kind of what's new category I'll add is the high-flow nasal oxygen and non-invasive ventilation. These were not addressed at all in 2017. These are actually only addressed in the ESICM document. They're not addressed as part of the ATS document. And we'll go through each of them very quickly. And I'll just note that these I think have gained increasing importance in one, the era of COVID where these were used for the management of what we might call non-intubated ARDS. We'll come back to that term in a moment, for many numbers of patients as we all know. And the second is in a growing recognition that this may be the highest modality that's available for respiratory support in many parts of the world. And we'll also come back to that in a few minutes. So looking first at high-flow nasal oxygen or high-flow nasal cannula versus conventional oxygen therapy, ESICM finds that their mortality analysis shows no benefit. But they do find a benefit for intubation rate, and intubation being a patient-centered outcome, a cost-centered outcome related to longer-term physical strength outcomes and so forth, worthwhile making a recommendation in favor, a moderate degree of evidence, but in favor of using high-flow nasal oxygen therapy over conventional oxygen therapy to reduce the risk of intubation. That's true in all-comer ARDS and also applies to patients with COVID-19. Invasive ventilation was a little bit less convincing in their pooled meta-analyses, both for mortality and for intubation. And so they were unable to make a recommendation of NIV over conventional oxygen therapy for all-comer ARDS, but did find slightly more evidence in favor of reducing the risk of intubation in patients with COVID-19, and allowed that as a suggestion with a low degree of evidence. And then finally, trying to kind of compare the two, really inability to make a suggestion that one is superior over to the other. I think that that probably resonates with a lot of us after the years of COVID, but with a suggestion that perhaps non-invasive therapy may be more efficacious than high-flow nasal oxygen at reducing the risk of intubation, specifically in that COVID population. So again, high degree of evidence, but offered as a suggestion rather than a recommendation. So a few summary points on ARDS management. There seems to be persistent broad consensus agreement about the benefits of long-productive ventilation and prone positioning, a new consensus emerging of ECMO patients, of the benefit of ECMO for carefully selected patients who have undergone all other prior non-invasive therapies, and an emerging consensus to avoid prolonged recruitment maneuvers in these patients. There seems to be disagreement, or at least differences in interpretation of the evidence surrounding high PEEP versus low PEEP management and neuromuscular blockade. I think this probably reflects the high degree of heterogeneity in that data, and really how you approach interpreting those data are going to potentially give you different recommendations. And I think these two documents are probably a little bit closer than you might think at first glance, but certainly there is room for debate there. And then a single evaluation or endorsement of high-flow nasal oxygen and non-invasive ventilation in particular as emerging from the COVID era. I know I'm running two minutes long. I apologize. I'm almost there. In addition, in the ESICM document, they had two narrative sections without specific recommendations but more of a discussion. The first on an ARDS definition question. And they make what they call points of discussion relative to the 2012 Berlin definition. So how can we apply an ARDS definition under resource settings? What do we do about use of high-flow nasal oxygen? What do we do about PEEP requirements and the suggestion that we could use an S to F ratio? And how do we interpret bilateral infiltrates and assess that? And the continued missing direct measurement of inflammation versus host response. And so I'll give it not enough real estate than it deserves, but to close out, I'll talk very, very briefly about the proposed new global definition of ARDS, which was just published earlier this month. This expert group set out to maintain the current ARDS framework, so not rewrite the concept, but to provide potentially a newer modified definition that facilitated rapid ARDS diagnosis, that was applicable in resource-limited settings, useful for testing therapies and practical for communicating to patients and caregivers. And this is what is put forward. I'm going to speed up because I know I'm out of time here. But for intubated ARDS, they maintained the mild, moderate and severe criteria that we've all come to know using P to F ratio, but they added the ability to do so by S to F ratio. This allows for the use of peripheral pulse oximetry without arterial blood gas measurements if that's not available where you are in the world, or for any other reason that you might want to do those less frequently. It adds a category of non-intubated ARDS, which I think we all kind of came to use that term during the COVID pandemic, but it codifies it here as a P to F ratio of less than 300 and an S to F ratio of less than 315. But using hyaluronasal oxygen therapy with at least 30 liters per minute of flow or non-invasive with a PIPA-5. And then in addition, they add a modified definition for resource-limited settings. This is formalizing what we used to call the Kigali modification, which allows for a diagnosis of ARDS with an S to F ratio in the absence of any consideration of oxygen support, knowing that that may be very heterogeneous or not available in many parts of the world. And we shouldn't exclude those patients from a diagnosis just for that fact alone. So I will end with just future work questions that were proposed in these documents and in other locations. We need to understand the incidence and outcomes of ARDS using this proposed new global definition. We need to understand that we struggle with heterogeneity in this patient population, and that the new global definition embraces even more heterogeneity. And so we're going to have to understand the stability of subtypes over time, reproducibility in diverse populations, and pathophysiologic pathways, and ultimately whether precision treatment strategies based on any subphenotyping, global definition, or more sophisticated with biomarker technologies can improve outcomes. I'll stop there. I welcome questions, discussion. I look forward to participating in this type of work going forward. Thank you so much for the opportunity. Thank you.

ARDS management

mechanical ventilation

prone positioning

high PEEP strategies

neuromuscular blockade

high-flow nasal oxygen