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In this 2020 noninferiority trial, a lower PEEP ventilation strategy was noninferior to a higher PEEP strategy for ventilator-free days at day 28. Marcus J. Schultz, MD, PhD, of the Amsterdam University Medical Centers, the Netherlands, presents findings from the RELAx Collaborative Group at the European Society of Intensive Care Medicine (ESICM) LIVES Digital 2020 virtual conference on December 9.
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>> Well, the next speaker is a longtime associate and friend of mine, Marcus Schultz, from Amsterdam, the Netherlands, and he has spent the last 20 years or so on the pressures and volumes on mechanical ventilation, and his title now is The Effect of Lower versus Higher Positive End-Expiratory Pressure Strategy on Ventilator-Free Days in Intensive Care Unit Patients without ARDS, a Randomized Clinical Trial. Marcus, please.
>> Marcus J. Schultz: Chairman, ladies and gentlemen, thank you very much for your interest in this presentation during which I will show you the results of the RELAx Trial, a study into the effects of a lower versus higher PEEP strategy on ventilator three days, end-of-life, in ICU patients without ARDS. The findings of this study will be presented in a JAMA publication that is released simultaneously with this presentation, and here I would like to thank the editor-in-chief, and the section editor for their help in preparing this document. I have no real conflicts of interest with regard to the content of this presentation. The presentation in JAMA comes as a very infographic, summarizing what we did over the last three years. So, we performed a randomized clinical trial in eight ICUs in the Netherlands, randomizing 980 patients to a lower PEEP strategy or higher PEEP strategy, and we compared the primary outcome of the number of ventilator-free days by study day 28 using non-inferiority design. The findings are found on the right of the slides showing us that there is no inferiority of the lower PEEP strategy versus a higher PEEP strategy in these patients. Meaning that a lower PEEP strategy is as good as a higher PEEP strategy. These are the investigators involved in this study. A large group of investigators that worked very hard over the last three years, and a special thank you to Anna Geke Algera and Frederique Paulus, who did most of the work. So, I will discuss now the background of this study. The questions that we had, the methods that we used, and finally, the results and conclusions. In patients with ARDS, several randomized clinical trials over the last two decades showed no benefit of a higher PEEP strategy when compared to a lower PEEP strategy. One IPD meta-analysis suggested benefit, but only in patients with moderate to severe ARDS, and actually, the harm was suggested from a higher PEEP strategy in patients with mild ARDS, as in these patients, it seemed to delay extubation. Meanwhile, there is increasing interest in how patients without ARDS are being ventilated and the role of PEEP in these patients. This was an observational study in which patients at a high risk for ARDS but not having ARDS were compared to patients with a low risk or no risk of ARDS, nicely showing that a higher PEEP level is increasingly being used with these data are compared with previous studies. Seven to 8 centimeters of water is standard of care in these patients in many ICUs in many countries. Now is this a good thing or is it a bad thing? Is there benefit or harm use of a higher PEEP strategy in these patients? Benefit could exist, for instance, if there's an improved aeration, leading to a better oxygenation, and some studies suggest that there may be less ARDS. There may be less ventilator-associated pneumonia with the use of higher PEEP. Animal studies, however, suggest that there is a risk of over distention, and maybe, there is an increase in the worsening or inducing of new lung injuries. This is all based on animal studies. We also noted the use of a high PEEP is associated with impaired hemodynamics, or could impair the hemodynamics, and it may, in theory, delay extubation, as we clinicians usually extubate patients at a lower level of PEEP. So, we asked the following question. In ICU patients who received invasive ventilation for reasons other than ARDS, is a ventilation strategy using a lower PEEP non-inferior to a strategy using a higher PEEP, with respect to the number of ventilator-free days and alive at day 28? Why did we use a noninferiority design? Noninferiority designs are increasingly being used in drug studies, in which you ask the question is a lower dose, in this case, a lower level of PEEP, as good as a higher dose, in this case, a higher level of PEEP? And we use the composite endpoint of ventilator-free days at day 28, because it combines mortality with duration of mechanical ventilation. So, this was a randomized controlled trial performed in eight centers in alliance with a pre-published protocol and a pre-published statistical analysis plan. So, it was approved by the local institutional review boards, and we use deferred informed consent. We had DSMB for oversight, and we performed no interim analysis. Patients were eligible if they were intubated shortly before or in the ICU and were expected not to be extubated within the next 24 hours. We also wanted only to have patients that started with mechanical ventilation within one hour of randomization in the ICU. We had all our exclusion criteria like ARDS or COPD if you would like to refer to the trials and JAMA paper for the additional exclusion criteria. We used a one-to-one ratio randomization performed by local investigators using a web-based program, and we had random block sizes of two to eight patients per center. Mechanical ventilation in the two protocols were nearly the same. The only difference were the PEEP FiO2 titrations. In the lower PEEP group, PEEP started at 5 centimeters of water, which was then down titrated in steps of one centimeter of water until the oxygenation was worsening. Meaning it could not be sufficient with an increased risk of FiO2 with a maximum of 60%. In the higher PEEP group, ventilation started with 8 centimeters of water and stayed at 8 centimeters of water PEEP until extubation. Standard of care was the same in all hospitals, and I also would like to refer to the trials in the JAMA paper on information regarding that. The primary and the secondary outcomes are depicted on this slide. So, we had the ventilator-free days and alive at day 28 as the primary endpoint. ICU and hospital length of stay at 28-day and 90-day mortality, with also the occurrence of pulmonary events like ARDS or ventilator-associated pneumonia, and we collected data recording the use of rescue therapies for hypoxemia or atelectasis like prone positioning, higher ventilation pressures to open up lung tissue that may have been collapsed. Now we also collected data with vasopressors and days with sedation, but I will not discuss them here in this presentation. We calculated that we needed 490 patients per group to show, or demonstrate, the noninferiority of the lower PEEP strategy. We used intention to treat analysis, and we used Caplan-and Meier curves to show several of the outcomes. The randomization resulted into a well-balanced group of patients. Eighty percent of them were medical, and 30% were intubated because of acute respiratory failure. The two ventilation strategies resulted in a contrast with regard to the PEEP level, as shown here on top, and with regard to the FR2 level shown here on the bottom of the slide. This is regarding the primary end points. First, I would like you to refer to the noninferiority margin, which is shown here in blue. If the line of the 95% confidence interval of the mean ratio difference does not cross the blue line, it means that the intervention, in this case, a lower PEEP strategy, is noninferior with comparison to the higher PEEP group. And as you can see, this is not happening, bringing us to the conclusion that a lower PEEP strategy is not worse than a higher PEEP strategy with regard to the primary endpoint. We found similar findings for the subgroups that were predefined. The other endpoints are shown here like duration until extubation, hospital and ICU length of stay, mortality, and in all these endpoints, there were no differences between the two groups. Patients with a higher PEEP strategy were having better oxygenation and less hypoxemic events and less rescue therapies, but these differences were not statistically significant. So, we conclude that a lower peep strategy is noninferior with respect to the number of ventilator free days end-of-life at day 28, as compared to a higher PEEP strategy. This study has several strengths. We minimized bias. We performed the study in academic and nonacademic centers, meaning that the findings are generalizable, and we used a short randomization period of one hour to prevent against the carryover effects. The non-blinded design and the large heterogeneity in the two groups is a weakness, but we did not find any difference in the subgroup analysis. So, in conclusion, a lower PEEP strategy is as good as a higher PEEP strategy, and this adds to our knowledge about the influence, or the effects, of PEEP in patients without ARDS. Thank you very much.
>> Howard Bauchner: Thank you.
>> Jozef Kesecioglu: Thank you very much, Marcus, for this very nice and interesting study, and I have a couple of issues to discuss with you, actually. If we look at the 50 years of history of PEEP use with ARDS patients, we have a very clear-cut reasons to do that, you know? All the compression atelectasis and all the pathophysiology, and etc., while if the patients do not have ARDS, that does not, of course, necessarily mean that the lungs are completely normal, but I'm very much interested to know from you what was the idea, the physiological hypothesis, with patients without ARDS that high PEEP would be better, or why did you have the necessity of showing that low PEEP is also not inferior? What was the pathophysiological hypothesis behind the design of this study?
>> Marcus J. Schultz: Thank you for this question, Jozef, and thank you for your kind words. I think it's all a matter of balance between overdistention that could be because by a high level of PEEP and atelectasis that could be cause by a lower level of PEEP. And this balance may be more in favor of using higher PEEP in patients with ARDS or injured lungs, as compared to patients with noninjured lungs, as we were testing in this study. And yes, we have a long history of always the best people of all. You were my trainer 20 years ago, and learned me actually at 5 centimeters of PEEP was good, but only because we have five fingers, and there is no [audio blurbs] for using five or something else like that. And this is exactly what I took into the study. So, thank you for your inspiration, Jozef, 20 years ago.
>> Jozef Kesecioglu: Another question comes from the floor with congratulations, and the question is can you explain the use of 8-centimeter water as high PEEP? Many intensivists would not consider this to be the case.
>> Marcus J. Schultz: Good question again, and I would like to think that one of the audience who's asking this. We had the same discussion with the editors of the journal and with the reviewers. What is high and what is higher, and what is low and what is lower? We deliberately chose here for naming 8 centimeters high or higher, and we chose that level because we found in the Provent study that this is increasingly being used, especially in the Netherlands where we did a Dutch study, or another study, just only focusing on those centers, showing that it was 8. Now you could ask yourself the question if 8 is high enough? I don't know, actually.
>> Jozef Kesecioglu: Well, I mean, the next question is maybe about it, because the person who asked the question says, "What about obese patients?" I think you will be saying the extension of your answer will be there.
>> Marcus J. Schultz: Well, actually, you can think of a new study looking only or focusing on all these patients, because I would like to refer to several studies that have been performed now in the operating room like the Pro-B study [assumed spelling], as an extent of the Provilo [assumed spelling] that was especially looking at the levels, or the effect of high levels of PEEP in obese patients, finding no benefit of a higher PEEP level in patients who are obese. So, at the working floor, at the bedside, I am against this arguing that we should use a higher level of PEEP in more obese patients.
>> Jozef Kesecioglu: Okay, Howard, as the editor-in-chief of this paper, do you have any comments to add?
>> Howard Bauchner: Well, I think, firstly, it's a remarkably handsome study, multisite, academic, nonacademic, and the intervention really differentiated between the two groups, which is one of -- always a challenge, particularly in mechanical ventilation studies, that you get the effect you were looking at. I think we, internally, and I think people know that our section editor for more than a decade has been Derek Angus, although he was just promoted to becoming senior editor, and Chris Seymour is now the section editor. So, feel free to contact either of them. The real question was the noninferiority margin, which comes up all the time in noninferiority studies. Who decided that 10% was sufficient? That is always a question in noninferiority studies, and then, secondly, and Marcus, already commented on it, as did all three of the reviewers, all well-known respiratory physiologists, was 8 centimeters of PEEP. Was that the appropriate target? And I think the good news for Marcus is it allows him to do more studies, because I think that remains a question, and if you look at the tote board, as is often the case with mechanical ventilation studies, there's quite a few questions for you, Marcus. So, I'm sure they'll be quite a few letters to the editor.
>> Marcus J. Schultz: Looking forward to that.
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