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Everybody. Welcome back to Paul Pee.

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I'm joined today by Luke He, our associate

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Editor who's in charge of Rapid fire Journal

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Clubs. Hey, Luke How are you doing?

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Hey, Dave. I'm good. It's good be back.

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Yeah. I like that Sure. You're looking good.

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This is a App over recording video. So

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you guys may be able to check this

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out on, Youtube review med. So you you

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look the park for today.

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Thanks, Man. I I got back from the

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beach like, a week and a half ago.

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So It felt very... I'm trying to hold

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on to that vacation feeling. Yes. You. It's

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a good shot.

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I'm excited about a new initiative that we're

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going forward with and rapid fire journal club.

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Every time we do journal club, I feel

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like in person at the hospital, people love

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it. And 1 very common request that I

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hear from learners is can we do this

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type of journal club review of old landmark

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trials? I don't have as much of an

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understanding of those is it's great to hear

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new trials, but I would like to understand

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those old trials.

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And so we're diving in with that

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mentality as it's July and early in the

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academic year to try to give a review

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of some

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landmark trials that are shaped critical care, and

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we're being a little bit focused about it

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So, luke, why don't you tell our listeners

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a little bit more about what we're gonna

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do over the next few weeks.

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Yeah. So over the next few weeks. I'm

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excited we're gonna have

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series of episodes about some of the landmark

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trials in Air ards management.

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A lot of those are gonna be about

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ventilation, but some of the other non ventilator

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aspects of care for these really sick patients.

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I feel like when I was starting fellowship

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a year ago and as a resident,

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I often knew that these were things we

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did, but I didn't necessarily have the best

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understanding of the literature,

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underlying those decision making those management points. And

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so Our hope is that this serves as

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a

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quick dive into the deep end for people

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who are starting training or for people who

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have Icu rotations coming up.

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Yeah, A hundred percent, and I think that

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in going through these, we're gonna try to

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do it quickly, but we're gonna try to

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raise some of the issues that really helped

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define these trials as the paradigm. I always

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say this about trials when not I'm teaching

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them is that knowing the names of trials

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is like being able to do card tricks.

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It doesn't actually make you a better poker

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player. It just looks cool. So we often

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do this. We say, we do low title

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because of arm. But it's important to understand

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what the actual conduct conduct was of the

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trial. So we 1 know, doesn't it apply

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to our patients? How does it apply to

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our patients. How did it become so defining?

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And then 2, what are the next steps?

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What are the remaining questions and research that

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we have to answer. And so that's what

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we're gonna try to delve into a little

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bit for this? So to kick it off,

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we are gonna start with that exact trial.

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We're gonna start with the Arm trial. Luke,

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why don't you give us a little background

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in introduction. And Yeah. So this is the

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Arm trial. You may have heard it referred

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to as the Ar trial as well. This

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was published in the New England Journal back

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in 2000.

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And it was a trial looking at

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ventilation strategies for patients with Ari ards.

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In terms of kind of the background of

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where this came from,

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At the time, some traditional approaches to mechanical

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ventilation, we're using large tidal volumes, of like

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10 to 15 Ccs per kilo,

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primarily in an effort to normalize someone's Pac

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2 and their ph at the expense of

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high ins airway pressures.

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There were some emerging data at the time

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that suggested that over extension and stress induced

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lung injury could be causing harm,

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But smaller trials and some uncontrolled studies of

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lower title volumes had varying a purchase to

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airway management and unsurprisingly had excuse me, airway

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pressure management and had conflicting results gone surprisingly.

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Yeah. And I love to think about this.

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We take a lot for granted by... Standing

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on the shoulders of giants. But when they

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first were doing mechanic ventilation obviously well before

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the 2 thousands. But there's no

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normal to go by. When we're trying to

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decide what are the targets and what are

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the harmful measurements that we may end getting

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or the home for parameters that we should

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try to avoid. Obviously, an evolving landscape that

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we had to get some more answers about,

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and there well has a lot of preliminary

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data leading up to this, but nothing definitive.

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I... Also with today, I think this is

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the number 1 most cited pulmonary critical care

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trial. I believe I'm right and saying that.

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So certainly, we're starting off with the bang.

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Yeah. And if that's not a hundred percent

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factual, it feels a hundred percent factual, I

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thought like this is maybe, like 1 of

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the most cited. On rounds papers if not

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in the actual literature. Okay. So tell us

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about what the design looked like and what

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kind of patients we ended up examining for

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this study. Okay. So this was a a

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randomized trial at 10 academic medical centers in

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the Us that ran from early spring 19

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96 to spring 19 99.

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The primary outcomes they were looking at were

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mortality and vent free days.

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They defined event free day. It counted if

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the

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period of, quote, una assisted breathing lasted at

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least 48 consecutive hours.

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And technically, for mortality, they looked at death

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before discharge and breathing una, which for the

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sake of time. We're just gonna call mortality.

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In terms of their inclusion criteria and who

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the patients were, it was just integrated patients

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with Ards. For

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In terms of their exclusion criteria,

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essentially, the goal here because there's a handful

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of these, but big picture, the goal here

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was to enroll patients early before the ship

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had sailed with their lung damage,

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and to exclude conditions that may con their

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pulmonary mechanics

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So they excluded folks who were over 36

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hours from eligibility

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who

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had an elevated Ic

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neuromuscular disease.

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Severe chronic lung disease,

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cirrhosis, pregnancy, things that could affect kinda intra,

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the way your, abdomen may, impact your pulmonary

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mechanics,

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if they had significant obesity, which they define

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as, like, a weight to weight to centimeter

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height ratio.

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They excluded folks. With greater than 30 percent

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total body surface area burns, and then folks

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you'd had a history of a bone marrow

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or lung transplant

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Yeah. Thanks, a Look. The ventilator free days

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is a really interesting thing. We won't get

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into it too much right now, but some

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of that interesting definition of death before discharge

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and breathe the united

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comes from the fact that if you just

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look at Vent free days, that if people

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pass away early and then are not on

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the bend. It can skew that statistics. Users

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usually always have to be cognizant of it

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when you're doing the contact of your trial,

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which, of course, they were in this trial.

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I love the inclusion exclusion proprietary for this,

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very broad integrated patients with the Ards, and

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really just trying to rule out things. That

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would

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have a disproportionate impact on mortality or your

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ability to liberate from the ventilator.

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So within those context, 2 were these patients

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at the end of the day, once now,

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we've enrolled, that we have these inclusion exclusion,

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who are we looking at?

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Yeah. So at the end of the day,

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who they actually got in the trial was

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middle aged patients that were

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with early moderate Ards and multi system organ

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failure. So they didn't intend to enroll patients

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with multi system organ failure,

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but the mean non pulmonary systems that had

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failed at the time of enrollment was like,

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1.8 in both groups. So a pretty sick

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group.

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And the mean P to f ratio at

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the time of enrollment was in the 1

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thirties in both arms.

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Yeah. And as as you pointed out, I

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leave smarter areas. But mean of 01:30. You

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have some pretty sick Ards s patients there.

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So at the definitely we're examining the group

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that we wanna be looking at. Alright. Now

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the most important thing for us to understand

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when we're gonna take the

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results of a trial and apply it to

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our bedside practice or future research initiatives. What

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were the 2 strategies that they ended up

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looking at between these patients?

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Yeah. So there were 861

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patients. That got randomized to 1 of 2

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ventilator strategies.

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And I emphasize that because I think often

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this gets remembered it as a title volume

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trial and it was a little more to

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it than just tidal volumes.

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So the control arm, they started at a

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tidal volume of 12 ccs per kilo of

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predicted body weight with a step

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titration of those tidal volumes to achieve a

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plateau pressure of 45 to 50

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with a maximum upper limit on the tidal

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volume of 12 cc per kilo ideal body

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weight.

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And a limitation of this paper is that

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10 to 12 ccs per kilo is not

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necessarily something that we would be doing in

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any way at this point. But at in

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some ways, the reason we wouldn't be doing

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that is in large part because of this

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study. And at the time, I think this

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was a little more common than it certainly

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would be now.

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Yeah. I think that's really important point. It's

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1 of the things that's talked about when

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you really look at this trial in detail.

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Is that at 12 Cc at plots of

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45 to 50. These are numbers that are

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nowhere near the standard of care today. And

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so sometimes in re,

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people

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compare 6 ccs versus this sort of extreme

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high volume

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and wonder what the comparison would be like

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at lower title volumes. I think as you

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said, it's very important to remember that this

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reflected practice that time. This is the game

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changing trial. And I think we've got a

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lot of data now that suggest that smaller

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type volumes were beneficial for almost everybody in

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the Ards,

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group with some attention being paid, and that

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should be paid to long recruit and the

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personalization of ventilator care. That's probably the future

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of where we're going. But even though this

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is sometimes viewed as a criticism of this

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trial that the title volumes in the control

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group were so high. I think it's very

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reasonable at the time, and I think it

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ends up giving us a a good comparator

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group.

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And so then diving back into the actual

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intervention or what they did. This will sound

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more familiar to you guys. This was a

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tidal volume of 6 ccs per kilo predicted

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body weight. With that step wise titration to

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achieve a plateau pressure of 25 to 30,

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00:10:01,927 --> 00:10:03,835
they had a minimum of 4 ccs per

268
00:10:03,835 --> 00:10:05,605
kilo, so they... What gonna let you vent

269
00:10:05,605 --> 00:10:07,605
someone with 2 ccs per kilo ideal body

270
00:10:07,605 --> 00:10:10,325
weight. And if there was really severe D,

271
00:10:10,565 --> 00:10:12,804
you were allowed to increase your tidal volumes

272
00:10:12,804 --> 00:10:15,207
up, to 8 hcc per kilo ideal body

273
00:10:15,207 --> 00:10:17,434
weight, but only if the plateau pressure was

274
00:10:17,434 --> 00:10:18,628
still 30 or less.

275
00:10:20,233 --> 00:10:22,461
And then anytime we talk about a, trial

276
00:10:22,461 --> 00:10:24,449
and Ards, it's important to think about all

277
00:10:24,449 --> 00:10:26,518
the other ventilator goals because those can affect

278
00:10:26,518 --> 00:10:28,666
your event meaning and your mortality and whatnot.

279
00:10:29,319 --> 00:10:31,876
And so both groups had shared goals of

280
00:10:31,876 --> 00:10:33,953
with Po to 55 to 80,

281
00:10:34,673 --> 00:10:36,910
Pulse ox of 88 to 95 percent,

282
00:10:37,640 --> 00:10:39,623
Their peep was tit by table. It was

283
00:10:39,623 --> 00:10:40,654
the same in both arms,

284
00:10:41,368 --> 00:10:43,510
and then they had standardized waning off the

285
00:10:43,510 --> 00:10:45,747
vent by pressure support and they were acquired

286
00:10:45,747 --> 00:10:48,212
by protocol to do that once the FF2

287
00:10:48,212 --> 00:10:49,564
was at 40 percent or less.

288
00:10:50,836 --> 00:10:52,904
Yeah. This just touches on a point that's

289
00:10:52,904 --> 00:10:55,782
so hard about ventilator trials. That there are

290
00:10:55,782 --> 00:10:57,850
so many components. If you are adjusting just

291
00:10:57,850 --> 00:10:59,998
tidal volume, how much paper k are you

292
00:10:59,998 --> 00:11:01,748
doing? And if you're just looking at plateau

293
00:11:01,748 --> 00:11:04,149
pressure, is how does that involve the optimal

294
00:11:04,149 --> 00:11:05,900
peep setting. So you really need to have

295
00:11:05,900 --> 00:11:07,889
a good comparison between the 2 groups And

296
00:11:07,889 --> 00:11:09,957
as you stated, they were very consistent between

297
00:11:09,957 --> 00:11:12,039
the 2 groups and this. So the differences

298
00:11:12,039 --> 00:11:14,101
we see we really can chalk up to,

299
00:11:14,498 --> 00:11:16,878
however you wanna conceptualize it tidal volume or

300
00:11:16,878 --> 00:11:17,671
plateau pressure.

301
00:11:18,385 --> 00:11:19,910
The So we have a good understanding. We

302
00:11:19,910 --> 00:11:23,328
have a patient group, moderate superior Ards, broadly

303
00:11:23,328 --> 00:11:26,110
inclusive. We have 2 ventilator strategies, 1 reflecting

304
00:11:26,110 --> 00:11:28,034
the standard of care at the time. And

305
00:11:28,034 --> 00:11:30,431
1 with his goal of 60 per k

306
00:11:30,431 --> 00:11:32,667
with a plateau about third key. That's our

307
00:11:32,667 --> 00:11:34,185
magic number that we're using here.

308
00:11:34,999 --> 00:11:37,077
So what did we refinery? What were the

309
00:11:37,077 --> 00:11:38,595
outcomes and how did these patients do?

310
00:11:39,395 --> 00:11:41,872
Yeah. So unsurprisingly since we're talking about it

311
00:11:41,872 --> 00:11:44,842
here, this was a f positive trial. So

312
00:11:44,842 --> 00:11:46,776
when you look at mortality, the

313
00:11:47,390 --> 00:11:49,961
intervention group had a 31 percent mortality versus

314
00:11:50,018 --> 00:11:51,212
39.8

315
00:11:51,212 --> 00:11:52,645
percent in the control group.

316
00:11:53,296 --> 00:11:54,647
That's a number needed to treat of, like,

317
00:11:54,805 --> 00:11:57,426
just over 11, which is pretty remarkable when

318
00:11:57,426 --> 00:11:59,571
you think about how common Ari ards is

319
00:11:59,571 --> 00:12:00,286
in the Icu.

320
00:12:01,254 --> 00:12:03,564
In terms of event free days, the control

321
00:12:03,564 --> 00:12:05,716
group had... Excuse me, the intervention group had

322
00:12:05,716 --> 00:12:08,287
about 2 more days free from the ventilator

323
00:12:08,345 --> 00:12:10,496
at 28 days and the control group did.

324
00:12:11,229 --> 00:12:12,827
And then when they looked at just the

325
00:12:12,827 --> 00:12:14,825
percentage of people in the 2 arms that

326
00:12:14,825 --> 00:12:17,142
had been liberated from the ventilator by 28

327
00:12:17,142 --> 00:12:20,114
days, that also favored lower tidal volumes this

328
00:12:20,114 --> 00:12:22,910
long protective ventilation, at it, like, just over

329
00:12:22,910 --> 00:12:26,766
65 percent versus 55 percent. Yeah. Extremely

330
00:12:27,145 --> 00:12:29,707
compelling. Evidence and pretty definitive here that we

331
00:12:29,707 --> 00:12:32,809
have, benefit both in terms of liberating somebody

332
00:12:32,809 --> 00:12:35,195
from the ventilator and then having an overhaul

333
00:12:35,195 --> 00:12:36,125
the tyler's benefit

334
00:12:36,483 --> 00:12:38,472
significant differences between the groups and and pretty

335
00:12:38,472 --> 00:12:40,064
hard to argue with that everything's going in

336
00:12:40,064 --> 00:12:40,780
the right direction.

337
00:12:41,656 --> 00:12:43,645
What about the safety outcomes? I think we

338
00:12:43,645 --> 00:12:45,418
really talk about safety

339
00:12:45,809 --> 00:12:48,300
ventilator in an interesting way, and this paper

340
00:12:48,517 --> 00:12:51,305
really a good examination of what we're truly

341
00:12:51,305 --> 00:12:54,013
discussing, but things like new authorities, things like

342
00:12:54,093 --> 00:12:56,173
Barr cha, what did they look at and

343
00:12:56,173 --> 00:12:57,046
what did we end up, John?

344
00:12:57,760 --> 00:12:59,981
Yeah. Interestingly, so they looked at Bar trauma,

345
00:13:00,140 --> 00:13:02,296
and there was no difference between the... 2

346
00:13:02,296 --> 00:13:04,200
groups. So it was 10 episodes of Bar

347
00:13:04,200 --> 00:13:06,048
trauma in the a

348
00:13:06,420 --> 00:13:08,165
intervention group in 11 in the control group,

349
00:13:08,402 --> 00:13:09,592
which is a little surprising,

350
00:13:10,004 --> 00:13:11,839
You would imagine if you had plateau pressures

351
00:13:11,839 --> 00:13:14,391
that were like, almost twice as high that

352
00:13:14,391 --> 00:13:16,305
you would expect there to be more trauma.

353
00:13:16,784 --> 00:13:18,698
And then in terms of non pulmonary organ

354
00:13:18,698 --> 00:13:20,706
failure free days, which was quite the mouthful,

355
00:13:20,866 --> 00:13:23,017
but it's organ failure free days except lung,

356
00:13:23,256 --> 00:13:23,735
basically.

357
00:13:24,213 --> 00:13:26,604
That favored the intervention. So it was 15

358
00:13:26,604 --> 00:13:27,321
versus 12.

359
00:13:27,894 --> 00:13:29,812
Which is interesting. And I think there is

360
00:13:29,812 --> 00:13:32,448
maybe some physiological possibility here or too, because

361
00:13:32,448 --> 00:13:35,005
remember that, like, the minority of people with

362
00:13:35,579 --> 00:13:38,052
Who die from hypo. It's often the non

363
00:13:38,052 --> 00:13:40,843
pulmonary organ failure that causes mortality in these.

364
00:13:41,003 --> 00:13:43,156
And so it's not surprising that if your

365
00:13:43,396 --> 00:13:45,445
Ards patients were doing better that you would

366
00:13:45,564 --> 00:13:47,799
spectrum non pulmonary organs to be doing better

367
00:13:47,799 --> 00:13:47,959
too.

368
00:13:48,678 --> 00:13:50,594
Yeah. I think that this safety outcomes are

369
00:13:50,594 --> 00:13:53,148
extremely interesting. Hard to explain why there's not

370
00:13:53,148 --> 00:13:55,479
evidence of more trauma and not higher title

371
00:13:55,479 --> 00:13:56,997
volume group, I think we would expect to

372
00:13:56,997 --> 00:13:58,675
see that. And maybe with a large enough

373
00:13:58,675 --> 00:14:00,352
group or over time we would see more,

374
00:14:00,752 --> 00:14:03,802
but really wanna highlight that this incidents of

375
00:14:03,802 --> 00:14:06,355
non pulmonary organ failure reflects something that I

376
00:14:06,355 --> 00:14:08,670
think we know now that patients who are

377
00:14:08,670 --> 00:14:12,113
on ventilator settings that are not protective, or

378
00:14:12,113 --> 00:14:15,058
really end the ventilator settings, get ventilator induced

379
00:14:15,058 --> 00:14:17,287
lung entry. And this happens from a variety

380
00:14:17,287 --> 00:14:18,186
of factors

381
00:14:19,134 --> 00:14:21,443
is sort of stretch even if it doesn't

382
00:14:21,443 --> 00:14:23,992
lead to pure arrow trauma where you end

383
00:14:23,992 --> 00:14:27,279
up having pneumothorax can cause increased levels of

384
00:14:27,417 --> 00:14:27,576
inflammation,

385
00:14:28,227 --> 00:14:31,721
increase adverse effects that then get proliferate through

386
00:14:31,721 --> 00:14:34,500
the entire system, and that's our theory of

387
00:14:34,500 --> 00:14:36,882
why using lung protection ends up having to

388
00:14:36,882 --> 00:14:38,731
benefit it's not just for the lungs itself,

389
00:14:38,971 --> 00:14:41,765
but for protecting the entire ph physiological system.

390
00:14:42,963 --> 00:14:45,118
Alright. So in general, if we're looking at

391
00:14:45,118 --> 00:14:47,208
this, and I'm looking at the outcomes, I

392
00:14:47,208 --> 00:14:49,516
think we see lower mortality, more event free

393
00:14:49,516 --> 00:14:52,383
days and less non pulmonary organ failure in

394
00:14:52,383 --> 00:14:55,502
this intervention. So everything is looking very positive

395
00:14:55,502 --> 00:14:57,093
to this and again, this is why this

396
00:14:57,093 --> 00:14:59,320
becomes a landmark trial for us and shapes

397
00:14:59,320 --> 00:15:01,070
the way that we manage J ards going

398
00:15:01,070 --> 00:15:01,388
forward.

399
00:15:02,279 --> 00:15:04,597
Luke, anything we should know about different groups

400
00:15:04,597 --> 00:15:07,313
in this trial or different subsequent analysis just

401
00:15:07,313 --> 00:15:08,752
as more of a deep dive.

402
00:15:09,791 --> 00:15:10,804
Yeah. There is

403
00:15:11,321 --> 00:15:12,933
if you look in in terms of subgroups

404
00:15:12,989 --> 00:15:13,489
at

405
00:15:14,339 --> 00:15:16,427
the effect that the low tidal volume

406
00:15:16,801 --> 00:15:18,707
ventilation had with folks compliance,

407
00:15:19,359 --> 00:15:22,236
Interestingly, they found that mortality benefit did not

408
00:15:22,236 --> 00:15:24,553
vary with static compliance at baseline,

409
00:15:25,113 --> 00:15:27,211
which is to say low tidal volume volume

410
00:15:27,350 --> 00:15:29,997
ventilation or the lung protective ventilation is beneficial

411
00:15:29,997 --> 00:15:33,185
in Ards regardless of someone's baseline compliance.

412
00:15:33,902 --> 00:15:35,895
But when you look at the actual figure,

413
00:15:36,229 --> 00:15:38,383
that's in the paper the trend they displayed

414
00:15:38,383 --> 00:15:41,175
would suggest in my own interpretation that there

415
00:15:41,175 --> 00:15:43,090
might be a greater benefit in sicker patients.

416
00:15:43,424 --> 00:15:46,154
Even if it's not enough to reach statistical

417
00:15:46,370 --> 00:15:46,848
significance.

418
00:15:48,122 --> 00:15:50,272
Yeah. What is a really interesting point. And

419
00:15:50,432 --> 00:15:51,808
I think the natural

420
00:15:52,438 --> 00:15:55,629
next step in that analysis is what ended

421
00:15:55,629 --> 00:15:58,261
up happening with driving pressure analysis is to

422
00:15:58,261 --> 00:16:01,371
say, who's benefiting from these lower volumes, who's

423
00:16:01,371 --> 00:16:03,855
benefiting certain repeat titration and why.

424
00:16:04,333 --> 00:16:06,721
And I think that you're hitting on that

425
00:16:06,721 --> 00:16:08,234
you can see in the images, you can

426
00:16:08,234 --> 00:16:09,747
see in the data. There's this sort of

427
00:16:09,747 --> 00:16:11,512
hint that even though it doesn't look like

428
00:16:11,512 --> 00:16:13,661
there's an overall subgroup. This is helpful for

429
00:16:13,661 --> 00:16:16,287
everyone, maybe some people are benefiting more. And

430
00:16:16,685 --> 00:16:18,435
in my personal opinion and I think where

431
00:16:18,435 --> 00:16:21,480
the data supports, although not at a randomized

432
00:16:21,480 --> 00:16:23,475
trial level. Yeah. Is that what we're end,

433
00:16:23,554 --> 00:16:25,310
you end up looking at is driving pressure.

434
00:16:25,549 --> 00:16:27,876
To predict how we shouldn't manipulate our event

435
00:16:27,876 --> 00:16:29,462
settings and who may end up having the

436
00:16:29,462 --> 00:16:30,097
most benefit.

437
00:16:31,366 --> 00:16:33,745
Alright, Luke. This is a great review. What

438
00:16:33,745 --> 00:16:36,383
is our 1 line takeaway of what people

439
00:16:36,383 --> 00:16:38,697
should take know about the Arm trial when

440
00:16:38,697 --> 00:16:39,894
they're are gonna take care of patients in

441
00:16:39,894 --> 00:16:40,772
the Icu this month.

442
00:16:41,650 --> 00:16:43,725
Yeah. I think the newspaper headline version of

443
00:16:43,725 --> 00:16:46,625
this. Is that a strategy of lung protective

444
00:16:46,761 --> 00:16:48,826
ventilation with tidal volumes of 4 to 8

445
00:16:48,906 --> 00:16:51,449
Ccs per kilo ideal body weight and plateau

446
00:16:51,449 --> 00:16:54,415
pressures of 30 less 30 or less improves

447
00:16:54,415 --> 00:16:54,815
mortality,

448
00:16:55,455 --> 00:16:56,434
liberation from the ventilator

449
00:16:56,815 --> 00:16:58,675
and non pulmonary organ failure

450
00:16:59,055 --> 00:17:00,735
and that this has become the standard of

451
00:17:00,735 --> 00:17:00,894
care.

452
00:17:02,262 --> 00:17:03,932
Couldn't said it better. I think this is

453
00:17:03,932 --> 00:17:05,839
a standard of care for our patients. These

454
00:17:05,839 --> 00:17:07,986
numbers of 6 ccs per kg and plateau

455
00:17:07,986 --> 00:17:10,226
pressures of 30. Are really what we are

456
00:17:10,226 --> 00:17:11,896
gonna say in the Icu all the time,

457
00:17:12,134 --> 00:17:14,201
and that our learners in the Icu should

458
00:17:14,201 --> 00:17:14,678
know about.

459
00:17:15,552 --> 00:17:17,460
Alright. This is just the first in many

460
00:17:17,460 --> 00:17:19,462
episodes coming up. About some of these landmark

461
00:17:19,462 --> 00:17:21,928
trials. Luke. See you shortly, and and we'll

462
00:17:21,928 --> 00:17:23,440
go on to the next 1. Yeah. I'm

463
00:17:23,440 --> 00:17:24,076
looking forward to it.