Everybody. Welcome back to Paul Pee. I'm joined today by Luke He, our associate Editor who's in charge of Rapid fire Journal Clubs. Hey, Luke How are you doing? Hey, Dave. I'm good. It's good be back. Yeah. I like that Sure. You're looking good. This is a App over recording video. So you guys may be able to check this out on, Youtube review med. So you you look the park for today. Thanks, Man. I I got back from the beach like, a week and a half ago. So It felt very... I'm trying to hold
on to that vacation feeling. Yes. You. It's a good shot. I'm excited about a new initiative that we're going forward with and rapid fire journal club. Every time we do journal club, I feel like in person at the hospital, people love it. And 1 very common request that I hear from learners is can we do this type of journal club review of old landmark trials? I don't have as much of an understanding of those is it's great to hear new trials, but I would like to understand those old trials.
And so we're diving in with that mentality as it's July and early in the academic year to try to give a review of some landmark trials that are shaped critical care, and we're being a little bit focused about it So, luke, why don't you tell our listeners a little bit more about what we're gonna do over the next few weeks. Yeah. So over the next few weeks. I'm excited we're gonna have series of episodes about some of the landmark trials in Air ards management.
A lot of those are gonna be about ventilation, but some of the other non ventilator aspects of care for these really sick patients. I feel like when I was starting fellowship a year ago and as a resident, I often knew that these were things we did, but I didn't necessarily have the best understanding of the literature,
underlying those decision making those management points. And so Our hope is that this serves as a quick dive into the deep end for people who are starting training or for people who have Icu rotations coming up. Yeah, A hundred percent, and I think that in going through these, we're gonna try to do it quickly, but we're gonna try to raise some of the issues that really helped
define these trials as the paradigm. I always say this about trials when not I'm teaching them is that knowing the names of trials is like being able to do card tricks. It doesn't actually make you a better poker player. It just looks cool. So we often do this. We say, we do low title because of arm. But it's important to understand what the actual conduct conduct was of the trial. So we 1 know, doesn't it apply to our patients? How does it apply to our patients. How did it become so defining?
And then 2, what are the next steps? What are the remaining questions and research that we have to answer. And so that's what we're gonna try to delve into a little bit for this? So to kick it off, we are gonna start with that exact trial. We're gonna start with the Arm trial. Luke, why don't you give us a little background in introduction. And Yeah. So this is the Arm trial. You may have heard it referred to as the Ar trial as well. This was published in the New England Journal back in 2000.
And it was a trial looking at ventilation strategies for patients with Ari ards. In terms of kind of the background of where this came from, At the time, some traditional approaches to mechanical ventilation, we're using large tidal volumes, of like 10 to 15 Ccs per kilo, primarily in an effort to normalize someone's Pac 2 and their ph at the expense of high ins airway pressures.
There were some emerging data at the time that suggested that over extension and stress induced lung injury could be causing harm, But smaller trials and some uncontrolled studies of lower title volumes had varying a purchase to airway management and unsurprisingly had excuse me, airway pressure management and had conflicting results gone surprisingly. Yeah. And I love to think about this. We take a lot for granted by... Standing
on the shoulders of giants. But when they first were doing mechanic ventilation obviously well before the 2 thousands. But there's no normal to go by. When we're trying to decide what are the targets and what are the harmful measurements that we may end getting or the home for parameters that we should try to avoid. Obviously, an evolving landscape that we had to get some more answers about, and there well has a lot of preliminary data leading up to this, but nothing definitive.
I... Also with today, I think this is the number 1 most cited pulmonary critical care trial. I believe I'm right and saying that. So certainly, we're starting off with the bang. Yeah. And if that's not a hundred percent factual, it feels a hundred percent factual, I thought like this is maybe, like 1 of the most cited. On rounds papers if not in the actual literature. Okay. So tell us about what the design looked like and what kind of patients we ended up examining for
this study. Okay. So this was a a randomized trial at 10 academic medical centers in the Us that ran from early spring 19 96 to spring 19 99. The primary outcomes they were looking at were mortality and vent free days. They defined event free day. It counted if the period of, quote, una assisted breathing lasted at least 48 consecutive hours. And technically, for mortality, they looked at death before discharge and breathing una, which for the sake of time. We're just gonna call mortality.
In terms of their inclusion criteria and who the patients were, it was just integrated patients with Ards. For In terms of their exclusion criteria, essentially, the goal here because there's a handful of these, but big picture, the goal here was to enroll patients early before the ship had sailed with their lung damage, and to exclude conditions that may con their pulmonary mechanics So they excluded folks who were over 36 hours from eligibility who had an elevated Ic neuromuscular disease.
Severe chronic lung disease, cirrhosis, pregnancy, things that could affect kinda intra, the way your, abdomen may, impact your pulmonary mechanics, if they had significant obesity, which they define as, like, a weight to weight to centimeter height ratio. They excluded folks. With greater than 30 percent total body surface area burns, and then folks you'd had a history of a bone marrow or lung transplant Yeah. Thanks, a Look. The ventilator free days
is a really interesting thing. We won't get into it too much right now, but some of that interesting definition of death before discharge and breathe the united comes from the fact that if you just look at Vent free days, that if people pass away early and then are not on the bend. It can skew that statistics. Users usually always have to be cognizant of it when you're doing the contact of your trial, which, of course, they were in this trial.
I love the inclusion exclusion proprietary for this, very broad integrated patients with the Ards, and really just trying to rule out things. That would have a disproportionate impact on mortality or your ability to liberate from the ventilator. So within those context, 2 were these patients at the end of the day, once now, we've enrolled, that we have these inclusion exclusion, who are we looking at?
Yeah. So at the end of the day, who they actually got in the trial was middle aged patients that were with early moderate Ards and multi system organ failure. So they didn't intend to enroll patients with multi system organ failure, but the mean non pulmonary systems that had failed at the time of enrollment was like, 1.8 in both groups. So a pretty sick group. And the mean P to f ratio at the time of enrollment was in the 1 thirties in both arms. Yeah. And as as you pointed out, I
leave smarter areas. But mean of 01:30. You have some pretty sick Ards s patients there. So at the definitely we're examining the group that we wanna be looking at. Alright. Now the most important thing for us to understand when we're gonna take the results of a trial and apply it to our bedside practice or future research initiatives. What were the 2 strategies that they ended up looking at between these patients? Yeah. So there were 861
patients. That got randomized to 1 of 2 ventilator strategies. And I emphasize that because I think often this gets remembered it as a title volume trial and it was a little more to it than just tidal volumes. So the control arm, they started at a tidal volume of 12 ccs per kilo of predicted body weight with a step titration of those tidal volumes to achieve a plateau pressure of 45 to 50 with a maximum upper limit on the tidal volume of 12 cc per kilo ideal body weight.
And a limitation of this paper is that 10 to 12 ccs per kilo is not necessarily something that we would be doing in any way at this point. But at in some ways, the reason we wouldn't be doing that is in large part because of this study. And at the time, I think this was a little more common than it certainly would be now. Yeah. I think that's really important point. It's 1 of the things that's talked about when you really look at this trial in detail. Is that at 12 Cc at plots of
45 to 50. These are numbers that are nowhere near the standard of care today. And so sometimes in re, people compare 6 ccs versus this sort of extreme high volume and wonder what the comparison would be like at lower title volumes. I think as you said, it's very important to remember that this reflected practice that time. This is the game
changing trial. And I think we've got a lot of data now that suggest that smaller type volumes were beneficial for almost everybody in the Ards, group with some attention being paid, and that should be paid to long recruit and the personalization of ventilator care. That's probably the future of where we're going. But even though this is sometimes viewed as a criticism of this trial that the title volumes in the control
group were so high. I think it's very reasonable at the time, and I think it ends up giving us a a good comparator group. And so then diving back into the actual intervention or what they did. This will sound more familiar to you guys. This was a tidal volume of 6 ccs per kilo predicted body weight. With that step wise titration to achieve a plateau pressure of 25 to 30, they had a minimum of 4 ccs per kilo, so they... What gonna let you vent someone with 2 ccs per kilo ideal body
weight. And if there was really severe D, you were allowed to increase your tidal volumes up, to 8 hcc per kilo ideal body weight, but only if the plateau pressure was still 30 or less. And then anytime we talk about a, trial and Ards, it's important to think about all the other ventilator goals because those can affect your event meaning and your mortality and whatnot. And so both groups had shared goals of with Po to 55 to 80, Pulse ox of 88 to 95 percent,
Their peep was tit by table. It was the same in both arms, and then they had standardized waning off the vent by pressure support and they were acquired by protocol to do that once the FF2 was at 40 percent or less. Yeah. This just touches on a point that's so hard about ventilator trials. That there are so many components. If you are adjusting just tidal volume, how much paper k are you doing? And if you're just looking at plateau pressure, is how does that involve the optimal
peep setting. So you really need to have a good comparison between the 2 groups And as you stated, they were very consistent between the 2 groups and this. So the differences we see we really can chalk up to, however you wanna conceptualize it tidal volume or plateau pressure. The So we have a good understanding. We have a patient group, moderate superior Ards, broadly inclusive. We have 2 ventilator strategies, 1 reflecting the standard of care at the time. And 1 with his goal of 60 per k
with a plateau about third key. That's our magic number that we're using here. So what did we refinery? What were the outcomes and how did these patients do? Yeah. So unsurprisingly since we're talking about it here, this was a f positive trial. So when you look at mortality, the intervention group had a 31 percent mortality versus 39.8 percent in the control group.
That's a number needed to treat of, like, just over 11, which is pretty remarkable when you think about how common Ari ards is in the Icu. In terms of event free days, the control group had... Excuse me, the intervention group had about 2 more days free from the ventilator at 28 days and the control group did.
And then when they looked at just the percentage of people in the 2 arms that had been liberated from the ventilator by 28 days, that also favored lower tidal volumes this long protective ventilation, at it, like, just over 65 percent versus 55 percent. Yeah. Extremely
compelling. Evidence and pretty definitive here that we have, benefit both in terms of liberating somebody from the ventilator and then having an overhaul the tyler's benefit significant differences between the groups and and pretty hard to argue with that everything's going in the right direction.
What about the safety outcomes? I think we really talk about safety ventilator in an interesting way, and this paper really a good examination of what we're truly discussing, but things like new authorities, things like Barr cha, what did they look at and what did we end up, John? Yeah. Interestingly, so they looked at Bar trauma, and there was no difference between the... 2
groups. So it was 10 episodes of Bar trauma in the a intervention group in 11 in the control group, which is a little surprising, You would imagine if you had plateau pressures that were like, almost twice as high that you would expect there to be more trauma. And then in terms of non pulmonary organ failure free days, which was quite the mouthful, but it's organ failure free days except lung, basically. That favored the intervention. So it was 15 versus 12.
Which is interesting. And I think there is maybe some physiological possibility here or too, because remember that, like, the minority of people with Who die from hypo. It's often the non pulmonary organ failure that causes mortality in these. And so it's not surprising that if your Ards patients were doing better that you would spectrum non pulmonary organs to be doing better too. Yeah. I think that this safety outcomes are
extremely interesting. Hard to explain why there's not evidence of more trauma and not higher title volume group, I think we would expect to see that. And maybe with a large enough group or over time we would see more, but really wanna highlight that this incidents of non pulmonary organ failure reflects something that I think we know now that patients who are on ventilator settings that are not protective, or really end the ventilator settings, get ventilator induced
lung entry. And this happens from a variety of factors is sort of stretch even if it doesn't lead to pure arrow trauma where you end up having pneumothorax can cause increased levels of inflammation, increase adverse effects that then get proliferate through the entire system, and that's our theory of why using lung protection ends up having to benefit it's not just for the lungs itself, but for protecting the entire ph physiological system.
Alright. So in general, if we're looking at this, and I'm looking at the outcomes, I think we see lower mortality, more event free days and less non pulmonary organ failure in this intervention. So everything is looking very positive to this and again, this is why this becomes a landmark trial for us and shapes the way that we manage J ards going forward. Luke, anything we should know about different groups in this trial or different subsequent analysis just as more of a deep dive.
Yeah. There is if you look in in terms of subgroups at the effect that the low tidal volume ventilation had with folks compliance, Interestingly, they found that mortality benefit did not vary with static compliance at baseline, which is to say low tidal volume volume ventilation or the lung protective ventilation is beneficial in Ards regardless of someone's baseline compliance.
But when you look at the actual figure, that's in the paper the trend they displayed would suggest in my own interpretation that there might be a greater benefit in sicker patients. Even if it's not enough to reach statistical significance. Yeah. What is a really interesting point. And I think the natural next step in that analysis is what ended up happening with driving pressure analysis is to say, who's benefiting from these lower volumes, who's benefiting certain repeat titration and why.
And I think that you're hitting on that you can see in the images, you can see in the data. There's this sort of hint that even though it doesn't look like there's an overall subgroup. This is helpful for everyone, maybe some people are benefiting more. And in my personal opinion and I think where the data supports, although not at a randomized trial level. Yeah. Is that what we're end, you end up looking at is driving pressure.
To predict how we shouldn't manipulate our event settings and who may end up having the most benefit. Alright, Luke. This is a great review. What is our 1 line takeaway of what people should take know about the Arm trial when they're are gonna take care of patients in the Icu this month. Yeah. I think the newspaper headline version of
this. Is that a strategy of lung protective ventilation with tidal volumes of 4 to 8 Ccs per kilo ideal body weight and plateau pressures of 30 less 30 or less improves mortality, liberation from the ventilator and non pulmonary organ failure and that this has become the standard of care. Couldn't said it better. I think this is a standard of care for our patients. These numbers of 6 ccs per kg and plateau
pressures of 30. Are really what we are gonna say in the Icu all the time, and that our learners in the Icu should know about. Alright. This is just the first in many episodes coming up. About some of these landmark trials. Luke. See you shortly, and and we'll go on to the next 1. Yeah. I'm looking forward to it.