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.