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Refractory Hypoxemia
10 Plays6 years ago
Lung protective ventilation for ARDS includes the use of low tidal volumes, positive-end expiratory pressure (PEEP), and limiting of airway plateau pressure to minimize ventilator-induced lung injury. However, in the sickest subset of patients with ARDS hypoxemia may persist despite optimal lung protective strategies. In this episode of Critical Matters, we discuss salvage therapies for patients with refractory hypoxemia. Our guest is Dr. Robert Hyzy, Medical Director of the Critical Care Medicine Unit and Co-Chair of the Critical Care Committee at the University of Michigan Hospital.
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Transcript
Introduction to Critical Matters Podcast
00:00:09
Speaker
Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:17
Speaker
And now, your host, Dr. Sergio Zanotti.
00:00:23
Speaker
In a previous episode of Critical Matters, we discussed the initial management of patients with ARDS,
00:00:28
Speaker
During this discussion, we covered the concept of lung protective ventilation, which includes low tidal volumes, PEEP, and limiting airway plateau pressures.
00:00:36
Speaker
These are the interventions that every patient with ARDS should receive.
Challenges in ARDS Management
00:00:40
Speaker
However, there is a subset of patients in whom, despite the application of evidence-based lung protective ventilation, hypoxemia persists and can be life-threatening.
00:00:50
Speaker
Today, we discuss the management of such patients, what some refer to as salvage therapy, in patients with refractory hypoxemia and ARDS.
00:00:58
Speaker
Our guest is Dr. Robert Heise.
00:01:01
Speaker
Dr. Heise is the medical director of the critical care medicine unit and co-chair of the critical care committee at the University of Michigan Hospital.
00:01:08
Speaker
He's faculty, a professor of medicine, Division of Pulmonary and Critical Care at the University of Michigan in Ann Arbor.
00:01:14
Speaker
His research interests include ARDS, ventilator-associated pneumonia, and quality improvement.
00:01:20
Speaker
Dr. Heise is an accomplished investigator, clinician, and educator.
00:01:23
Speaker
He is a member of the American College of Chest Physicians Guidelines Oversight Committee and the American Thoracic Society Quality Improvement Committee.
00:01:30
Speaker
Dr. Heise has spoken nationally and internationally on several topics related to critical care medicine and has a special interest in ARDS.
00:01:38
Speaker
He has published multiple articles and chapters in medical journals and textbooks and has been a reviewer for the Annals of Internal Medicine, American Journal of Respiratory and Critical Care Medicine, Chest and Critical Care Medicine.
Understanding Refractory Hypoxemia
00:01:51
Speaker
Bob, welcome to Critical Matters.
00:01:53
Speaker
Thank you, Sergio.
00:01:55
Speaker
So today we want to expand a little bit on a previous conversation that we had in the podcast related to ARDS and really think about those patients in whom we apply low tidal ventilation, we apply appropriate PEEP, we protect the plateau pressures, but they're still in what we call refractory hypoxemia, are still having trouble.
00:02:15
Speaker
And I think that a good starting point might be, Bob, is
00:02:20
Speaker
How do you define refractory hypoxemia?
00:02:22
Speaker
I know in the literature there's a variation of definitions, but in your concept, what would you call refractory hypoxemia?
00:02:30
Speaker
Well, that's a great point because there is a lot of variability and no uniform definition.
00:02:34
Speaker
There was an article in the Annals of ATS I reviewed and wrote an editorial for where the Canadians resorted to their definition, which did not really include recruiting with PEEP.
00:02:45
Speaker
So for me, if you're talking about moving on to some of the therapies you mentioned,
00:02:49
Speaker
that would be patients who are not adequately saturating or oxygenating despite high levels of FiO2 and appropriate attempts to recruit with PEEP.
00:02:58
Speaker
So I can't give you some numbers, but ballpark numbers, let's say if your PO2 is still in the 50s when you're on 1820 of PEEP and you're not doing well, I mean, that's close enough.
00:03:10
Speaker
But I don't have a single working definition because there isn't a uniform definition agreed upon in critical care medicine.
Stepwise Approach to ARDS Treatment
00:03:18
Speaker
And from a practical and tactical standpoint, I think that you mentioned something very important.
00:03:23
Speaker
I mean, in terms of it's hard to say this is the exact number, but you did mention in somebody who's already on 20 or more of PEEP.
00:03:30
Speaker
So I guess that my question is, this is not something that you make a diagnosis as soon as the patient hits the ICU, but really something that you consider after doing some things first, right?
00:03:40
Speaker
I mean, exactly.
00:03:42
Speaker
You mentioned low tidal volume ventilation.
00:03:43
Speaker
Sure, exactly so, but it doesn't end there.
00:03:48
Speaker
when you're saying refractory hypoxemia you're generally talking about a what we call berlin severe patient who will have a pdf ratio under 100 on at least five a peep that's a that's a starting point for someone who uh might be uh a trouble to manage and then and then you recruit them and if you if they're eminently recruitable you might get by with say i don't know 15 a peep and next thing you know the fio2 is dialed down to 50 and i'm good to go i don't think i need to resort to these other things we're about to discuss
00:04:18
Speaker
Okay.
00:04:19
Speaker
And I think that this is important because I often encounter clinicians who very quickly, before a lot of these basic interventions are given any time to work or applied, are thinking of salvage therapies of all sorts.
00:04:32
Speaker
And I think that it's important to go in a stepwise approach and implement what's been proven to work first, see how patients respond.
00:04:39
Speaker
And then if we still have trouble, we now start thinking about this patient has refractory hypoxemia.
00:04:45
Speaker
Absolutely.
00:04:45
Speaker
We'll get to a sequence, ECMO, at the end, but there was one series that showed that only 31% of patients in this one series who received ECMO had an attempt to have prone ventilation before they pulled the trigger on ECMO.
00:04:59
Speaker
I think you're exactly right.
00:05:00
Speaker
There is an explicit evidence-based hierarchy here, but I do think there is some logic to this.
00:05:07
Speaker
Let's start with that logical approach.
00:05:10
Speaker
If you have implemented a lung protective ventilation, have optimized your PEEP,
00:05:15
Speaker
and after, let's say, a couple of hours, your patient's in the ICU, and you're still having hypoxemia, you still have a PAO2 that is not making you comfortable, like you said, what would be your next step, or what would be the first tier of interventions that you would try for that patient?
Neuromuscular Blockades in ARDS Management
00:05:31
Speaker
Well, there's two things I think about then.
00:05:33
Speaker
One, at this juncture, with current evidence, would be neuromuscular RAC-K to avoid dyssynchrony, and that might improve the patient's stead.
00:05:42
Speaker
We're going to have more information about
00:05:44
Speaker
We're part of the Pedal Network, and Mark Moss and Derek Angus are the PIs on our publication.
00:05:49
Speaker
It will be out, I believe, at the SCCM meeting regarding whether or not the Acurisis article is really the way to go.
00:05:57
Speaker
We'll have more evidence on that.
00:05:58
Speaker
The other thing I often think about is body habitus.
00:06:02
Speaker
Danny Calmore has EpiVent 2 coming out.
00:06:05
Speaker
We participated here as a site for that.
00:06:07
Speaker
And patients whose abdomen is in play, post-op bellies, ascites,
00:06:14
Speaker
morbid obesity if I get to 20 a peep and think that I'm not helping the patient enough another thing to think about is we'll do transpulmonary pressure we'll put esophageal balloon in now admittedly that's not a technology that's uniformly available but we have that ability we have to switch out a ventilator for that and in that case you could argue that 20 people aren't really seeing that airway pressure because we think about a plateau pressure a plateau pressure
00:06:42
Speaker
incorporates the chest wall and the belly is part of the chest wall.
00:06:45
Speaker
So in circumstances where the abdomen is exerting significant pressure, if you will, on the lungs, that can be another thing to do.
00:06:53
Speaker
So those are the two sort of branch points I hit at that moment.
00:06:57
Speaker
So I think that those are excellent points.
00:06:59
Speaker
And like you said, I mean, first think about is there anything individual about this patient, such as morbid obesity, that might mean that what I'm doing right now is not optimized for their physiology.
00:07:10
Speaker
And I think that's a great example of where maybe you need more than just driving pressure or maybe where you need more than just measuring compliance.
00:07:18
Speaker
And esophageal balloons might become helpful for that subpopulation, like you said.
00:07:23
Speaker
And then the second thing that I would like to poke your brain a little bit more about is the use of neuromuscular blockers.
00:07:29
Speaker
And obviously, it's a great way to decrease patient ventricular asynchrony.
00:07:34
Speaker
There is one large randomized trial, the French trial, like you mentioned, that has shown positive outcomes.
00:07:40
Speaker
But could you give us a little bit more in terms of practical aspects?
00:07:44
Speaker
How long do you do it?
00:07:45
Speaker
Do you follow training for?
00:07:47
Speaker
I think some people have talked about that all you have to do is really target to your ventricular support.
00:07:53
Speaker
and how long do you do it?
00:07:56
Speaker
Well, you know, in a curasis it was done for 48 hours, but in patients in whom I do it, I do it as long as it's necessary.
00:08:01
Speaker
In other words, at 48 hours, if you remove neuromuscular K and you desaturate, well, I go longer, and if sooner than 48 hours you have gas exchange that has improved significantly, I'll back away.
00:08:15
Speaker
So, there's sort of a 48-hour notion, but I'd certainly go either way on that.
00:08:20
Speaker
In terms of training a four,
00:08:23
Speaker
You know, that was a criticism of the Curisys article.
00:08:27
Speaker
And frankly, I'm not sure it matters as much in the modern era with the Etercurium being the agent of choice for so many individuals.
00:08:33
Speaker
That's broken down in the blood.
00:08:36
Speaker
You don't get the kinds of prolonged paralysis issues we used to see with Vecuronium in the setting of organ dysfunction.
00:08:41
Speaker
So I'm not against Trinafore, but I think really it's not a critical piece here.
00:08:48
Speaker
If you're not triggering the vent, you're not triggering the vent.
00:08:51
Speaker
So I'm not against it.
00:08:52
Speaker
I think a more challenging and least evidence-based issue relates to monitoring of sedation during neuromuscular blackade.
00:09:01
Speaker
And it's a controversial issue.
00:09:03
Speaker
We still have a bis monitor, bispectral analysis, and the literature on that has been not particularly supportive or great.
00:09:10
Speaker
But what else do you have?
00:09:13
Speaker
In other words, the notion of a family member walked in a room and a patient's pulse went from 100 to 110, therefore they must be too light
00:09:20
Speaker
with their sedation when they're blockaded, that doesn't really help you that much.
00:09:26
Speaker
I admittedly, BIS is a mixed bag, and I'm not going to dispute that.
00:09:30
Speaker
But to me, training a four, I'm not against it, but I don't think it's completely essential for guiding you.
00:09:38
Speaker
I'm more concerned about ensuring your patients are sedated because, of course, neuromuscular blocking agents are not sedative.
00:09:43
Speaker
Yeah, absolutely.
00:09:44
Speaker
I think that you point out to great issues that not everything that we use has the highest level of evidence, but as long as you understand what are the limitations.
00:09:55
Speaker
And I guess the other aspect that I think is very important, and we'll probably touch on this when we get to pronin and ECMO.
00:10:01
Speaker
is also the routine or the discipline of doing things a certain way in your unit trains your team to be very efficient in handling that.
00:10:09
Speaker
And I think that people can learn from that as well, obviously at a lower level of evidence that may be large randomized trials.
00:10:16
Speaker
But I think that having expertise in your own unit with certain things and having a way of doing it is always, I think, a good thing while we wait for more evidence.
00:10:26
Speaker
I couldn't agree more.
Salvage Therapies and Prone Positioning
00:10:27
Speaker
Process of care, we call that.
00:10:28
Speaker
And having a solid process of care...
00:10:31
Speaker
is very impactful and meaningful for good care delivery.
00:10:34
Speaker
And you mentioned one of the studies that looked at ECMO in the ATS annals.
00:10:41
Speaker
I've reviewed some articles that have looked at kind of the spectrum of what's going on with salvage therapy.
00:10:47
Speaker
And that was very interesting to me in two articles that looked at this at the ATS journals.
00:10:55
Speaker
They talked about the lack of an established process for salvage therapy in most ICUs, how very few of the ICUs that they examine have a very defined protocol and process of how they escalate this.
00:11:11
Speaker
Could you comment on that a little bit?
00:11:13
Speaker
Well, we have one here at University of Michigan, and we try to, within reason, adhere to it.
00:11:18
Speaker
It echoes at the bottom of the page, which is to say these other things are attempted prior to
00:11:24
Speaker
And as I mentioned to you, that article about some of these modalities not having been attempted prior to ECMO cannulation is a concern.
00:11:35
Speaker
So we have a protocol because we have a lot of these patients.
00:11:39
Speaker
We have patients referred in.
00:11:41
Speaker
And also because we're all here big believers in process of care and not just sort of approaching things willy-nilly.
00:11:49
Speaker
And I think that's an important point.
00:11:51
Speaker
And as people will find out that they don't know yet, ECMO has a long story in the University of Michigan, and there's tremendous experience there.
00:11:59
Speaker
So I think that we'll touch on that a little bit more.
00:12:02
Speaker
So after you've optimized, Bob, for the individual patient, an example you gave was a morbid obese patient, you've thought about neuromuscular blockers.
00:12:12
Speaker
If you're still having trouble, what's next?
00:12:16
Speaker
Well, prone positioning is on my list, right?
00:12:20
Speaker
And the Perseva article, which came out a few years ago now, I think had an incredible mortality benefit.
00:12:28
Speaker
And there's been a lot of reading of the tea leaves there with regard to what that meant.
00:12:33
Speaker
Either they got lucky or they finally got it right, if you will.
00:12:35
Speaker
I mean, earlier proning articles and studies have been negative, were criticized for lack of use of lung protective inhalation, not keeping them prone long enough.
00:12:46
Speaker
things of that sort.
00:12:47
Speaker
And so if you look at the historic timeline, it looks like things are getting better until finally Proceva hit and hit big.
00:12:53
Speaker
If you look at a force plot for treatment effect, it was pretty dramatic, but it doesn't matter to me.
00:12:58
Speaker
I mean, I'm sold.
00:13:00
Speaker
And it's become a go-to thing at that point, particularly in the context of other potential go-to things such as oscillation, which has had some negative studies.
00:13:11
Speaker
So I think proning should be done.
00:13:14
Speaker
Now, I've been
00:13:16
Speaker
Around the country, I've got a good friend, Ivor Douglas, at Colorado.
00:13:19
Speaker
They're big believers in proning.
00:13:22
Speaker
They'll do it pretty quickly.
00:13:24
Speaker
In Proceva, they waited 12 hours.
00:13:26
Speaker
And so, in other words, I'm going to optimize the patient.
00:13:28
Speaker
If I can optimize the patient, like I said, if I'm at 18 to 50% oxygen, I'm not going to prone.
00:13:34
Speaker
But if we're talking refractory, as I've kind of amorphously described it to you, that would be my next thing.
00:13:40
Speaker
And I think that in terms of talking about more of the practicalities and what we can learn from the proning trials that were positive, why don't we start with maybe reminding the audience, what are the theoretical benefits of prone position ventilation in a patient with ARDS?
00:13:57
Speaker
Well, so in ARDS, despite having lungs that leak, if you will, diffusely, there's still gas exchange heterogeneity due to compressive atelectasis.
00:14:07
Speaker
By that, I mean,
00:14:08
Speaker
the weight of the lung causes smush in the dependent lung zones.
00:14:12
Speaker
And so does the weight of the heart when you're lying on your back.
00:14:16
Speaker
So the distribution of ventilation is more equitable when you are lying prone and the weight of the heart is removed and the posterior inferior aspects of the lung where a lot of that smush occurred are now able to be aerated.
00:14:28
Speaker
So you're redistributing where the delivered mechanical ventilation breath will get to when you put a patient prone.
00:14:37
Speaker
And that goes back to what some people call ventral preservation, which are dorsal preservation, which is kind of a evolutionary, um,
00:14:44
Speaker
aspect of biology.
00:14:47
Speaker
And in terms of, Bob, in terms of, you talked about some of the things that people thought we were doing wrong.
00:14:52
Speaker
So one of the things that they did in the proning trials that were positive is they selected their population a little bit better, right?
00:14:59
Speaker
They only took patients who, A, were severe ARDS, so were very hypoxemic, but also they standardized what everybody got before they got proning.
00:15:09
Speaker
I think that those are two important aspects.
00:15:12
Speaker
I know clearly I should have mentioned that because I did mention other notions of earlier criticisms for not being lung protective and so forth.
00:15:18
Speaker
But that was another criticism was if you're not that severe, you're not going to be helped one way or another.
00:15:25
Speaker
And so if you enroll patients aren't that sick, then you're not going to see what you need to see in terms of a difference in outcomes.
00:15:33
Speaker
And one of the things that has always attracted me from prone positioning, especially with our group that practices in a diverse range of hospitals in the community, some very large and with a lot of technology, some, I mean, that are smaller, is that good proning is not about technology but about process.
00:15:54
Speaker
However,
00:15:55
Speaker
But before we go into some of the details of how you prone, there are a lot of commercial beds that have tried to capitalize on the proning.
00:16:04
Speaker
Do you use those?
00:16:05
Speaker
Do we need those?
00:16:06
Speaker
We do not have the luxury of having them.
00:16:08
Speaker
So my experience with them is limited in terms of visiting other institutions.
00:16:13
Speaker
So we do it the old fashioned way with hard work and lots of nurses.
00:16:18
Speaker
And it works fine, right?
00:16:19
Speaker
So as long as you train people and you have a team.
00:16:21
Speaker
Listen, these people, as you can imagine, one reason this is not embraced, if you will, is because these people are sick and they're plugged in with tubes and lines and such.
00:16:31
Speaker
And, you know, you want to get all tangled up.
00:16:33
Speaker
So it is not easy to...
00:16:36
Speaker
Other than the fact that it's the right thing to do, there's no reason to do it, right?
00:16:40
Speaker
In other words, it's not easy, but it is the right thing to do.
00:16:43
Speaker
And when you decide to prone somebody, so you said, I mean, you start with optimizing everything and they're still not responding.
00:16:50
Speaker
At that point, you might consider, okay, my next step is proning.
00:16:52
Speaker
Absolutely.
00:16:54
Speaker
How long do you usually let them prone?
00:16:56
Speaker
Minimum of 16 hours a day.
00:16:58
Speaker
I mean, this is the point.
00:16:59
Speaker
This is one of the issues.
00:17:00
Speaker
If you look at the โ there's lots of ways to look at the โ
00:17:04
Speaker
croning studies have done in the past, but I think there was a Cochrane analysis, for example.
00:17:08
Speaker
Clearly, you need to spend the vast majority of the 24-hour period face down.
00:17:14
Speaker
I think that has been shown to be one of the reasons this can be impactful.
00:17:19
Speaker
So, minimum 16 hours a day, and then flip them back for the remainder, and then back and forth, but mainly down until you really get a break in the action and see that they're oxygenating better.
00:17:31
Speaker
I had a colleague of mine
00:17:34
Speaker
He texted me about a case the other day, he said, when do you stop?
00:17:35
Speaker
I said, well, when they're better.
00:17:38
Speaker
But it is clear that you need to be face down for much of the day.
00:17:45
Speaker
And like you said, I mean, you see how the response is and when you stop getting that response is when probably when it, when a plateau is that maybe it's not working anymore.
00:17:54
Speaker
What about somebody that you prone and has no improvement 10 hours later?
00:17:59
Speaker
What do you do?
00:18:01
Speaker
Well, I mean, that's the point.
00:18:04
Speaker
We don't have โ well, no, we're ECMO center, and oscillation used to be sort of in my algorithm, but the OSCR, but especially the Oscillate trial, which we did at this place, part of the Canadian critical care trials group, had a worse outcome.
00:18:21
Speaker
So, to me, that's kind of getting towards the end of the road towards ECMO.
00:18:27
Speaker
So, you say you're prone, and you're peeped, and you're paralyzed, and
00:18:32
Speaker
so forth, sedated, and you're still not getting anywhere, and it's early on, right?
00:18:36
Speaker
We're not talking about on day 10.
00:18:38
Speaker
We're talking more on day two or three.
00:18:42
Speaker
I will call my surgical colleagues.
00:18:43
Speaker
I don't do ECMO here.
00:18:45
Speaker
That's my surgical colleagues do that.
00:18:46
Speaker
You mentioned Bob Barlett, who is no question a visionary in this regard.
00:18:52
Speaker
And so we have a strong ECMO program and always have.
00:18:55
Speaker
I admit the fact that for me, it's easy, right?
00:18:58
Speaker
You don't have to make a transfer.
00:19:01
Speaker
They're already in the building.
00:19:02
Speaker
But if things aren't working, that's where I go with it.
00:19:07
Speaker
Now, I would mention that the oscillate trial, oscillators were not routinely distributed throughout the land either.
00:19:15
Speaker
Ours are collecting dust in the closet following the oscillate trial, but there was a post-hoc analysis of oscillate data last year showing that the PDEF under 50 may have had a mortality benefit, even accounted for confidence intervals.
00:19:30
Speaker
When you have a trial that shows no benefit, the true believers can say, like what they did with proning for many years, yeah, you didn't do it right until they finally got it to hit.
00:19:39
Speaker
Oscar in Britain had no mortality change, and Oscillate had a worsened mortality.
00:19:45
Speaker
So if things actually are made worse, then you've got to stop doing it.
00:19:49
Speaker
But like I say, the post hoc analysis suggested that maybe the very sickest of the sick
00:19:54
Speaker
might benefit.
00:19:55
Speaker
But that's not back in my algorithm, but I'm aware of that information and kind of a little bit tempted.
00:20:02
Speaker
And before we leave the proning procedure, any recommendations, any practical tips or what are the things that you worry about with proning that could be, I mean, useful for our audience?
Complications and Interventions in ARDS
00:20:15
Speaker
Well, I mean, there can be, in terms of sort of side effects or complications, you can get local necrosis of the forehead or bridge of the nose.
00:20:23
Speaker
There may be an increased
00:20:25
Speaker
ventilator-associated pneumonia risk.
00:20:27
Speaker
So there's no free lunch in critical care.
00:20:29
Speaker
I mean, everything we do has got limitations in terms of benefits and risks.
00:20:34
Speaker
But I think I am a believer at this point, and I think it, just like going for protective ventilation, unfortunately, is probably underutilized.
00:20:43
Speaker
In fact, not probably.
00:20:44
Speaker
I can show you the data.
00:20:44
Speaker
It is underutilized.
00:20:47
Speaker
So I think that before we jump into a little bit more of alternative modes of ventilation and ECMO, just to summarize, in terms of what the evidence would suggest right now is make sure that everybody's getting low tidal ventilation, that we're protecting their plateau pressures and utilizing PEEP.
00:21:02
Speaker
And those who we still have problems, evaluate for individual aspects of the patient, like morbid obesity that might require maybe a more invasive or more refined way of optimizing lung protective strategies.
00:21:17
Speaker
If that is done and we still have trouble, then think about neuromuscular blockers.
00:21:22
Speaker
And then the next step would be prone ventilation, which, like you said, is important to do for prolonged periods during a 24-hour period, so 16 hours or more.
00:21:32
Speaker
and to do it as long as we need to, and as long as the patient is showing improvement.
00:21:37
Speaker
If all that fails, we then have to move to other directions.
00:21:41
Speaker
So you did mention oscillations.
00:21:43
Speaker
I think that it would be worth talking a little bit about alternative modes of mechanical ventilation.
00:21:49
Speaker
And you talked about high-frequency oscillatory ventilation, and after the H1N1
00:21:55
Speaker
influenza epidemic and a lot of people thought that oscillation was the go-to therapy and I know a lot of hospitals that bought oscillators and even governments about oscillators and it made sense I mean because we were keeping people at a higher mean airway pressure we thought we were protecting the lung from from better induced lung injury yet like you mentioned the trials did not show that what are your thoughts on are we done with oscillation for the for now
00:22:25
Speaker
Well, we are for now because when you have a trial showing harm, you really can't justify routine clinical use in sort of your algorithm.
00:22:34
Speaker
And I worry that there might not be another trial.
00:22:37
Speaker
I mean, if you kind of think about a randomized trial, how about a randomized trial where at that point you go to ECMO versus oscillation?
00:22:43
Speaker
That's an interesting and very, very challenging trial to do.
00:22:48
Speaker
But I am intrigued by the notion of recruitment
00:22:53
Speaker
it would, like I say, PDEF under 50.
00:22:55
Speaker
I mean, that's bad, right?
00:22:57
Speaker
That's a very, very sick patient.
00:22:59
Speaker
And it would be unfortunate if there were no, there was not an opportunity in the future to maybe examine that more carefully.
00:23:10
Speaker
But an RCT with that population, it makes for a very, very difficult trial.
00:23:14
Speaker
So I have to say we're probably done with oscillation, but I'm intrigued by the post-hoc hypothesis generating notion
00:23:22
Speaker
that PDEF under 50 might benefit.
00:23:26
Speaker
Interesting.
00:23:27
Speaker
And the other, we were talking before we started recording the podcast that in terms of alternative modes of ventilation, Bob, I have observed, I mean, either in sign out or visiting some of our programs that there is a certain amount of clinicians who like to use APRV or airway pressure release ventilation in ARDS.
00:23:48
Speaker
Could you tell us a little bit about APRV and where it fits in your algorithm?
00:23:54
Speaker
Well, it's sexy and it's trendy and it lacks evidence.
00:23:57
Speaker
And I try to know as much as I can about it.
00:24:00
Speaker
Let me tell you.
00:24:01
Speaker
Well, what it is, of course, is you give a mean airway pressure, you're allowed to breathe spontaneously, and episodically you're released, if you will, to a lower airway pressure at some level of PEEP.
00:24:12
Speaker
And the idea here is that high mean airway pressure around which you're allowed to spontaneously breathe recruits the lung maximally.
00:24:20
Speaker
I'm not against it, I just need to, you know, sort of the old state of Missouri, you gotta show me.
00:24:25
Speaker
And I'm completely well versed in this.
00:24:28
Speaker
In fact, I had the opportunity to venture out earlier this year to Syracuse, where they do basic science research, and Neil Hibashi came in from Shock Trauma.
00:24:38
Speaker
I mean, I'm all about trying to do the right thing and figure it out.
00:24:42
Speaker
And there's no question that they have a heartfelt belief in this modality,
00:24:48
Speaker
And if it is superior, I want to know it.
00:24:50
Speaker
Now, the literature is wanting.
00:24:53
Speaker
About a year ago in intensive care medicine, there was a Chinese article which had a small single center.
00:24:59
Speaker
The randomization was they had sicker people in the control group, but it did seem to have more ventilator-free days.
00:25:05
Speaker
There was a pediatric trial in the Blue Journal earlier this year where APRV had a higher mortality.
00:25:10
Speaker
There was an EPUB done out of Utah.
00:25:13
Speaker
where they were thinking about doing an RCT, they stopped after 50 patients because they found the release tidal volumes were very high.
00:25:21
Speaker
There was a basic science article by Kavanaugh out of Toronto, just EPUB a week or so ago in the Blue Journal showing that, I think it was a mouse model or rat model, the release going from that high mean air pressure to that lower thing can precipitate lung injury.
00:25:38
Speaker
So now you know the world's literature.
00:25:40
Speaker
And I don't doubt that I have talked to, as you have, people
00:25:43
Speaker
who use it and swear by it.
00:25:45
Speaker
And I'm okay with that, that they believe what they believe, and I would like to see a larger trial.
00:25:53
Speaker
Now, I was recently awarded some money by the Chess Foundation, and we might attempt to try to look at APRV with biomarker endpoint as part of that small clinical sort of phase two.
00:26:08
Speaker
But I would like to see a big trial because
00:26:11
Speaker
There are people that really believe it.
00:26:12
Speaker
Now the problem with APRV is that there's a lot of ways, it's not like, it's just as refractory hypoxemia.
00:26:19
Speaker
There's not a single best definition.
00:26:22
Speaker
I think the folks out in Syracuse would argue that this must be tailor-made to the pressure waveforms of each individual patient rather than employing a single one-size-fits-all approach to this.
00:26:36
Speaker
And so they would argue any negative trials relate to not having done it right
00:26:42
Speaker
And so there's heterogeneity in the literature too with regard to what's been done.
00:26:48
Speaker
I looked at a recent submission for a meta-analysis that tried to look at the handful of very small RCTs, 300 patients.
00:26:57
Speaker
This is still under review elsewhere, but that's one of the challenges.
00:27:01
Speaker
Can you do a meta-analysis when you haven't done the same thing to every patient in every study, right?
00:27:06
Speaker
I mean, it's a gamish.
00:27:08
Speaker
So I am happy to...
00:27:12
Speaker
see whether APRV for the severe patient, the Berlin severe, the refractory hypoxemic patient, if you will, is superior.
00:27:19
Speaker
I would love to see a trial.
00:27:21
Speaker
But until such time as that trial occurs, everyone's got their anecdotes.
00:27:27
Speaker
I've got mine.
00:27:28
Speaker
And until we have evidence, I think it's very nice to look at lung recruitment, but that's not enough.
00:27:36
Speaker
That's not enough to say you've got a superior modality.
00:27:39
Speaker
And I think that those are great points because in some patients, if you've exhausted the evidence-based supported interventions, sometimes you might try things.
00:27:51
Speaker
I mean, truly as a salvage kind of left throw.
00:27:54
Speaker
But I do think that what is troublesome from an evidence-based perspective is that we still don't have 100% penetration in the things that are proven to work.
00:28:05
Speaker
And people are jumping to the new and sexy where there's really no good literature to tell us, are we harming or helping our patients?
00:28:13
Speaker
Yeah, I mean, just having a quote, get an oscillate.
00:28:15
Speaker
Let me take the opposite point of view.
00:28:16
Speaker
With an oscillator, that recruits the lung really well, too.
00:28:19
Speaker
And you think that ought to work.
00:28:21
Speaker
And it didn't.
00:28:22
Speaker
Or with the ARC trial, you know, the very large recruitment, you want to recruit the lung, these very large recruitment maneuvers that
00:28:29
Speaker
they use with a decremental PEEP approach.
00:28:31
Speaker
That's really recruiting and opening the lung.
00:28:33
Speaker
Everyone thought that would work.
00:28:34
Speaker
That improved harm.
00:28:35
Speaker
So you never know until you study it.
00:28:38
Speaker
And I'm fine with people having opinions provided they recognize the limitations of those opinions.
Exploring ECMO for Severe ARDS
00:28:43
Speaker
Fair.
00:28:44
Speaker
So I think that at this point, really, we should maybe jump into ECMO.
00:28:49
Speaker
And ECMO, I think, is fascinating because a lot of people talk of it as new technology.
00:28:55
Speaker
It's been around for decades.
00:28:57
Speaker
It's evolved.
00:28:59
Speaker
But yet, I mean, despite some attempts to really study this, I think that we still have the people who believe it and people who don't believe it, and we don't really have the best answer.
00:29:08
Speaker
But clearly, it's utilized.
00:29:10
Speaker
And I think that
00:29:11
Speaker
how to utilize it with the available evidence in the best way, whether you do it or you don't, and you should be thinking of when to refer patients, I think is definitely a worthwhile discussion.
00:29:22
Speaker
Do you want to start maybe just telling us a little bit about the literature behind ECMO?
00:29:28
Speaker
And I guess CESAR and EOLIA are probably the most important for us.
00:29:34
Speaker
So the CESAR trial published in Lancet, and I believe 09, was done in the UK in
00:29:39
Speaker
And the randomization there was you get referred, you get randomized, and then you either were left wherever you were and told to be lung protective with a wild type, if you will, or brought to Leicester to get ECMO.
00:29:53
Speaker
And just as our experience here, you know, where only about a third of the ECMO transfers actually get ECMO, many patients referred to Leicester to randomized to ECMO, didn't get ECMO, and in fact,
00:30:07
Speaker
the mortality benefits seem to be accounted for by that fact.
00:30:11
Speaker
And that's fine, but the criticism of CESAR was, were you testing the technology, were you testing regionalization of care?
00:30:20
Speaker
And that people in Leicester know about RDS, they care about it deeply, they know what they're doing, and they didn't put everyone on ECMO because they got them better without it, which is the right thing to do, of course.
00:30:31
Speaker
So that's what led to Eolia, and I will tell you, it's one of the fun things is to
00:30:35
Speaker
At the ATS, they have a session where they announce trial results live in front of the studio audience, if you will.
00:30:41
Speaker
And EOLIA was announced live this past May.
00:30:44
Speaker
And folks, you can't make this up because it was powered for a 20% mortality difference.
00:30:52
Speaker
And then the trial was stopped early for futility with only 11% mortality difference.
00:30:58
Speaker
So the Kaplan-Meier survival curves look really widely separated.
00:31:02
Speaker
And yet it was a negative trial.
00:31:06
Speaker
stopped for futility.
00:31:07
Speaker
Now, there was a lot of problems, one of which was a 28% crossover between the control group and ECMO.
00:31:13
Speaker
And if you take those crossovers out and say they probably would have been dead without crossing over, you get a fairly impressive mortality difference.
00:31:21
Speaker
So the ECMO believers would argue this was a positive trial.
00:31:25
Speaker
The statisticians would say it was stopped early for futility.
00:31:28
Speaker
Now, there was a further analysis, a Bayesian analysis performed a
00:31:34
Speaker
that was published in JAMA within a month.
00:31:37
Speaker
And I think it probably has a mortality benefit.
00:31:39
Speaker
And one of the things, of course, was patient selection.
00:31:41
Speaker
And they had very rigorous, these were really sick people.
00:31:45
Speaker
We talked about the definition of refractory hypoxemia before.
00:31:48
Speaker
These were even more refractory than that.
00:31:50
Speaker
You had to be pretty hypoxemic over various intervals of time to qualify.
00:31:54
Speaker
So I'm willing to accept that this was a positive trial based on the Bayesian analysis, based on
00:32:02
Speaker
the crossover issue, but technically it was a negative trial.
00:32:05
Speaker
So it was so funny because everyone knew the study was coming out and wanted to, that's why the hall was packed, I believe, that day at the American Thoracic Society meeting.
00:32:17
Speaker
And then to have it come out as a technically negative trial with a big mortality difference.
00:32:22
Speaker
One of the things is, you know, you're going to power a trial for a 20% mortality difference.
00:32:26
Speaker
That's being pretty optimistic for critical care trials.
00:32:29
Speaker
You don't see that every day.
00:32:30
Speaker
So it was a fascinating moment when they came out.
00:32:36
Speaker
And then, of course, there's been a lot of back and forth since then.
00:32:42
Speaker
But the Bayesian paper in JAMA being perhaps the most recent word on that.
00:32:47
Speaker
But I mean, you can't argue that it's already hurt people, and it probably helped them.
00:32:53
Speaker
And you mentioned the H1N1 epidemic.
00:32:55
Speaker
That also was a big driver for ECMO,
00:32:59
Speaker
programs opening up because in that epidemic, these were young, previously healthy people who had extra-refractory hypoxemia.
00:33:08
Speaker
You just couldn't oxygenate them.
00:33:10
Speaker
I think that if you're a 24-year-old kid, you'd probably want them on ECMO.
00:33:16
Speaker
I think that in the severest cases, that's probably the case.
00:33:18
Speaker
Now, hey, I'd love to see, based on what I mentioned before, oscillator versus ECMO.
00:33:24
Speaker
That'd be an intriguing thing in that really refractory population.
00:33:29
Speaker
I'm willing to accept that something happened in Neolia, and it was probably a good thing.
00:33:37
Speaker
And I think that, obviously, on a larger or higher level, what it speaks also to is that the construct of the clinical trial, despite being
00:33:48
Speaker
what we consider the highest level of evidence based on scientific method, it has limitations in answering every question that we have.
00:33:55
Speaker
And it's not perfect.
00:33:56
Speaker
And it's very difficult sometimes to conduct these trials, to complete these trials.
00:34:01
Speaker
I know one of the commentary that has emerged out of Terriolia was that the enrollment rate was so low that to reproduce this trial again would take again, I mean, a very long time in a lot of centers and with believers and non-believers who
00:34:17
Speaker
right?
00:34:18
Speaker
Sometimes that might be very hard to pull off.
00:34:21
Speaker
Well, that's the dirty little underbelly of being a trialist.
00:34:24
Speaker
I use a quote by Bismarck that said, politics is like making sausage.
00:34:27
Speaker
I modify it and say clinical trials are like making sausage.
00:34:30
Speaker
It tastes great, but you don't want to know what's inside.
00:34:34
Speaker
When you see the PDF coming off the wire, it looks like revealed wisdom, but there's a lot going on there to get to that publication.
00:34:43
Speaker
And you recruit patients one by one,
00:34:47
Speaker
And I am a trialist hoping something good happens at the end, something makes sense.
00:34:51
Speaker
But on an individual patient by patient basis, it seems like chaos at times.
00:34:57
Speaker
And in terms of, I think just to refresh our audience,
00:35:03
Speaker
Some of the aspects that I think are important about this trial that we can learn is like you said, 28% of the patients who were randomized to conventional therapy actually did cross over to ECMO and the thought was that they were probably going to die.
00:35:17
Speaker
But none of those patients crossed over at day 10, 12, or 13, right?
00:35:21
Speaker
It was early.
00:35:22
Speaker
That's important.
00:35:24
Speaker
All of those patientsโฆ So you're saying that maybe they weren't going to die.
00:35:26
Speaker
I mean, that's absolutely true and there's no way to know that.
00:35:30
Speaker
Also, I think it's important to remember that the patients who were part of this trial were very sick just to enter.
00:35:37
Speaker
And I have the notes here, but basically, you had to have a PAO2 to FiO2 ratio of less than 50.
00:35:45
Speaker
for three hours, consecutive three hours, or a PAO2, FiO2 of less than 80 for more than six hours after optimization of the things that you talked about as well.
00:35:56
Speaker
So these were sick patients.
00:35:58
Speaker
It's not like, oh, they showed up hypoxemic and they just got randomized to ECMO or conventional therapy.
00:36:05
Speaker
which I think goes to your point that in the patients that you would consider ECMO, the first step is to make sure that you go through that algorithm of things that work.
00:36:14
Speaker
And if they're still having problems, you still think that they might die from hypoxemia.
00:36:19
Speaker
And then I think that that's when you would probably consider.
00:36:23
Speaker
Are there any patients, Bob, that why don't we talk about the people who would not be candidates for ECMO in your book in terms of you've done everything you can, but
00:36:34
Speaker
They're still having problems.
00:36:35
Speaker
Not every patient is going to get ECMO.
00:36:37
Speaker
Are there some contraindications that you would consider?
00:36:41
Speaker
Oh, sure.
00:36:41
Speaker
I mean, obviously, the most important one being comorbidities.
00:36:45
Speaker
If someone has widely metastatic cancer, for example, I don't think that it would be indicated.
00:36:51
Speaker
Duration of hypoxemic respiratory failure is also a consideration.
00:36:56
Speaker
Historically, my center here will not consider cannulating beyond about a week.
00:37:01
Speaker
So, I mean, I think those would be two precautions.
00:37:03
Speaker
pretty clear-cut ones.
00:37:06
Speaker
And, you know, extremes of age, you could argue, too.
00:37:09
Speaker
I mean, they're really going to put a 90-year-old on ECMO or something like that.
00:37:14
Speaker
So, but the comorbidities, at least in my world, again, it's not a question of waiting longer than a week.
00:37:22
Speaker
They're already in the building.
00:37:23
Speaker
But, you know, bone marrow transplant patients, we have a lot of people who have a lot of illnesses at the time they develop ARDS.
00:37:31
Speaker
And, you know,
00:37:33
Speaker
You can certainly manage things on a case-by-case basis, so you can get a consult and see what they say, and then you can tell the family you've done everything, I mean, with a clear conscience.
00:37:42
Speaker
But I think patient selection is an important and reasonable consideration.
00:37:49
Speaker
You talk about triage, you know, we use, and rationing, I mean, we use explicit rationing for organ transplantation.
00:37:55
Speaker
There's no question, who do you select?
00:37:57
Speaker
Well, we only have so many circuits, right, ECMO circuits.
00:38:03
Speaker
And there are some clear-cut pediatric evidence-based indications that we get referrals for as well for the circuit.
00:38:08
Speaker
So it is also a situation of some rationing and triage.
00:38:14
Speaker
And you're not morally obligated to give ECMO if you have comorbidities that are overwhelming.
00:38:24
Speaker
And in terms of timing, you mentioned earlier during the podcast that this should be an intervention that we should apply early, right?
00:38:32
Speaker
I mean, for people who've been in ARDS for a long time and not responding or getting worse, it might be too late.
00:38:38
Speaker
Can you talk about that a little bit, Bob?
00:38:40
Speaker
Well, that's what Bob Barlett always handed down.
00:38:42
Speaker
I mean, in general, I'll tell you what, when I come on service and get an ARDS patient after about a week, I'm not that happy, not because I didn't use ECMO, but
00:38:50
Speaker
But B, I happen to think that the situation with regard to the lung component anyway, putting aside any comorbidities, tends to be won and lost early, getting them recruited early.
00:39:01
Speaker
There was old days with literature about oscillate with the first three days.
00:39:05
Speaker
To me, the first couple of days, trying to really be aggressive and getting them recruited or treated, proned, or what have you, my bias is the dysent tends to get cast.
00:39:17
Speaker
And so the notion of...
00:39:20
Speaker
that the lung is going to heal particularly well when you're, whatever, say two weeks into an ARDS run and refractory at that point, is not that likely.
00:39:30
Speaker
In the bad old days of high tidal volumes, what we used to see were macroscopic airesis and recurrent pneumothoraces.
00:39:36
Speaker
So if the lung doesn't heal, it can be pretty nasty.
00:39:38
Speaker
Now that might have been more a function of a large tidal volumes, but if the lung doesn't repair it, we say that most patients with ARDS don't die hypoxemic death, but some do.
00:39:48
Speaker
And there comes a point at which that you can put them on ECHO if you want, but the lungs aren't going to heal.
00:39:54
Speaker
Now, we don't have a day-by-day rendering.
00:39:57
Speaker
There is clinical judgment involved.
00:39:58
Speaker
So it's not to say that day eight, you're completely unsalvable, and day six, you are completely salvageable.
00:40:04
Speaker
But it does get factored in.
00:40:07
Speaker
Terrific.
00:40:07
Speaker
And I think it's an important point.
00:40:09
Speaker
And I think that it's a balance, right?
00:40:10
Speaker
On one hand, implement therapies that have been proven to help first.
00:40:15
Speaker
Make sure you go through your arsenal or your toolkit of what's evidence-based.
ECMO Implementation and Outcomes
00:40:20
Speaker
And if you're still having trouble early on, think about you're referring to an ECMO center,
00:40:25
Speaker
If you don't have one, I also think that ECMO is one of those things that probably should be done at places where they do it a lot.
00:40:32
Speaker
So doing one or two cases of ECMO a year probably does not make you an ECMO center.
00:40:37
Speaker
And that patient will be better served in a place that does one or two a month or a week.
00:40:42
Speaker
And I think that that's very important.
00:40:44
Speaker
Yeah, no argument.
00:40:44
Speaker
That's called the volume quality paradigm.
00:40:48
Speaker
Would you rather be two bypasses a year or 200, right?
00:40:52
Speaker
Exactly.
00:40:53
Speaker
And I think that that's something that everybody likes to do as an intensivist or most intensivists like to do new things.
00:40:58
Speaker
But I think it's also important to remember that and have clear criteria of what are the things that you do well at your unit and what are the things that maybe because of volume would be better served patients at another place, which I think is very important.
00:41:11
Speaker
So I think, Bob, that as a summary, I do think that some very tactical points for our clinicians at the bedside are that there are things that have been proven to improve mortality.
00:41:24
Speaker
That includes a lung protective strategy with low tidal ventilation, using PEEP and protecting patients from high plateau pressures.
00:41:32
Speaker
When that should, everybody should get that immediately.
00:41:36
Speaker
When that doesn't work, try to optimize based on individual patient aspects such as body habitus.
00:41:41
Speaker
And you talked about esophageal pressures being of use in that population specifically.
00:41:47
Speaker
Neuromuscular blockers early on for patient asynchrony, and like you said, probably in the next coming months, we'll hear from a larger trial that is being conducted or has been completed.
00:41:58
Speaker
So we'll have more about that to discuss.
00:42:02
Speaker
Prone positioning, proven to work in patients who have severe RDS.
00:42:06
Speaker
The key here is to do it for 16 hours or more per day and to do it, I mean, to find a process in your unit where everybody knows exactly how to contribute and do it in a good way.
00:42:17
Speaker
And alternative modes of ventilation either have been proven not to work or there's no data right now.
00:42:23
Speaker
So we can talk about where that fits.
00:42:26
Speaker
I mean, in individual cases, but it's hard to recommend at a widespread range.
00:42:30
Speaker
And then we talked about ECMO that's been around for a while and your takes on eolia and how you utilize it in your patients.
00:42:36
Speaker
And I think that all of those are very applicable to day-to-day practice.
00:42:41
Speaker
And I hope that our audience, I mean,
00:42:43
Speaker
If follows those, we'll link a lot of these studies that you've mentioned in the show notes so people can look at them.
00:42:52
Speaker
And what we like to do at Critical Matters, Bob, is kind of close with a couple of questions that tap on your wisdom but are not related directly to ARDS.
00:43:01
Speaker
Would that be okay?
00:43:03
Speaker
Sure, of course.
Concluding Thoughts and Future Directions
00:43:05
Speaker
So the first question relates to books.
00:43:08
Speaker
And is there a book that you have either gifted often or that has really impacted you in terms of how you think about life and critical care in general?
00:43:19
Speaker
Well, I'll be shameless and promote my own critical care textbook published by Springer.
00:43:25
Speaker
So I had the opportunity to create a new format case-based critical care textbook and
00:43:33
Speaker
What we tried to do, I also write for Up to Date.
00:43:34
Speaker
I'm very proud of what I write for Up to Date on mechanical ventilation.
00:43:38
Speaker
But we felt that that was not really contextualized sufficiently.
00:43:43
Speaker
So we made a case-based book.
00:43:46
Speaker
So I gift it.
00:43:46
Speaker
Well, our residents can go through our firewall and download it as a PDF.
00:43:51
Speaker
So I'm not quite giving it for free, but they are getting it for free.
00:43:54
Speaker
It's a PDF available to them.
00:43:57
Speaker
Excellent.
00:43:57
Speaker
So we'll make sure that we link that in the show notes for the book so people can find it.
00:44:04
Speaker
And you mentioned it's case-based, so it's really cases around different pearls in critical care.
00:44:08
Speaker
Is that correct?
00:44:10
Speaker
Absolutely.
00:44:10
Speaker
Every chapter starts with a case and sort of a question with the answer.
00:44:17
Speaker
And then we have the principles of management section.
00:44:20
Speaker
And then the last section is what I dubbed evidence contour, which is to say what are the
00:44:26
Speaker
things that are in evolution and controversial with regard to the management of that particular kind of patient.
00:44:34
Speaker
Excellent.
00:44:34
Speaker
And I think that there's obviously information available everywhere right now, but I think that putting things together around what's practical based on cases and also an appraisal, I mean, of what we know and what we don't know is always going to be very useful for our trainees, but also for our practitioners in real life.
00:44:55
Speaker
So the next question, Bob, is what did you believe to be true in medicine or life that most other people don't believe?
00:45:02
Speaker
Well, I don't know if they don't believe it, but you can tell from our earlier conversation, I'm kind of known a little bit at times to torture my house staff with quotes, and my favorite one is Pasteur, which is, chance favors only the prepared mind.
00:45:15
Speaker
And I think that's true in medicine, and I think that's true in life, particularly in medicine and critical care when you're confronted with a very complex milieu of variables to try to sort out in your brain, and you can't, I guess you can't get to where you want to get with the patient without having a sense of where you want to be, and
00:45:33
Speaker
and looking at things on the fly to manage.
00:45:35
Speaker
And so a chance favors only prepared mine.
00:45:37
Speaker
That's my all time favorite quote.
00:45:40
Speaker
Excellent.
00:45:40
Speaker
And I think that, like you said, I mean, quotes are very powerful in terms of they're easy to remember, but they capture really a lot of wisdom that applies to how we conduct ourselves on a daily basis.
00:45:52
Speaker
And the final question is, what would you want every intensivist who's listening to us to know?
00:45:58
Speaker
Well, I'll go back and quote again, because this is funny, because that Pasteur quote is so eloquent.
00:46:03
Speaker
The quote that I get teased about that is mine, if you want to give the evidence, the interest rather, one quote, it's dry them out and wean them.
00:46:11
Speaker
That's my aphorism.
00:46:12
Speaker
Certainly people accumulate fluid when they're sick and they need to pee it out when they're better.
00:46:17
Speaker
So I sometimes tell people, I only know five things and that's one of them and it's got me this far.
00:46:25
Speaker
So I'm sticking to it.
00:46:26
Speaker
Dry them out and wean them.
00:46:28
Speaker
And I think that that's what patients really want.
00:46:30
Speaker
Wean them and get them home, right?
00:46:31
Speaker
Exactly.
00:46:32
Speaker
And I know that.
00:46:33
Speaker
I think you have actually, I heard you talk about the ABCDF bundle as a bundle of a lifetime.
00:46:41
Speaker
And I think it applies exactly to that concept, right?
00:46:44
Speaker
I mean, in terms of drying up and wean them is part of that and getting people back to real life.
00:46:49
Speaker
So I think that's a great place to stop.
00:46:52
Speaker
Thank you very much for your time.
00:46:54
Speaker
We might talk a little bit more about after SCCM, see what new evidence comes in the direction of neuromuscular blockers and where trials might be coming up in mechanical ventilation.
00:47:05
Speaker
And we look forward to having you back as a guest on Critical Matters.
00:47:08
Speaker
Thank you very much.
00:47:09
Speaker
Well, thank you for having me.
00:47:13
Speaker
Thanks again for listening to Critical Matters.
00:47:16
Speaker
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