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Corticosteroids in Critical Illness Update
20 Plays1 year ago
In this episode, Dr. Zanotti is joined by Dr. Stephen Pastores to discuss the 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia, published by the Society of Critical Care Medicine.
Dr. Pastores is Program Director for Critical Care Medicine and Vice-Chair of Education for the Department of Anesthesiology and Critical Care Medicine at Memorial Sloan Kettering Cancer Center. In addition, Dr. Pastores is a professor of anesthesiology and medicine at Weill Cornell Medical College in New York, NY.
Additional resources:
2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Medicine 2024: https://journals.lww.com/ccmjournal/pages/articleviewer.aspx?year=9900&issue=00000&article=00275&type=Fulltext
Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. ADRENAL Trial. N Engl J Med 2018. https://www.nejm.org/doi/full/10.1056/NEJMoa1705835
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. APROCCHSS Clinical Trial. N Engl J of Med 2018: https://www.nejm.org/doi/full/10.1056/NEJMoa1705716
Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomized controlled trial. The Lancet 2020: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(19)30417-5/abstract
Hydrocortisone in Severe Community-Acquired Pneumonia. CAPE-COD Trial. N Eng J Med 2023: https://www.nejm.org/doi/full/10.1056/NEJMoa2215145
Books mentioned in this episode:
Elon Musk. By Walter Isaacson: https://bit.ly/3PVXWsG
The Autumn Ghost: How the Battle Against a Polio Epidemic Revolutionized Modern Medical Care. By Hannah Wunsch: https://bit.ly/4avevns
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Transcript
Podcast Introduction
00:00:06
Speaker
Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:14
Speaker
Sound provides comprehensive critical care programs to hospitals across the country.
00:00:19
Speaker
To learn more about our programs and career opportunities, visit www.soundphysicians.com.
00:00:26
Speaker
And now your host, Dr. Sergio Zanotti.
Today's Topic: Corticosteroid Treatment Debate
00:00:33
Speaker
Corticosteroid treatment in critically ill patients has been a topic of debate within the field for decades.
00:00:39
Speaker
Today's podcast episode will discuss the 2024 Focused Update, Guidelines on Use of Corticosteroid and Sepsis, Acute Respiratory Distress Syndrome, and Community Acquired Pneumonia, published recently by Society of Critical Care Medicine.
Guest Introduction: Dr. Stephen Pastores
00:00:53
Speaker
Our guest today is Dr. Stephen Pastores, Program Director, Critical Care Medicine, Vice Chair of Education, the Department of Anesthesiology and Critical Care Medicine at Memorial Sloan Kettering Cancer Center.
00:01:05
Speaker
In addition, Dr. Pastores is a Professor of Anesthesiology and Medicine at Weill Cornell Medical College in New York.
00:01:13
Speaker
Dr. Pastores is a renowned clinician, educator, and researcher.
00:01:17
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He served as co-chair for the clinical guidelines we are discussing today.
00:01:20
Speaker
Steve, welcome back to Critical Matters.
00:01:23
Speaker
Thank you for having me, Sergio.
00:01:26
Speaker
Always a pleasure.
00:01:26
Speaker
And we had the opportunity to talk about the same topic many years ago when the 2017 guidelines were released.
00:01:36
Speaker
And maybe you could just give us as a mode of introduction, a brief history of the Society of Critical Care Medicine corticosteroid guidelines that you've been involved in over several years.
00:01:47
Speaker
Sure.
History of Corticosteroid Guidelines
00:01:48
Speaker
The first iteration of the corticosteroid guideline was first published in 2008.
00:01:54
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This was a joint collaboration between experts from both the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.
00:02:06
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And in that first iteration of the guideline, we...
00:02:10
Speaker
Defined the term critical illness related corticosteroid insufficiency or SIRSI which we Defined as the state of dysregulated response to inflammation that was associated with adrenal insufficiency and tissue resistance to the action of glucocorticoids at that time that was our working definition and from that we
00:02:39
Speaker
created guidelines for the management of several conditions, particularly sepsis, ARDS, and a few other conditions.
2017 Guidelines Update & Corticosteroid Insufficiency
00:02:50
Speaker
Fast forward to 2017, the second iteration of the guidelines, where there was part 1 and part 2,
00:02:59
Speaker
where we again elaborated a little bit more the understanding of this critical illness related corticosteroid insufficiency or SEARC and
00:03:11
Speaker
At that time, we recognized that besides the dysfunction of the hypothalamic pituitary adrenal axis and tissue resistance to corticosteroid action at the end organ level, there actually was also a problem of how cortisol is being broken down by enzymes in the liver and the kidneys.
00:03:30
Speaker
So there's actually three mechanisms as to why this corticosteroid insufficiency syndrome occurs in critically ill patients.
00:03:39
Speaker
In addition to that, the 2017 guidelines updated and specifically focused on some of the diagnostic criteria as well as the management specific to sepsis and septic shock, ARDS,
00:03:56
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community acquired pneumonia, trauma, burns, influenza, and other entities.
00:04:04
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That was again a collaboration between experts of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.
00:04:13
Speaker
We knew around that time in 2017
00:04:17
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When the second iteration of the guidelines came out, that two large septic shock trial with corticosteroid versus placebo trials were happening, and we knew that it was just a matter of time where the guidelines would get tested.
00:04:32
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be updated yet again.
2024 Guidelines Update on Sepsis, ARDS, CAP
00:04:34
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And so fast forward to 2024 and earlier this year, January 19 to be exact, 2024, the updated guidelines for the use of corticosteroids in patients with sepsis and septic shock, acute respiratory distress syndrome, or ARDS,
00:04:53
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and severe community-acquired pneumonia were published.
00:04:57
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We focused, for this particular updated version, we only focused on sepsis septic shock ARDS
00:05:04
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and CAP because we felt these were the three most common conditions in the intensive care unit where corticosteroids usually are commonly used.
00:05:13
Speaker
And we felt that the focus update would deal primarily with those three entities.
00:05:19
Speaker
And for this particular update, only the Society of Critical Care Medicine was the sponsor of the guideline.
00:05:28
Speaker
We did have membership broadly.
00:05:31
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from Europe as well as from Africa and Canada, Australia, New Zealand.
00:05:40
Speaker
But for the most part, this was largely a guideline that was supported by funding from the Society of Critical Care Medicine.
00:05:47
Speaker
Perfect.
00:05:47
Speaker
And obviously, like you mentioned, in these three clinical arenas that we'll talk about areas, septic septic shock, ARDS, and acquired pneumonia, there's also been, since 2017, a significant number of clinical trials
00:06:06
Speaker
that maybe have changed the way we should appreciate that evidence and apply it at the bedside.
00:06:13
Speaker
Before we go into the clinical topic itself, I would like to ask you, Steve, if you could give us a little bit of a...
Guideline Development Process: PICO and GRADE
00:06:22
Speaker
overview of the guidelines process just to review for our audience.
00:06:26
Speaker
There's three things in particular that I wanted you to talk about is the idea of PICO.
00:06:33
Speaker
How does that originate and what it means for guidelines, the use of grades, and then the meaning of your recommendations in terms of the terminology.
00:06:42
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Yes.
00:06:43
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For the first steroid guideline that was published in 2008, that was largely using a modified Delphi methodology where a consensus of just the experts were used with multiple rounds of voting until we got at least 80% of the members to agree on what the recommendations and how we would do.
00:07:07
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kind of grade the evidence at the time.
00:07:09
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The 2017 guideline used a grade approach, and the grade approach is the approach that has been developed now for many, many years and is used for updating guidelines.
00:07:20
Speaker
And the grade really stands for the Guidelines in Intensive Care Development and Evaluation Group.
00:07:27
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And what it is really is you work with largely a methodology team.
00:07:32
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In this case, we have been working closely with the McMaster group in Canada.
00:07:40
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And we have the PICO questions.
00:07:43
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And the PICO is a mnemonic that stands for patients, intervention, population control and outcomes, where we look at
00:07:53
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specifically at all the trials that have been published in the area and develop these questions as to what we think are going to be the major outcomes of interest.
00:08:04
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So whereas in the earlier guidelines, you know, there were several more PICO questions because we were tackling more
00:08:12
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syndromes at the time for this particular focus update in 2024 we only focus on five PICO questions for the update and these were questions specific to how corticosteroids are used in sepsis and septic shock as well as in ARDS and in severe and less severe community acquired pneumonia and
00:08:38
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Perfect.
00:08:39
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And could you tell us a little bit about the meaning of recommendations in terms of when, based on the appraisal of the evidence, you say we recommend versus we suggest?
00:08:53
Speaker
Okay.
00:08:54
Speaker
So, yes.
00:08:54
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So...
How Recommendations are Made
00:08:56
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When the evidence is reviewed and you have evidence tables that are created, the panel of the task force assigned to this guideline kind of just goes over each of these.
00:09:10
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And we develop the recommendation using what we call the grade evidence to decision framework.
00:09:16
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which basically looks at the certainty of the evidence, balancing the desirable and undesirable effects of the intervention, patient values and preferences, what resources need to be used to provide the treatment recommendation, and whether it's acceptable and feasible to administer the intervention based on all of those factors.
00:09:43
Speaker
An evidence is recommended as strong and we use the phrase we recommend for those and or conditional for those that we use the phrase we suggest.
00:09:56
Speaker
So generally strong recommendations where we might suggest we recommend, usually that means that the evidence is quite strong from randomized controlled trials suggesting that it's been shown that the intervention led to a positive outcome.
00:10:13
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Whereas if we say we suggest or conditional, which traditionally we used to call weak recommendation, and that's largely because there's some, you know, balancing of the risk and benefit.
00:10:26
Speaker
And maybe the definitive evidence may not be totally there or there are some questions about issues related to maybe the studies that were evaluated, whether they were very heterogeneous, for example, or whether there was a high risk.
00:10:42
Speaker
imprecision or risk of bias in how the trials were assessed by the panel.
00:10:49
Speaker
And I think it's important just to review for our listeners because obviously there's a platitude of clinical guidelines today that use the great methodology.
00:11:03
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I think, like you said, the University of McMaster in Canada has been like really pioneers in trying to give structure to evidence-based medicine analysis.
00:11:13
Speaker
But when you say we recommend, it really is that the level of evidence is strong enough that most patients would want this, most clinicians should do this for most patients, and these could be utilized as quality measures by entities that are looking at this, right?
00:11:30
Speaker
Correct.
00:11:31
Speaker
Perfect.
00:11:32
Speaker
And the other question I had, which you did talk about critical illness-related corticosteroid insufficiency and the definitions and how that term got coined and some of the mechanisms.
00:11:45
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Before we start talking about the specific diseases, could you just tell us where we stand today in terms of diagnosis of Searcy?
Challenges in Diagnosing Searcy - Clinical Approach
00:11:53
Speaker
Yes, so it's been very challenging to get a precise diagnostic criteria for Searcy.
00:12:02
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Traditionally, we're using a variety of ways to do this, either getting a random cortisol level or doing a formal procedure.
00:12:15
Speaker
what I call ACTH stimulation test.
00:12:19
Speaker
And there's the 250 microgram dose where we get first a baseline, we inject 250 micrograms of cocyntropin synthetic ACTH, and then we would check the level at 30 and 60 minutes, and we would see the increment from the baseline dose.
00:12:35
Speaker
to 30 minutes and 60 minutes and if that increment was less than nine, sort of like that was consistent with what we were describing as SIRC or corticosteroid insufficiency related to critical illness.
00:12:47
Speaker
And there was the much lower dose or what we call the low dose ACTH-TIM test where you would only use like one microgram for example.
00:12:57
Speaker
And there were some issues related to interpreting results based on whether you were using the one microgram versus a 250 dose.
00:13:05
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There were arguments for both strategies.
00:13:12
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deliberately decided that for the updated guideline we would not be touching the diagnostic criteria.
00:13:19
Speaker
And the main reason for that is because when clinicians feel that a specific syndrome or disease entity warrants the use of corticosteroids, for example, in somebody with septic shock or ARDS, there really is no utility to be trying to
00:13:43
Speaker
use criteria for corticosteroid insufficiency if the clinician is already intending to use corticosteroids.
00:13:50
Speaker
And it doesn't, it doesn't no longer clinically useful to make that determination.
00:13:57
Speaker
If you're going to use corticosteroids on patients, then the results of the ACTH-TIM test or a random cortisol is not going to help you if it's clinically indicated that you should be using steroids on those patients.
00:14:09
Speaker
So
00:14:10
Speaker
For the purposes of our focused update for 2024, we stayed away from updating the diagnostic criteria for Searcy and basically we're focused more on situations where you think the syndrome is happening, you want to use steroids, it seems clinically appropriate.
00:14:32
Speaker
We don't feel that there is any added utility in detecting whether or not
00:14:39
Speaker
adrenal insufficiency occur.
00:14:41
Speaker
Now that does not hold true for patients who you might be suspecting adrenal insufficiency for other reasons other than the condition that they are presenting whether it's sepsis or ARDS whereas if you're working somebody up where you suspect they may be adrenal insufficient and that can occur in a variety of instances other than
00:14:59
Speaker
in septic shock or ARDS, for example, then of course in those patients, you would have to be doing cortisol stimulation test and additional testing to make that diagnosis.
00:15:11
Speaker
And I think what's interesting, Steve, is that also, obviously, the choice to not dive into this and these update, I think also aligns nicely with the overall feeling of these guidelines, which I think are very practical and have simplified a lot of the recommendations to try to really help clinicians at the bedside make decisions of appropriate use of corticosteroid in these patient populations.
00:15:38
Speaker
Yes.
00:15:39
Speaker
So why don't we start and talk about corticosteroids and sepsis and septic shock, which obviously was probably the disease that started a lot of this discussion many, many years ago with the original studies in septic shock.
00:15:53
Speaker
But if you could just maybe start telling us what is the current recommendation from the 2024 guidelines update for this disease category, and then maybe we can go a little bit deeper into the rationale and the evidence supporting it
00:16:08
Speaker
and some other considerations.
2024 Guidelines for Septic Shock Patients
00:16:11
Speaker
Yes, so we gave two high-level recommendations for the use of corticosteroids in adult patients with septic shock.
00:16:24
Speaker
I just want to point out Sergio that the focus update is only for adult patients with sepsis, septic shock, ARDS, and CAP.
00:16:31
Speaker
We could not make recommendations for the use of steroids in pediatric patients for any of these disease entities for lack of available trials in the literature.
00:16:42
Speaker
So this is an adult focus guideline.
00:16:44
Speaker
So for patients with septic shock, we suggested that
00:16:49
Speaker
administering corticosteroids.
00:16:51
Speaker
We gave that a conditional or weak recommendation with low certainty evidence.
00:16:57
Speaker
That's a bit in contrast to the 2017 guidelines where our recommendation for corticosteroids was largely based on whether the patients, despite fluid resuscitation, were requiring moderate to high dose of vasopressors.
00:17:18
Speaker
For the focused update for 2024, we're saying we're not saying what
00:17:24
Speaker
the presser requirement should be.
00:17:25
Speaker
That's a major difference because we feel that if the patient is in septic shock with whatever dose of presser that they're on, there is already an indication to suggest the use of corticosteroids on those patients.
00:17:41
Speaker
The other important recommendation was a reinforcing of the recommendation against the use of high dose, what we call
00:17:52
Speaker
greater than 400 milligrams of hydrocortisone equivalent, short duration corticosteroids, by short duration we mean less than three days for adult patients with septic shock.
00:18:05
Speaker
So high dose short duration should not be what's used.
00:18:10
Speaker
We should be using low dose, longer duration of corticosteroids in patients with septic shock.
00:18:18
Speaker
The difference from the 2017 guidelines is that in the 2017 guidelines, that was a lower certainty.
00:18:23
Speaker
That was a...
00:18:32
Speaker
a moderate certainty of evidence as compared to the 2024 where we actually made the, we switched the conditional recommendation against high dose to a stronger recommendation.
00:18:46
Speaker
So it's a reinforcing of the recommendation against using high dose short duration steroids.
00:18:54
Speaker
in patients with septic shock.
00:18:55
Speaker
And in terms of some of the evidence, obviously, there's some departures here or some, not departure, but really an evolution is a better word, I think, Steve, of the recommendations, like you said, from previous guidelines.
00:19:08
Speaker
There's been a lot of studies in septic shock.
00:19:11
Speaker
We've been back and forth with on, off, but now really, if they're on pressors, if you have a sick patient with septic shock,
00:19:20
Speaker
The suggestion is that there will probably be benefit.
00:19:23
Speaker
Could you tell us a little bit more about the literature and what are the benefits that we are likely to see or that have been demonstrated more consistently in studies?
00:19:32
Speaker
Yes.
00:19:33
Speaker
So what has been consistent is corticosteroids have been strongly shown to reverse shock faster.
00:19:45
Speaker
And in so doing, lessen duration of mechanical ventilation as well as ICU length of stay in general.
00:19:55
Speaker
The mortality difference is what has been very sticky.
00:20:00
Speaker
It hasn't been consistently demonstrated.
00:20:04
Speaker
And if it does, in general, it's been very, very slight, very, very modest.
00:20:09
Speaker
For the focused update for steroid use in patients with sepsis and septic shock, we reviewed 46 RCTs that compared steroids with placebo or standard care in these patients.
00:20:25
Speaker
There were trials that included patients with only sepsis.
00:20:30
Speaker
others that included patients with sepsis and community-acquired pneumonia, and other studies that included sepsis and ARDS, and then the rest were septic shock studies.
00:20:43
Speaker
And when you look carefully as an aggregate, the consistent signal seems to be that corticosteroids reverse shock faster
00:21:00
Speaker
They reduce short-term mortality, very modest, and they reduce length of stay in the ICU without major significant adverse effects.
00:21:16
Speaker
most commonly seen with the regimens that are used.
00:21:20
Speaker
And a lot of the stronger evidence for corticosteroid use has come from the two largest trials of steroids that came out in 2018, a year after we had published the 2017 guidelines.
00:21:32
Speaker
And that's the ADRENAL trial and the APPROACH trial.
00:21:36
Speaker
The ADRENAL trial was the Australia-New Zealand trial and the APPROACH trial was the French trial.
00:21:42
Speaker
They interestingly had kind of
00:21:47
Speaker
a little bit difference in terms of their overall results.
00:21:50
Speaker
What was consistent with the two trials was that shock reversal was definitely consistently shown with steroid use versus placebo.
00:21:59
Speaker
And the side effects again were similar, hyperglycemia being the most common, along with hypernatremia and some neuromuscular weakness, but no major risk of secondary infections, GI bleeding, which
00:22:11
Speaker
has always been the concern when using corticosteroids in patients with sepsis and septic shock.
00:22:18
Speaker
Whereas the adrenal trial did not show a positive signal for mortality, the approach trial in France did show.
00:22:27
Speaker
But there was also a difference in terms of steroids that were used.
00:22:31
Speaker
The adrenal trial used only hydrocortisone, whereas the French trial used the combination
00:22:38
Speaker
of hydrocortisone and flutrocortisone.
00:22:41
Speaker
Both trials use hydrocortisone with or without flutero for up to seven days.
00:22:46
Speaker
So that was sort of like those two trials comprised at least 5,000 patients.
00:22:51
Speaker
So they clearly weighed a lot in terms of the analysis of the trials overall in terms of how we came about with the recommendation.
00:23:02
Speaker
Perfect.
00:23:03
Speaker
And you did mention, obviously, the second recommendation is against the use of high dose, more than 400 milligrams per day of hydrocortisone equivalent doses for short periods, less than three times.
Dosing and Administration for Septic Shock
00:23:18
Speaker
So what is the current recommendation for dosing?
00:23:24
Speaker
And I know that there might be different ones based on the evidence, but if you could just give us an idea of what would be an appropriate dose.
00:23:31
Speaker
And then the second question that follows on that, Steve, is when do you stop and how do you stop?
00:23:38
Speaker
Yes.
00:23:39
Speaker
So the most common molecule and dosing regimen is
00:23:47
Speaker
that is used in patients with sepsis and septic shock is still intravenous hydrocortisone, 200 milligrams daily, typically in divided doses.
00:23:57
Speaker
So a common regimen is 50 milligrams IVQ, six hours.
00:24:01
Speaker
I personally use a loading dose of 100 milligrams up front first before I go on a 50Q6 regimen.
00:24:09
Speaker
Other places might do a continuous infusion of 10 milligrams an hour.
00:24:14
Speaker
That translates to about 240 milligrams, so it's within that range.
00:24:19
Speaker
Some might even push up to 300 milligrams of hydrocortisone, 200 to 300, I think somewhere in that range, as long as it's under 400 milligrams.
00:24:30
Speaker
I think is a good regimen.
00:24:33
Speaker
The duration that currently is most commonly used is somewhere between five to seven days with or without a taper.
00:24:43
Speaker
And that really depends on whether the patient is coming off vasopressors quickly.
00:24:49
Speaker
So
00:24:50
Speaker
For me personally, when I see that, let's say it's, I'm not yet at five days, but the patient is getting off vasopressors already, let's say by day three or four, and most commonly in patients with septic shock, the need for vasopressors is usually around three to five days in most patients, unless they're on more than two vasopressors, but commonly anywhere between three to five days.
00:25:14
Speaker
So 200 to 300 milligrams is a commonly used dose in divided doses, either 50 Q6, 100 Q12, and for five to seven days or shorter, depending on whether the patient is off pressers.
00:25:27
Speaker
And then really the tapering is really done.
00:25:32
Speaker
I personally taper within 24 hours if the patient comes off.
00:25:38
Speaker
the vasopressor, and then I cut the dose in half until I'm off of it, usually by no more than seven to eight days in most patients.
00:25:49
Speaker
Perfect.
00:25:50
Speaker
And the last question I have on corticosteroids is the use of flujocortisone.
00:25:55
Speaker
Yes.
00:25:56
Speaker
So there was a lot of healthy debate among the panelists.
00:26:01
Speaker
And certainly for this particular question, the co-chair, Jilali Anand, my co-chair, was recused from voting because he clearly has been a major trialist in this field.
00:26:16
Speaker
And most of the positive studies with flutocortisone have been his studies where he was the PI.
00:26:22
Speaker
And
00:26:24
Speaker
Some studies clearly have shown just like the approach trial and the earlier trial from the early 2000s with flutrocortisone being added to hydrocortisone.
00:26:36
Speaker
So yes, flutocortisone, 50 micrograms enterally daily, in addition to hydrocortisone, has been shown in some studies to affect mortality.
00:26:49
Speaker
And a very recent meta-analysis, patient-level meta-analysis published a couple of years ago, where they looked at
00:26:58
Speaker
the addition of flutrocortisone making the difference versus just low dose hydrocortisone alone but the panel felt that the credibility of that subgroup finding was really not clear and based on our understanding and knowledge that if you are getting at least a hundred milligrams of
00:27:21
Speaker
or more of hydrocortisone equivalent, you really should have mineralocorticoid effect from that dose already of hydrocortisone.
00:27:30
Speaker
And so the additional 50 mcs of fludrocortisone probably is not going to materially affect
00:27:40
Speaker
how the patient will respond to the corticosteroid that's used.
00:27:46
Speaker
Nevertheless, it's hard to argue with the studies that have shown that the combination works.
00:27:52
Speaker
I usually say if your patient profile fits
00:27:57
Speaker
criteria that was used in the approach trial where there was clearly a benefit to the addition of fludrocortisone, then go ahead and certainly use it.
00:28:10
Speaker
But the task force was not unanimous in making a specific recommendation.
00:28:16
Speaker
And so for my own practice, I consider it optional.
00:28:20
Speaker
Perfect.
00:28:22
Speaker
Let's talk a little bit about ARDS now, and maybe we can start with the current recommendations from the 2024 guideline on using corticosteroids in acute respiratory distress syndrome.
Corticosteroids in ARDS Treatment
00:28:34
Speaker
So for adult ARDS, we suggested...
00:28:40
Speaker
using corticosteroids in adult critically ill patients with ARDS.
00:28:44
Speaker
We gave this a conditional recommendation based on moderate certainty evidence.
00:28:52
Speaker
Very closely similar to what we recommended in 2017 with the only caveat that whereas we were very specific in quantifying having a PF ratio under 200
00:29:10
Speaker
for the use of steroids in moderate to severe ARDS, we basically, for this particular focus update, we did not
00:29:21
Speaker
make it very granular in describing the criteria and the thinking there was that it's really a spectrum and you can start off with very mild but very rapidly progress so we did not want the situation to be where you're not thinking of steroids early on because it's just simply mild ARDS versus
00:29:43
Speaker
you know, going very quickly or deteriorating quickly into moderate to severe ARDS.
00:29:48
Speaker
And for this particular recommendation, we evaluated 18 RCTs and
00:29:56
Speaker
about a dozen of those included the American European Consensus Conference definition or the Berlin definition from 2012.
00:30:05
Speaker
And then we also analyzed the COVID-19 ARDS trials and there were about six of them.
00:30:13
Speaker
The challenge was that in all of the ARDS trials
00:30:18
Speaker
various molecules of corticosteroids were used.
00:30:23
Speaker
The timing was different from trial to trial, how much steroids were being given and how long they were given.
00:30:33
Speaker
But what was
00:30:36
Speaker
to the panel very convincing was that there was moderate certainty that there was reduction, probable reduction in 28-day mortality in adult critically ill patients with ARDS, and it did not seem to matter.
00:30:53
Speaker
Whether you were using hydrocortisone or you were using methylprednisolone or dexamethasone, as we very commonly use, particularly during the COVID pandemic early on and even later on after that, we did not find any credible subgroup effects based on the type of steroid.
00:31:14
Speaker
So we basically, for this focus update, we gave the three most common regiments that are used based on the landmark trials that showed efficacy for the use of steroids for ARDS.
00:31:29
Speaker
And Steve, can you comment on the, there's also been a movement, I think, over time with ARDS from what was very focused on the late unresolving ARDS to using it earlier.
00:31:44
Speaker
And there are some comments in the guidelines about the early use, right?
00:31:48
Speaker
Yes.
00:31:49
Speaker
So what we suggest is really to consider the use of corticosteroids in early ARDS.
00:31:57
Speaker
severe ARDS and by early we generally mean within 72 hours of onset or at least within the first week.
00:32:05
Speaker
I think the literature has been very strong for many many years now that using corticosteroids for late or persistent ARDS, we're talking beyond two weeks of the onset of ARDS, that there was harm
00:32:22
Speaker
and increased mortality with corticosteroid use for those patients with late or persistent ARDS.
00:32:29
Speaker
And so the recommendation is to consider the use of steroids early, ideally within the first 72 hours, and to use a longer course of corticosteroids, generally more than seven days, because we felt that the survival benefit appeared to be in the patients that were receiving a longer course.
00:32:53
Speaker
corticosteroids as compared to the shorter course and the benefit of steroids was seen largely in terms of the reduction in the number of days on mechanical ventilation what we call ventilator free days and as well as a shorter length of stay in the hospital what was
00:33:16
Speaker
still considered probable, which is why we ended up with a conditional recommendation was the impact on mortality was there, but it was not very, very strong, except in the trials, of course, like with dexamethasone for COVID ARDS, where clearly the recovery trials showed a significant benefit.
00:33:39
Speaker
Before the COVID recovery trial, you may remember that a trial in Spain by Jess Villar showed with the use of dexamethasone for early ARDS, he also showed a benefit of
00:33:59
Speaker
with using dexamethasone, 20 milligrams for five days and then cut in half for the next five days or until the patient got exhumated.
00:34:07
Speaker
So this is why when we look very carefully at the type of steroids, it did not seem to make a difference whether dexamethasone, hydrocortisone or methylprednisolone was used.
00:34:19
Speaker
And you did mention COVID, obviously, and the recovery trial.
00:34:23
Speaker
Here specifically, we're just talking about ARDS.
00:34:25
Speaker
We're not making a distinction of the different types of pathogens that might cause ARDS, right?
00:34:30
Speaker
We're just talking about purely ARDS, and there's no comments on the guidelines on COVID specifically.
00:34:36
Speaker
No, no.
00:34:37
Speaker
We wrapped the COVID ARDS trials with the other 12 trials that were in non-COVID ARDS patients.
00:34:47
Speaker
Perfect.
00:34:48
Speaker
So the last topic is, or the last category of diseases really is the use of corticosteroids in community-acquired pneumonia.
Corticosteroids in Severe CAP
00:34:57
Speaker
And if we could start maybe with the current recommendations from the 2024 guideline, and then we can go from there.
00:35:05
Speaker
Sure.
00:35:06
Speaker
So we gave a strong recommendation based on moderate certainty evidence that
00:35:12
Speaker
for using corticosteroids in adult patients with severe bacterial community acquired pneumonia.
00:35:21
Speaker
And we did not make a specific recommendation for using steroids for adult patients with less severe bacterial community acquired pneumonia.
00:35:34
Speaker
To come up with that recommendation, we looked at 18 RCTs
00:35:41
Speaker
And we defined severe CAP based on how they were defined in the trials.
00:35:45
Speaker
And these were patients who had certain characteristics that defined them to be severe.
00:35:54
Speaker
Most of them were admitted to the ICU at the time that they were randomized to steroids.
00:35:59
Speaker
And generally, there were patients who had a high, what we call pneumonia severity index score.
00:36:06
Speaker
They generally had oxygenation impairment, mental status derangement.
00:36:09
Speaker
They were either hypotensive, hypoxemic, multiple infiltrates on chest x-ray and so forth.
00:36:16
Speaker
So they were clearly patients that were defined as severe.
00:36:20
Speaker
pneumonia, community-acquired pneumonia, using the traditional criteria from the various societies that have established this.
00:36:28
Speaker
For the less severe criteria, those that did not meet the severe community-acquired pneumonia definition, that particular subgroup of patients, we did not make any recommendation for using corticosteroids unless the patients had
00:36:48
Speaker
community acquired pneumonia and sepsis, if they had the sepsis syndrome in association with community acquired pneumonia, of course, those patients should be getting corticosteroids.
00:37:00
Speaker
But if they just had community acquired pneumonia that was in the less severe category based on the criteria that I mentioned that did not meet severe community acquired pneumonia definition, for those patients, we did not make any specific recommendation.
00:37:16
Speaker
Any comments, Steve, on the most relevant studies for CAP?
00:37:23
Speaker
Obviously, there's some recent large studies that I think I'm sure have impacted how you thought about this as a committee.
00:37:31
Speaker
Yes.
00:37:31
Speaker
I mean, clearly the more recent trials that was published in the New England Journal of Medicine, the Cape Cod trial, I think was the largest randomized controlled trial.
00:37:44
Speaker
And they...
00:37:46
Speaker
pretty much accounted for about 35% of the population that we analyzed for the severe community-acquired pneumonia subgroup.
00:37:55
Speaker
And that trial showed a strong mortality benefit for using corticosteroids.
00:38:01
Speaker
So clearly that trial accounted for a significant proportion of the patients that we analyzed that were
00:38:12
Speaker
made it more convincing that for patients with severe community-acquired pneumonia, there is a mortality benefit for using steroids on those patients.
00:38:22
Speaker
In terms of the formulation or the dosing regimens and corticosteroids used, it seems like with CAP there's the most options.
00:38:33
Speaker
Any comments on this from your perspective?
00:38:37
Speaker
So very, very similar dosing regimens.
00:38:41
Speaker
So the Cape Cod trial of hydrocortisone for patients with severe community acquired pneumonia also use the 200 milligram dose in divided doses or by continuous infusion.
00:38:57
Speaker
Other studies have used methylprednisolone, one mg per kilogram, or even prednisone for five to seven days and using criteria such as an elevated CRP or some other biomarker to decide what
00:39:15
Speaker
to use corticosteroids.
00:39:17
Speaker
But again, when we looked very carefully at whether there was any credible subgroup effect based on the type of corticosteroids that were used, as we found in the corticosteroid use literature for Shepsis, septic shock, and ARDS, there did not seem to be any major difference in terms of what corticosteroid you use.
00:39:45
Speaker
Excellent.
00:39:46
Speaker
So I think as we start wrapping, if you could put it all together for us as a clinician, Steve, could you give us a summary of how you approach the use of corticosteroids in your patient population as you're rounding in the ICU?
Clinical Practice Insights by Dr. Pastores
00:40:01
Speaker
Yes.
00:40:02
Speaker
I also want to highlight, I mean, corticosteroids are not, you know, without adverse effects, and that's clearly very, very important.
00:40:12
Speaker
You know, when you use steroids, they certainly can be associated with a lot of adverse effects.
00:40:18
Speaker
But typically in the manner in which corticosteroids are used, let's say for severe sepsis, septic shock, or even for community acquired pneumonia, for those two particular syndromes, usually the corticosteroid used there and duration is usually short,
00:40:35
Speaker
Generally, no more than a week in most patients.
00:40:39
Speaker
For AIDS, it's a little bit different story because there you have to use it for a longer period of time.
00:40:45
Speaker
And of course, in those settings, you will encounter some of the adverse effects maybe that are much more pronounced.
00:40:53
Speaker
Most common is of course hyperglycemia, which we know we can treat and manage in the ICU.
00:40:59
Speaker
Metabolic abnormalities like hypernatremia certainly can also occur.
00:41:05
Speaker
The risk however of secondary infections, GI bleeding, even some neuropsychiatric side effects, I mean they're there and they always have to be considered.
00:41:15
Speaker
So steroids have to be used very cautiously in patients where some of these other considerations might.
00:41:22
Speaker
So I always look at a patient through the lens of looking at the risk and benefits.
00:41:28
Speaker
Clearly in a patient with septic shock on two pressers where I need to reverse the shock as fast as I can to reduce further organ injury or somebody with severe community-acquired pneumonia or early severe ARDSs.
00:41:41
Speaker
Certainly, I would use corticosteroids there without hesitation.
00:41:45
Speaker
Where I usually, and I'm a little bit, in terms of my own practice, I tend to use hydrocortisone for septic shock with or without fludro, usually without fludro.
00:41:59
Speaker
For ARDS, I favor methylprednisolone.
00:42:02
Speaker
And then again, that's my own choice based on, you know,
00:42:07
Speaker
The knowledge that methylprednisolone resides longer in the lung and when you sample lavage fluid for different steroids, it seems to be the one that clearly resides longer in the lungs where you really want to make, you know, its anti-inflammatory action work.
00:42:27
Speaker
So that's my own choice.
00:42:29
Speaker
As I mentioned earlier, there did not seem to be any particular subgroup differences based on the type of corticosteroid use.
00:42:37
Speaker
So it's really a balance.
00:42:40
Speaker
But I always tell my fellows and residents and students and APPs that corticosteroid is widely available.
00:42:49
Speaker
It's inexpensive.
00:42:51
Speaker
I mean, the data is strong for specific syndromes like septic shock and community-acquired pneumonia and even
00:42:58
Speaker
for ARDS.
00:42:59
Speaker
Yes, we all want to see a very strong signal always for mortality, but, you know, it's a hard target.
00:43:06
Speaker
I think, you know, having shorter days on a ventilator, avoiding intubation in severe patients, getting them out of the ICU, you know, while managing some of the adverse effects that may occasionally occur, I think is worth it if we're going to try to, you know, improve the outcomes of our patients in the unit.
00:43:26
Speaker
For sure.
00:43:27
Speaker
And one of the things that we were commenting before we started recording was that the strong recommendation or the we recommend statement came for the use of corticosteroids and CAP, including acquired pneumonia.
00:43:41
Speaker
And perhaps in current practice, I mean, I don't have evidence of this, but my suspicion is that that might be an area of opportunity for clinicians to really pay attention to
00:43:50
Speaker
that there are patients with severe community-acquired pneumonia in whom maybe they're not on pressers or not classified as ARDS but are in the ICU and would probably benefit from the use of corticosteroids.
00:44:04
Speaker
I agree.
00:44:05
Speaker
I mean, you know, we've been debating this topic about steroid use for patients with pneumonia, both
00:44:11
Speaker
community acquired and hospital acquired.
00:44:13
Speaker
And for many, many years, there was a lot of reluctance using steroids.
00:44:19
Speaker
And certainly the literature against steroids got very strong during SARS and H1N1, as you know, where corticosteroids were deemed to be harmful and led to a higher mortality.
00:44:30
Speaker
And since many pneumonias tend to be viral, there was that huge concern about using steroids, but we clearly saw from the COVID experience from several years ago now, and the ongoing literature from the Cape Cod study, that clearly for patients with severe community-acquired pneumonia, with or without sepsis syndrome, there is a strong mortality benefit for using corticosteroids on those patients.
Future Research Needs in Corticosteroid Use
00:45:00
Speaker
To conclude the clinical discussion, are there any areas that you consider crucial for future research that we should be paying attention to in the upcoming years?
00:45:12
Speaker
Yes, there's still a lot of knowledge gaps.
00:45:15
Speaker
I mentioned early on that our focused update was mainly an adult guideline update.
00:45:21
Speaker
There is not much literature or ongoing trials.
00:45:25
Speaker
for the use of steroids in patients with pediatric septic shock or even ARDS or community acquired pneumonia in children.
00:45:33
Speaker
So clearly that's a knowledge gap right there.
00:45:37
Speaker
We also do not have a lot of patients that were enrolled in the clinical trials for sepsis and septic shock from the surgical side, from the neurocritical care patient population,
00:45:53
Speaker
We need more studies with steroids in less severe community-acquired pneumonia.
00:45:58
Speaker
But I think in the end, it's going to come down to the use, I think, of precision medicine and enrichment, the use of phenotyping and genotyping to identify the patients most likely to benefit, as well as those patients that might be harmed with steroids.
00:46:14
Speaker
And I think as we understand more the mechanism of action of steroid and we get information
00:46:19
Speaker
more understanding of the optimal dose and duration and some of the short-term and long-term side effects like neuromuscular weakness.
00:46:27
Speaker
This was a major discussion point among our panelists because while we know of short-term
00:46:35
Speaker
side effects of corticosteroids, there is a gap in our understanding of the longer side effects such as neuromuscular weakness.
00:46:43
Speaker
That might also be a problem that some of our survivors of sepsis and septic shock and ARDS who get post-intensive care syndrome, how many of those patients
00:46:54
Speaker
might have suffered from the consequences of steroid use.
00:46:58
Speaker
While they are alive, there may be some ill effects on neuromuscular function, which we know does occur, but how much of that can impact their overall survival in the long term, I think.
00:47:11
Speaker
we need to understand a little bit more mechanistically and study them on a longer term basis.
00:47:17
Speaker
So there are still a lot of research items that we clearly, the panelists understood, would probably form the basis for the next timeline update in a few years.
00:47:31
Speaker
For sure.
00:47:31
Speaker
And we'll have you back then as well.
00:47:34
Speaker
You've been to the podcast when we started.
00:47:38
Speaker
I think I mentioned to you, you were officially the second episode of the podcast several years ago.
00:47:44
Speaker
And I appreciate your willingness to come back and share your expertise with us.
00:47:49
Speaker
But we would like to close with a couple of questions that are not related to corticosteroids that really just, I mean, kind of try to tap into the wisdom
Books Influencing Dr. Pastores
00:47:58
Speaker
of our guests.
00:47:58
Speaker
Would that be okay?
00:48:00
Speaker
Sure, yeah, yeah.
00:48:02
Speaker
Are there any books or a book that has influenced you significantly or books that you have gifted often to other people?
00:48:10
Speaker
So the one book I just started reading, Sergio, but I haven't, you know, I'm only maybe, I don't know, a quarter of the book that I'm currently reading right now, which I'm sharing with my daughter who moved back from Los Angeles to New York recently is Elon Musk's book.
00:48:30
Speaker
And I have been fascinated by this person in terms of where he has evolved from his origins in South Africa to what
00:48:41
Speaker
he has done or continues to be doing with all the things that affect a lot of what we do now and what we're going to do in the future.
00:48:50
Speaker
So that's something that kind of has been intriguing me, although I'm still very early in the book right now.
00:48:58
Speaker
Is this the, just to make sure, I'm thinking of the same book.
00:49:03
Speaker
This is the Walter Isaacson biography?
00:49:05
Speaker
Yes.
00:49:07
Speaker
I think that you'll love it.
00:49:09
Speaker
I actually read that book and it was very humbling for me.
00:49:13
Speaker
I have to be quite frank that some of Elon Musk's opinions are not aligned with my worldview.
00:49:23
Speaker
However, I think that reading that biography, understanding the layers of complexity of any human being,
00:49:32
Speaker
It may allow me to be more empathetic, but also to recognize that there are aspects of him that are true genius and that are quite unique.
00:49:40
Speaker
Right.
00:49:40
Speaker
And that maybe we should evaluate people like we should evaluate studies in their totality, not only in the aspects that we like or don't like.
00:49:50
Speaker
Right.
00:49:52
Speaker
I agree.
00:49:52
Speaker
I mean, I have been a contrarian, you know, on the other side of the way he thinks and acts.
00:49:59
Speaker
But I'm beginning, as I read through the book, I'm beginning to appreciate, you know, and just like sometimes you can be stuck in one line of thinking, whether it's in medicine or in life, and not realize, you know, there's another side that maybe you need to understand, as you said, the totality of it.
00:50:17
Speaker
The other book, Sergio, that I was also reading of late is The Autumn Ghost by Hannah Wunsch.
00:50:26
Speaker
I don't know if you've read it.
00:50:27
Speaker
Hannah is an anesthesia critical care physician who has published a lot.
00:50:34
Speaker
She actually moved to Cornell across the street.
00:50:38
Speaker
several months ago, I think last fall, and she had a book club reading at the Cornell Library and she invited Neil and myself to go.
00:50:51
Speaker
So we sat through a reading of a couple of chapters of that book.
00:50:56
Speaker
And it's basically the story of how the battle against the polio epidemic changed our perspective in how modern critical care
00:51:07
Speaker
So I found the book very riveting as well and fascinating.
00:51:11
Speaker
And it's basically, and I didn't know that Hannah had, apparently this has been a pet project that she had been doing.
00:51:22
Speaker
aspiring to complete for some years, you know, off and on.
00:51:28
Speaker
But it's very riveting.
00:51:29
Speaker
I have found it to be, you know, just knowing the history of the polio pandemic and how patients were dying of respiratory failure and how students were basically providing ventilation by hand around the clock.
00:51:43
Speaker
You know, we've seen pictures of it, but the way it's described in the book and how it really became a turning point and inspired people
00:51:50
Speaker
you know, not only the creation of ICUs, but modern ventilators as we know them now.
00:51:55
Speaker
I found the book very inspiring and compelling to also read.
00:52:01
Speaker
For sure.
00:52:01
Speaker
And I think both wonderful recommendations and we'll definitely link them in the show notes for our listeners.
00:52:08
Speaker
And I would encourage people to pick them up.
00:52:12
Speaker
The second question, Steve, relates to beliefs.
00:52:15
Speaker
What do you believe to be true in medicine or in life that most other people don't believe or act as they don't believe?
00:52:26
Speaker
I'm trying to digest that question, Sergio, and it's a little tough for me to...
00:52:31
Speaker
to answer that, you know, like what I personally believe to be true in medicine or in life that most people do not.
00:52:41
Speaker
Because most of what I generally believe, you know, as a truth in life, usually most other people, at least my peer group, tends to also agree they believe in.
00:52:54
Speaker
So I'm not able to come up with something that
00:53:00
Speaker
I can tell you most people, you know, don't agree with it.
00:53:06
Speaker
Fair.
00:53:07
Speaker
And I think that a lot of times what I think about when I think of this question is examples of things that maybe people might say they believe, but we don't act like we really believe.
00:53:21
Speaker
And one example would be less is better in the ICU, right?
00:53:25
Speaker
Everybody says that when we're in a conference or in a podcast, but then in practice, that doesn't seem to be the operating principle.
00:53:33
Speaker
But I understand what you're saying, and that is a perfectly fine answer.
00:53:38
Speaker
I remember, Sergio, back in the day when the ARDSnet trial came out, and everybody was saying, sure, I practice low-tidal volume ventilation.
00:53:49
Speaker
And I was rounding in some ICUs, you know, some places in the country, and everybody was on 600, 700-tidal volume.
00:53:56
Speaker
whatever they think they're preaching in actuality, you know, they're not actually doing.
00:54:01
Speaker
And I think some data was published around that time or a year or two later, where even one or two sites that were part of the ArtsNet network similarly were not abiding by what was shown in the clinical trial.
00:54:13
Speaker
So it does happen, maybe unintentionally, but it is so true that
00:54:19
Speaker
In practice, sometimes, you know, we say we think we're doing or want to do in actuality is actually not something that ends up happening.
00:54:28
Speaker
For sure, human nature, for sure.
00:54:30
Speaker
And we're all, I think, guilty to some extent.
00:54:33
Speaker
And the last question and the closing question is, what would you want every listener, every intensivist, every clinician who's listening to us today to
Strategic Compassionate Care Advice
00:54:44
Speaker
know?
00:54:44
Speaker
It could be a quote, a fact, or a departing thought.
00:54:47
Speaker
I mean, I would just say the young critical care aspiring doctors or trainees that critical care is fun.
00:54:57
Speaker
You have to play a long game.
00:54:59
Speaker
I've been fortunate enough, you know, over the last 35 years or so to be in intensive care medicine.
00:55:08
Speaker
Although I trained in pulmonary critical care, my practice has been very exclusively critical care since I came out of fellowship training in the early 90s.
00:55:17
Speaker
It's fun.
00:55:18
Speaker
Um, it's, you, you have to prepare for the long haul and you have to be very strategic in how you plan your life.
00:55:25
Speaker
Of course, family comes first before work.
00:55:29
Speaker
So you have to enjoy, uh, the trappings of, uh, you know, your, your family support, your children, if you have children, um, but look at your career, uh, not in short bursts, but look at it as a trajectory.
00:55:43
Speaker
So you could,
00:55:44
Speaker
Enjoy it.
00:55:45
Speaker
There'll be ups and downs I think we have become masters of a lot of negative clinical trials in intensive care medicine, but I tell folks all the time you know for You know for every 100 negative trials one or two will come out that's positive or at least will show some difference and so if that's if that were to be the case try to practice as best available evidence as you can yeah you have to
00:56:13
Speaker
tweak here and there and not practice all cookbook.
00:56:15
Speaker
But where the evidence is strong, you should really try to practice and always look to improve.
00:56:20
Speaker
We all learn from each other.
00:56:22
Speaker
And I always say that on rounds that, you know, if there's something that I'm saying that, you know, you can, you know, you want to challenge, you know, please do so, speak up.
00:56:31
Speaker
But practice critical care with a long horizon and improve yourself every day and be kind to your patients and the families that clearly, particularly for those who don't do well in the ICU.
00:56:48
Speaker
You have to be compassionate.
00:56:50
Speaker
And as we get older, you realize it's not everything works, no matter how aggressive we do things.
00:56:55
Speaker
And you just have to stay a little, be a little humble about that and know that you'll save many, but there'll be a few patients that you won't.
00:57:05
Speaker
And for those, you know, don't get too down on yourself.
00:57:08
Speaker
And as long as you, you know, do your best and you care for the patient and their families and your coworkers around you, I think you'll do well.
00:57:17
Speaker
I think this is a perfect place to stop, Steve.
00:57:21
Speaker
Very nicely said.
00:57:22
Speaker
And I just want to thank you for all the work you've done, obviously, in the field, but also in the work you've done in CIRC and corticosteroids and the guidelines and sharing your expertise and time with us today.
00:57:38
Speaker
Thank you for listening to Critical Matters, a sound podcast.
00:57:42
Speaker
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00:57:48
Speaker
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00:57:52
Speaker
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