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Critical Illness-Related Corticosteroid Insufficiency
11 Plays6 years ago
In this episode, we discuss critical illness-related corticosteroid insufficiency (CIRCI). Our guest is Stephen Pastores, MD, FACP, FCCP, FCCM. Dr. Pastores is Director of the Critical Care Medicine Fellowship Training and Research Programs at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr. Pastores co-chaired an international multispecialty task force addressing this important topic. During our podcast, he discusses the recent publications by this task force on corticosteroid insufficiency and the role on corticosteroid replacement in critical illness.
Additional Resources:
- Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part 1): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Click here to read.
- Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Click here to read.
- Adjunctive Glucocorticoid Therapy in Patients with Septic Shockโ. ADRENAL Trial Investigators. Click here to read.
Additional Resources:
Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part 1): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.
https://www.ncbi.nlm.nih.gov/pubmed/28938253
Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).
https://www.ncbi.nlm.nih.gov/pubmed/28938251
Adjunctive Glucocorticoid Therapy in Patients with Septic Shockโ. ADRENAL Trial Investigators.
http://www.nejm.org/doi/full/10.1056/NEJMoa1705835?query=featured_home
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Transcript
Introduction to Podcast and Host
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
Welcome to another episode of Critical Matters, the sound critical care podcast.
Controversial Use of Corticosteroids
00:00:28
Speaker
Today we have a very interesting
00:00:30
Speaker
interesting topic that has been a topic of controversy and discussion for several years now in our field, which is the use of corticosteroids in critical illness.
Introduction of Dr. Steven Pastores
00:00:41
Speaker
It's a great pleasure to have as our guest Dr. Steven Pastores, who is a critical care medicine physician, is director of Critical Care Medicine Fellowship
00:00:50
Speaker
training and research programs at Memorial Sloan Kettering Cancer Center in New York and also a professor of medicine and anesthesiology and medicine at Weill Cornell Medical College.
00:01:00
Speaker
Dr. Pastores is actively involved in critical care medicine at a national and international level.
00:01:06
Speaker
He served as a member of the Board of Regents of the Society of Critical Care Medicine.
00:01:10
Speaker
He is also a member of several editorial boards including CHESS Journal, Critical Care Medicine, and the Journal of Critical Care.
00:01:17
Speaker
Dr. Pastores was the recipient of the Distinguished Service Award and the SAFAR Global Partner Award from the Society of Critical Care Medicine for exceptional leadership contributions to the vision and mission of the society.
00:01:29
Speaker
It's a great pleasure to introduce Dr. Pastores.
00:01:32
Speaker
Steve, welcome to Critical Matters.
00:01:35
Speaker
Thank you, Sergio.
00:01:36
Speaker
It's a pleasure.
Evolving Understanding of Corticosteroids
00:01:37
Speaker
So as I said, today we're going to talk about a topic that seems to be on a pendulum in critical care, which is corticosteroids and critical illness.
00:01:46
Speaker
And it seems that every 10 years, we have some new information or new approaches.
00:01:51
Speaker
And as we move forward, we seem to be becoming much more specific and I think educated in what really this means for our critical ill patients.
00:02:01
Speaker
And I think it's a timely discussion since, Steve, you have co-chaired a recent guideline
00:02:07
Speaker
from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine that has just been published.
00:02:14
Speaker
I understand it.
00:02:15
Speaker
Critical care medicine and intensive care medicine as a two-part document talking about CERCI.
00:02:21
Speaker
So maybe we should start with what is CERCI?
History of CERCI
00:02:25
Speaker
So CERCI stands for Critical Illness-Related Corticosteroid Insufficiency.
00:02:32
Speaker
It's a term and an acronym that we came up with
00:02:37
Speaker
back in the 2000 to 2007 period when we were charged to come up with the first set of guidelines on the use of corticosteroids in critically ill.
00:02:50
Speaker
At that time, our knowledge and understanding of critical illness-related corticosteroid insufficiency was rather very basic and somewhat lacking in granularity.
00:03:07
Speaker
We envisioned at that time, and most clinicians in practice thought that what we were referring to largely was a syndrome akin to relative adrenal insufficiency, that there was some impairment of the hypothalamic pituitary adrenal axis that was pronounced in critically ill patients, and that maybe there was some resistance of the tissues to the action of glucocorticoids.
00:03:36
Speaker
So,
00:03:36
Speaker
That was what our understanding was at the time and that corticosteroids were going to be used.
00:03:44
Speaker
And if it were in conditions associated with SIRSI, it would be not so much necessarily a replacement in situations where it was felt to be deficient, but rather trying to overcome perhaps some of that corticosteroid resistance problem.
00:04:04
Speaker
But it really was fundamentally somewhat of a very basic understanding at the time.
00:04:12
Speaker
Fast forward 10 years later, there has been a greater understanding of the syndrome.
Advancements in CERCI Understanding
00:04:19
Speaker
And really one of the other pillars of this syndrome is that in addition to the impairment of the HPA axis in critical illness and the tissue resistance to corticosteroids,
00:04:33
Speaker
there's really an alteration in the metabolism of cortisol that's largely been dictated by the mechanisms that break down cortisol in the liver and the kidney.
00:04:50
Speaker
And so it's the combination of these three factors right now that we think is responsible for why this syndrome develops in more specific conditions like sepsis
00:05:03
Speaker
ARDS, but may also be evident in other critical care syndromes as well.
00:05:09
Speaker
And I think, like you mentioned, this has been an evolution of our understanding.
00:05:14
Speaker
We started this maybe in the 1980s by trying to modulate inflammation and sepsis with high-dose steroids, and that has evolved into, it seems like every decade, a different iteration of our understanding.
CERCI Symptoms in Critical Illness
00:05:27
Speaker
And now,
00:05:28
Speaker
coming on 2018, 10 years after your previous guidelines, we're now talking of a syndrome related to critical illness in general that has many causes, as you mentioned, that we're much more aware now than we were before.
00:05:42
Speaker
Quick question regarding symptoms.
00:05:44
Speaker
I mean, I think it's always good to remember that we're clinicians and start with symptoms and signs.
00:05:51
Speaker
It seems that a lot of the patients
00:05:53
Speaker
potential signs and symptoms related to critical illness-related corticosteroid insufficiency or SIRSI are very nonspecific.
00:06:01
Speaker
Are there any that you want to comment that might be of more use at the bedside for our intensivist?
00:06:06
Speaker
So most of the studies examining the condition of SIRSI have largely focused in sepsis and septic shock and in the acute respiratory distress syndrome, or ARDS.
00:06:23
Speaker
And
00:06:25
Speaker
many of the signs and symptoms of these conditions can really have very nonspecific manifestations.
00:06:35
Speaker
I think the classic manifestations that we would think about at the bedside are the conditions where someone is hypotensive, is not responding appropriately to fluid therapy, and they additionally require
00:06:54
Speaker
a vasoactive or vasopressor agent.
00:06:58
Speaker
That would be like one classic manifestation where this syndrome might be thought about, which is what we normally see in patients who go into septic shock.
00:07:09
Speaker
The other presenting signs, as I mentioned, like fever, electrolyte, imbalances, generally are common enough in other settings.
00:07:21
Speaker
And so it's
00:07:22
Speaker
sometimes very hard to distinguish what truly is SIRSI to other conditions that may be related to not necessarily infectious conditions, but more metabolic or hormonal abnormalities like classic adrenal insufficiency, for example, would be very different in terms of how we would compare that to the more traditional syndromes that we see in ICU patients like sepsis, ARDS, and
00:07:51
Speaker
and even in patients with major trauma.
00:07:54
Speaker
Absolutely.
00:07:54
Speaker
And I think that as a take-home message for the listeners, really the cardiovascular signs of hypotension, refractory to fluid, decreased sensitivity to catecholamines in the context of a high cardiac index clearly seem to be something that we see often with our septic shock patients who might have manifestations of SIRSI.
Challenges in Diagnosing CERCI
00:08:17
Speaker
Steve, what about diagnostic?
00:08:19
Speaker
And I know that there's been a lot of debate, and I haven't reviewed the literature lately in terms of what's the best diagnostic tool other than clinical intuition for trying to establish a diagnosis.
00:08:29
Speaker
I know that there's a lot of controversy in this area and perhaps not necessarily a definitive answer, but what is the guidance from the group that you co-shared in the guidelines?
00:08:42
Speaker
So this was a very challenging question.
00:08:47
Speaker
for us.
00:08:47
Speaker
And in fact, we ended up being unable to make a very clear-cut recommendation on what the best single diagnostic test should be to identify this syndrome.
00:09:02
Speaker
Classically, we use the ACTH stimulation test, and we use a 250 microgram test where we get a basal level of cortisol.
00:09:14
Speaker
We then inject
00:09:16
Speaker
intravenously 250 micrograms of cosyntropin or synthetic ACTH.
00:09:22
Speaker
And then we check the increment in the cortisol level from baseline at 30 minutes and at 60 minutes.
00:09:30
Speaker
And we've been classically taught from other studies, including the study by my co-chair, Jalali Anand, that the failure to increase from basal at 30 and 60 minutes, or what we call the delta cortisol,
00:09:46
Speaker
greater than nine, and if someone did not get a response greater than nine, then they would be deemed a non-responder, and that would be something that would be seen commonly in patients with SIRC.
00:10:05
Speaker
There are many questions surrounding the ability of that test to actually really distinguish patients with or without the syndrome.
00:10:14
Speaker
The question about the 250,
00:10:17
Speaker
dose of ACTH being supraphysiologic.
00:10:21
Speaker
Other studies have used one microgram.
00:10:25
Speaker
And there have been different sensitivity and specificity rates to either of these two tests.
00:10:32
Speaker
And so other types of tests have been envisioned, including a random cortisol, including getting salivary cortisol even has come up.
00:10:44
Speaker
and other types of testing to try to get at it.
00:10:46
Speaker
But we were particularly challenged with the question of what's the single best test.
00:10:53
Speaker
And basically, we were unable to make a recommendation as to whether the delta cortisol or the random plasma cortisol would actually be truly diagnostic of this syndrome.
00:11:06
Speaker
We felt that most clinicians still go and use
00:11:12
Speaker
the 250 microgram synthetic ACTH dose and looking for that less than 9 delta cortisol change at 30 and 60 minutes.
00:11:25
Speaker
Others we know like to use the random plasma cortisol knowing that in critically ill patients you lose that diurnal variation in cortisol level so it really doesn't matter what time of the day you're getting a random cortisol.
Consensus on CERCI Diagnostic Tests
00:11:40
Speaker
But
00:11:40
Speaker
in reviewing the studies for the task force guideline, we simply could not get consensus, meaning 80% of the task force members could not agree on making a single recommendation on which test to use for this diagnosis.
00:12:00
Speaker
So that's really as far as we could go regarding that question.
00:12:04
Speaker
So from the point view of the task force,
00:12:08
Speaker
and the available evidence right now, either an ACTH stim with cosentropin at 250 or a random serum total cortisol in a critically ill patient, for example, somebody who's requiring basal pressure support that is below 10 would be potential tests that we could use, but it's hard to really recommend one over the other.
00:12:29
Speaker
Would that be the correct interpretation?
00:12:32
Speaker
Yes, and we felt that in many patients, particularly those
00:12:36
Speaker
who are already in septic shock requiring vasopressors, the decision to use corticosteroids should not rely on having to do this test as a requisite when deciding to use corticosteroid therapy in patients with refractory septic shock who are already adequately fluid repleted and are continuing to require vasopressor therapy to maintain
00:13:00
Speaker
an acceptable blood pressure, in this case, a mean arterial pressure of at least 65 millimeters of mercury or greater.
00:13:07
Speaker
Excellent.
00:13:07
Speaker
I think that's a very important point that these are tests that are available that have
00:13:12
Speaker
their strengths and limitations, but in the context of specific populations that we'll dive in a little bit, it might not be, like you said, a prerequisite to initiate
Guidelines and GRADE System
00:13:22
Speaker
therapy.
00:13:22
Speaker
So we'll get there.
00:13:23
Speaker
One more question regarding diagnostic testing.
00:13:27
Speaker
So I remember that around the time that the cortical study was published, there was a lot of discussion about plasma total versus free cortisol.
00:13:37
Speaker
Any comments on that, Steve?
00:13:39
Speaker
Yes.
00:13:40
Speaker
So there was a very nice study that was published in the New England Journal of Medicine in 2004 that looked at plasma-free cortisol being more healthful than total cortisol, realizing that free cortisol really is what we call the bioactive form of cortisol.
00:14:06
Speaker
And critically, patients are known to have low serum concentrations.
00:14:11
Speaker
of an important protein called cortisol-binding globulin, and most patients have low albumins.
00:14:18
Speaker
And so in patients with very low levels of cortisol-binding proteins, the use of the serum total cortisol, therefore, may not predict free cortisol, which is really what you want to measure.
00:14:32
Speaker
And so that particular study raised some concern about
00:14:39
Speaker
whether we should be switching and start using free cortisol rather than total cortisol.
00:14:47
Speaker
The problem with measuring free cortisol levels, however, is that the techniques to do this test are, as we say in the paper, are rather cumbersome and not available in most laboratories at many medical centers, and the turnaround time is not fast enough
00:15:07
Speaker
to get this test available immediately at the bedside.
00:15:12
Speaker
And so as a result of that, we suggested against using free cortisol and instead favor the use of plasma total cortisol for the diagnosis of CRC.
00:15:27
Speaker
Although, as you will note, Sergio, most of the recommendations throughout our guideline really are conditional recommendations.
00:15:36
Speaker
or what used to be called weak recommendations is using the strong versus weak terminology.
00:15:45
Speaker
And that is what it means, therefore, is in the settings where we have given a conditional recommendation, we are really letting the clinicians know at the bedside that based on the most current evidence from the literature,
00:16:02
Speaker
that these conditional recommendations, we're leaving it up to the judgment of the clinicians based on their individualized decision-making for caring for these patients, that the evidence might be weak in supporting this recommendation.
00:16:16
Speaker
And we quantify that level of evidence from low to high, depending on the availability of randomized control trials and specific study populations.
00:16:26
Speaker
So for the question on free cortisol versus total cortisol, the evidence for that
00:16:32
Speaker
was very low, and so the recommendation could only be made as conditional.
00:16:37
Speaker
Okay, and I think that it might be worth taking a little bit of a sidebar just to quickly talk about the guidelines, which really follow what I think most of our Society of Critical Care Medicine guidelines and similar guidelines are using is the GRADE system in terms of evaluating the available evidence and
00:16:57
Speaker
and making recommendations.
00:16:59
Speaker
And like you mentioned, Steve, there's two categories of recommendations, strong versus conditional, which are usually phrased as we recommend versus we suggest.
00:17:08
Speaker
Could you give us a little bit of an idea to the audience?
00:17:13
Speaker
We recommend or a strong recommendation.
00:17:17
Speaker
What does it mean for patients and what does it mean for clinicians?
00:17:21
Speaker
So there are many factors that are
00:17:24
Speaker
considered.
00:17:25
Speaker
We tried to make these guidelines to be truly applicable at the bedside by looking at it from the level of many, many factors.
00:17:37
Speaker
And among the many factors besides the evidence was basically how applicable these recommendations were going to be depending on the values and preferences, not only for the clinicians, but also more importantly,
00:17:54
Speaker
for the patients and what the cost implications might be.
00:17:58
Speaker
So the recommendations from GRADE, for example, really factor in not only the quality of the evidence, balancing the risk and benefits of the treatment, the values and preferences as applicable for the patient, and the cost of the interventions.
00:18:16
Speaker
And so
00:18:18
Speaker
where we use the phrase we recommend, we use that phrase for recommendations that are strong.
00:18:26
Speaker
And we use, we suggest for recommendations that we would call conditional or synonymous to the older term, weak recommendations and making the clinicians and the bedside providers understand that for conditional recommendations where we only suggest we are not prescribing a specific, you know,
00:18:47
Speaker
a practice intervention that you should be doing, but rather, in fact, cautioning and making sure that you're using that recommendation in a situation where you feel this is clinically appropriate, balancing the risks and benefits of the corticosteroid intervention to the quality of the evidence and, of course, to the cost implications.
00:19:15
Speaker
Excellent.
00:19:15
Speaker
I think that's a very important point.
00:19:17
Speaker
And also, like you mentioned, the spirit of the guidelines is to serve as a tool based on a review of the literature by experts and not necessarily as a mandate.
00:19:28
Speaker
And especially when we don't have enough evidence, I think that clinicians need to understand how that decision making has to be applied at the bedside at a very individual level for each patient.
00:19:40
Speaker
So I think that we can maybe jump in and talk a little bit more about the disease processes and where we stand today in terms of treating these patients with corticosteroids.
00:19:50
Speaker
And you had mentioned earlier that the three great groups of patients or big groups of patients in critical care where we think about SIRSI and we think about treatment with corticosteroids includes sepsis and septic shock, ARDS, and trauma.
Corticosteroids in Sepsis and Septic Shock
00:20:05
Speaker
So why don't we start with a sepsis and septic shock?
00:20:09
Speaker
Tell us where we stand today, Steve, in terms of treating patients who have severe sepsis but are not in shock with corticosteroids.
00:20:18
Speaker
So we felt very strongly that for patients who have sepsis or even severe sepsis but not in shock, that corticosteroids are not to be recommended.
00:20:32
Speaker
And that corticosteroid use should only be recommended in patients who
00:20:39
Speaker
who are in septic shock that is not responsive to fluid and requiring moderate to high dose vasopressor therapy.
Upcoming Trials and Future Guidelines
00:20:51
Speaker
We quantified the dose of moderate to high dose as anything that would require 0.1 micrograms per kilogram of norepinephrine or its equivalent.
00:21:04
Speaker
I would caution, though, and I know I've been asked this a few times, that
00:21:08
Speaker
depending on the patient's body weight, 0.1 micrograms per kilogram may not be truly considered to be a moderate dose.
00:21:18
Speaker
Somebody weighs 100 kilos, for example, well, that might only translate to 10 mics, and some might argue, well, maybe that's not even a moderate dose.
00:21:28
Speaker
But I think we leave that certainly for clinicians, but I think most clinicians will
00:21:38
Speaker
see that anything that's above 10 mcs is in the moderate zone and anything over 20 mcs of norepinephrine per minute would be considered to be a high dose range.
00:21:51
Speaker
So anybody that is fluid repleted and continues to require moderately high vasopressor requirement and is in septic shock, we felt we could make a recommendation there.
00:22:04
Speaker
It is a conditional recommendation.
00:22:08
Speaker
We quantified the evidence there as still low.
00:22:12
Speaker
There are two large trials that are going to have new information for us.
00:22:21
Speaker
One is the trial called the ADRENAL trial, which is going to be published hopefully soon, and that's from the Australia New Zealand group.
00:22:34
Speaker
And the other is the APPROACH trial,
00:22:38
Speaker
of corticosteroids alongside activated protein C. This was done before protein C got dropped, but the trial continued without the activated protein C arm.
00:22:48
Speaker
That's Jalali-Anane's trial in France.
00:22:51
Speaker
And these two studies will hopefully inform further recommendations.
00:22:57
Speaker
And so depending on how those results come out, we are anticipating
00:23:03
Speaker
the need to update these guidelines perhaps in the next few months, again, depending on how those studies are resulted in the literature.
00:23:13
Speaker
So it sounds like we'll have to have you back again to give us an update on those exciting studies.
00:23:18
Speaker
But just to summarize what you talked about in treating
00:23:24
Speaker
severe sepsis and septic shock.
00:23:26
Speaker
So in patients who are not requiring vasopressors, there's probably no role to think about SIRSI, test about SIRSI, or treat them in general terms.
00:23:38
Speaker
And in patients who, I'm sorry, go ahead.
00:23:41
Speaker
You want to comment on that, Steve?
00:23:42
Speaker
Go ahead.
00:23:42
Speaker
No, no, no.
00:23:43
Speaker
You're good.
00:23:43
Speaker
Yes, yes.
00:23:44
Speaker
Mm-hmm.
00:23:45
Speaker
And in patients who are in septic shock and are requiring vasopressors at a moderate to high dose, and you've defined that based on the amount of norepinephrine, we probably, as you had discussed earlier, would consider starting treatment without necessarily having to go through the diagnostic testing.
00:24:06
Speaker
Is that correct?
00:24:07
Speaker
That is correct.
00:24:09
Speaker
We felt strongly even though we graded the
00:24:12
Speaker
The evidence is moderate and made a conditional recommendation against the use of corticosteroids in adult patients with sepsis who are not in shock.
00:24:23
Speaker
And we also suggested that steroids only be used in patients who are in septic shock that's not responsive to fluid and moderate to high-dose face suppressor therapy.
00:24:35
Speaker
So let's dive in a little bit in terms of the specifics of your practice based on, obviously, you have a tremendous understanding of the literature and of the current guidelines.
00:24:46
Speaker
If you had a patient who you were treating, who's, like you said, fluid resuscitated, who requires high doses of vasopressor, let's say even more than one vasopressor, how would you treat that patient for SIRSI?
00:25:06
Speaker
So, I mean, if so normally a patient that's requiring high dose of one presser and a second presser is being introduced, my usual practice, Sergio, is when I see the norepinephrine dose escalating to about 15 mics per minute or greater, I already consider starting a second agent.
00:25:31
Speaker
And that second agent is more commonly vasopressin.
00:25:36
Speaker
But certainly epinephrine can be used instead of vasopressin with the goal of trying to reduce the dose of norepinephrine or at least to try to come off norepinephrine faster.
00:25:52
Speaker
In those patients that are on a single dose of high-dose vasopressors and or are in need of two vasopressors to maintain an adequate
00:26:05
Speaker
mean arterial pressure.
00:26:06
Speaker
Those generally are the patients that I use corticosteroids on.
00:26:11
Speaker
And the corticosteroid that we use is hydrocortisone, which I know most clinicians tend to use.
00:26:20
Speaker
And the dose is usually 100 milligrams Q8 or some version of that, depending, again, on how severe the hypotension is.
00:26:32
Speaker
But studies really have been done with a dose up to 400.
00:26:36
Speaker
So anything in that range, less than 400 milligrams per day in divided doses.
00:26:45
Speaker
What is not a good practice is to use very high doses of hydrocortisone.
00:26:51
Speaker
By that, I mean anything that goes beyond 400 milligrams a day of hydrocortisone or its equivalent would not be advisable.
00:27:01
Speaker
So it sounds like in terms of the dosing, a range of 200 to 400 milligrams of hydrocortisone or equivalent per day in divided doses is probably what will be supported by the current literature.
00:27:16
Speaker
And really the caveat here is not to exceed that 400 because there's probably no benefit and there can be potential harm.
00:27:22
Speaker
Is that correct?
00:27:23
Speaker
Yes.
00:27:24
Speaker
And we also stipulated a duration.
00:27:28
Speaker
and we know this is certainly very dynamic or fluid, we recommended that the dose, whatever it's used, whether it's 200, 300 per day of hydrocortisone or equivalent, usually hydrocortisone, that that be maintained for at least three full days at the full dose and not be tapered rapidly unless the patient is totally off day suppressors, in which case,
00:27:57
Speaker
the taper can then ensue.
00:28:01
Speaker
And that is where we felt the literature was more solid in terms of making that recommendation.
00:28:09
Speaker
I've been asked multiple times, what do you do with the patients?
00:28:13
Speaker
Do you really keep them seven days or 10 days?
00:28:16
Speaker
And that's really a question that clinicians have to look at besides the evidence.
00:28:22
Speaker
They have to look at the benefits and harms and
00:28:26
Speaker
and cost of keeping patients on steroids.
00:28:29
Speaker
Granted that they are relatively inexpensive, but I think we're more concerned about super infections, electrolyte issues, hyperglycemia, etc.
00:28:39
Speaker
That can become a problem.
00:28:40
Speaker
And so while steroids might be a good adjunct in shock reversal, steroids have a lot of side effects as well.
00:28:49
Speaker
And so that always has to be balanced.
00:28:51
Speaker
So
00:28:52
Speaker
if one were to use stress dose steroids or steroids for septic shock, it should be used at full dose for at least three or more days, depending on how the patient is responding.
00:29:05
Speaker
We don't advocate using high dose and then cutting out only after one or two days.
00:29:11
Speaker
So let's just use some scenarios to be very specific for the audience.
00:29:14
Speaker
So what you're saying is that at a minimum, if we initiate corticosteroids, we should probably treat them for three days at the full dose.
00:29:22
Speaker
And if after three days, they are off vasopressors and what we consider to be hemodynamically stable, would it be okay to just stop the corticosteroids at that point?
00:29:35
Speaker
So there are many clinicians who may be tempted to do that.
00:29:40
Speaker
There is some literature that there sometimes can be a rebound phenomenon when the steroids are abruptly stopped, where there can be rebound inflammation and cytokine release that can
00:29:51
Speaker
make the patient hypotensive again.
00:29:53
Speaker
Again, this is a clinical decision.
00:29:57
Speaker
I think I generally in practice wait until the vasopressors are off for a reasonably good period of time, not cutting out the steroids within a few hours of having gotten off the vasopressors.
00:30:13
Speaker
So whether that's 12 hours or 24 hours, it usually is within that timeframe.
00:30:19
Speaker
you know, if I'm going to be stopping the steroids, it usually will be not instantaneous after they come off the pressers.
00:30:26
Speaker
And you would, and is your practice, and I know that the literature is not definitive here, but based on what you mentioned with the potential rebound, your practice would be that after three days as a minimum, once you achieve hemodynamic stability, defined as 12 to 24 hours off base of pressers, you would do a taper.
00:30:45
Speaker
Is that correct?
00:30:46
Speaker
Yes, or a staper or even really a discontinuation at that point.
00:30:52
Speaker
Okay, excellent.
00:30:54
Speaker
So let's talk one more question regarding treatment.
00:30:57
Speaker
And where do we stand, Steve, on infusions of hydrocortisone?
00:31:03
Speaker
So let's say we choose the right dose, but instead of giving it in divided doses, we give it in a continuous infusion.
00:31:10
Speaker
And I guess the argument would be that it might help with glycemic control.
00:31:14
Speaker
Yes, so there are many...
00:31:17
Speaker
centers.
00:31:18
Speaker
In fact, in Europe, this is a more common practice than here in the U.S., where they give the hydrocortisone as a continuous infusion of 10 milligrams an hour.
00:31:31
Speaker
So that's 240 milligrams per day, whereas the practice in the United States tends to be more giving it an intermittent dosing of 100 Q12 or 100 Q8.
00:31:45
Speaker
And it's very common for those of us to see this hyperglycemia spike, you know, within an hour or so after that 100 or 200 doses given.
00:31:57
Speaker
So the claim has been that the continuous infusion does seem to be associated with less of those spikes and provides a better control of blood glucose in
00:32:10
Speaker
And some of the literature on glycemic control also state that, well, it's not like you're not keeping their sugars in a well-controlled range of, let's say, 140 to 180, which we tend to do now compared to, let's say, 10 years ago.
00:32:24
Speaker
But it's how much you're keeping them in that nice range versus the up and down swings, which many have been found to be associated, actually, with somewhat
00:32:37
Speaker
worse outcomes in some patients because of the erratic way the sugars are getting controlled in patients.
00:32:43
Speaker
And so I think there is literature to support the practice of continuous infusion, although in actual practice, whether it's because of the ease of maybe giving things intermittently rather than worrying about another bag of fluid with medication to hang,
00:33:06
Speaker
and administered to patients who may not tolerate another small amount of volume.
00:33:15
Speaker
I think these are more, I would say, more practical aspects.
00:33:19
Speaker
I think in centers that can do this well with their pharmacists in the ICU, I think the practice can be supported well, and those that prefer to do it intermittently, they just have to realize there are these spikes in glucose levels
00:33:34
Speaker
around the time of those higher dose administration, in which case more use of insulin may be required in those settings.
00:33:46
Speaker
Excellent.
00:33:46
Speaker
So I think that that's a great clarification and just gives our clinicians more options to think about.
00:33:53
Speaker
But like you said, it probably depends on what's the ability at each individual ICU to provide one or the other.
00:34:01
Speaker
Let's move on, Steve, to ARDS.
00:34:04
Speaker
And I think that you mentioned that a little bit earlier.
00:34:05
Speaker
That's one of the diseases, obviously, where we've centered a lot of our research regarding the use of corticosteroids.
00:34:12
Speaker
And now maybe the focus is more around Searcy.
00:34:15
Speaker
But where do we stand today in terms of treating patients with ARDS with corticosteroids?
00:34:21
Speaker
So I think we have very good to strong evidence that corticosteroids should not be used.
00:34:31
Speaker
for the treatment of patients with late ARDS.
00:34:34
Speaker
By that, I mean ARDS that develops in patients in the ICU, let's say two weeks or beyond.
00:34:43
Speaker
I think where much of the controversy or discussion or debate on rounds and in the literature and in practice is what about those patients where you're contemplating using it early and how would you define the severity
00:35:00
Speaker
of the ARDS.
00:35:02
Speaker
And so we have more recent definitions from the Berlin conference published in JAMA in 2012.
00:35:12
Speaker
But when we started doing the guidelines, we were still going with what the literature was showing us and many of the studies for early and late ARDS happened to be
00:35:29
Speaker
at time periods where the previous definitions of the severity of ARDS were still being used.
00:35:37
Speaker
And so when we set out to address this question in patients, again, adult, emphasizing that this was an adult guideline, even our recommendations in sepsis and septic shock really were meant for adults specifically.
00:35:53
Speaker
But for ARDS, particularly those with early
00:35:56
Speaker
and what we would call moderate to severe ARDS, that is a PA-FIO2 ratio less than 200, and within 14 days of onset, I would even maybe qualify that as within the first few days, we suggested, based on moderate quality of evidence, that corticosteroids could be considered for those patients.
00:36:23
Speaker
So in terms of the way I understand it is clearly the idea of treating that fiber-proliferative or late ARDS stage is not something that's recommended.
00:36:35
Speaker
And that if we are to use corticosteroids in our patients with ARDS, it should be for those who have moderate to severe ARDS as defined by the PAO2-FIO2 ratio, and it should be used in the early phases, correct?
00:36:50
Speaker
Yes.
00:36:52
Speaker
Can you mention a little bit more specifics in terms of the dosing and duration that you would use in your practice if you chose to use a steroid to ARDS?
00:37:00
Speaker
Yes.
00:37:01
Speaker
So we recommended that for patients with early ARDS up to day 7 of onset with a PF ratio less than 200, the dose of corticosteroid,
00:37:22
Speaker
would be one milligram per kilogram per day of methylprednisolone.
00:37:27
Speaker
Notice that methylprednisolone is favored for ARDS, astrocorticosteroid agent of choice, in contrast to hydrocortisone for patients with refractory septic shock.
00:37:42
Speaker
Methylprednisolone is certainly much more anti-inflammatory and I think is the most tested agent
00:37:50
Speaker
It has greater penetration into the lung.
00:37:52
Speaker
It stays in the lung longer.
00:37:54
Speaker
It's the most studied corticosteroid preparation for lung inflammation.
00:37:59
Speaker
So a dose of one milligram per kilogram per day in an adult patient with early ARDS, PF ratio less than 200 is what we suggested.
00:38:11
Speaker
And in the setting before day 14, let's say day 7 to day 13 where
00:38:19
Speaker
have a situation where the presentation of the ARDS is somewhat early but not too late, then we recommended in those patients who were remaining mechanically ventilated with continuing hypoxemic respiratory failure in ARDS, the dose there is the higher dose because that's been the dose of two milligrams per kilogram per day with slow taper over the next two weeks has been the most studied regimen and I think we
00:38:48
Speaker
have that information in the digital supplement.
00:38:53
Speaker
I will inform the readers of the article, Sergio, that there is a correction on the forest plots that are in the supplement for ARDS with regards to the mechanical ventilation free days and the mortality and superinfection
00:39:17
Speaker
graphs.
00:39:18
Speaker
We noted this after the online publication came out.
00:39:23
Speaker
The journals are waiting for when the print versions get released to add that erratum so that anybody referring to the supplement would see the corrected force plots for the ARDS corticosteroid evidence.
00:39:41
Speaker
That's a
00:39:42
Speaker
Good to know, and thanks for sharing that, Steve.
00:39:45
Speaker
So let me just clarify.
00:39:46
Speaker
For ARDS, if you were to start early in a very severe patient at the dose of one milligram per kilogram, how long would you treat them?
Corticosteroids in ARDS Patients
00:39:57
Speaker
So most clinicians will generally treat patients for at least several days.
00:40:06
Speaker
Again, the data and the studies are
00:40:12
Speaker
are many and using various types of regimens depending on what the cause of the ARDS.
00:40:21
Speaker
Is it community or hospital-acquired pneumonia leading to ARDS?
00:40:27
Speaker
Many of the studies in that particular setting have also used different preparations of steroids.
00:40:36
Speaker
And so I think
00:40:37
Speaker
The best that we could come up with is certainly to keep patients with whatever steroid preparation that they're using.
00:40:48
Speaker
I would just say in my practice, it's usually methylprednisolone and usually staying with the same dose until there is significant improvement in oxygenation, reduction in inflammation.
00:41:01
Speaker
Some centers will use inflammatory markers to guide that decision.
00:41:06
Speaker
and that the taper should be done slowly and not rapidly because of that rebound phenomenon that can occur in patients whose steroids are stopped rather abruptly.
00:41:18
Speaker
And to understand that using the lower dose of methylprednisolone has not been shown to be associated with a higher incidence of hospital-acquired infection.
00:41:31
Speaker
It has not been associated with a higher risk
00:41:33
Speaker
for GI bleeding or actual bleeding, neuromuscular weakness.
00:41:39
Speaker
It does certainly remains associated with hyperglycemia, but the other side effects or adverse effects of steroids really tend to be more prominent when the corticosteroid doses are in the higher range, at the 2 mg per kg per day range, rather than the 1 mg.
00:42:00
Speaker
So I think the 1 mg per kg per day for early
00:42:04
Speaker
severe ARDS has generally been well tolerated with less side effect profile.
00:42:10
Speaker
And most patients should stay on that same dose until there is significant improvement in oxygenation that could range from five to seven days and then slowly tapered over the next week or two after that if they've shown some clinical improvement.
00:42:25
Speaker
So it seems that a good distinction between treating patients with septic shock and patients with ARDS
00:42:32
Speaker
would be that in ARDS patients, we're using a different choice for corticosteroids, the methylprednisolone, but we're also treating probably for a longer period of time, and because of that, maybe our weaning or our tapering should be also more gradual.
00:42:47
Speaker
Is that correct?
00:42:48
Speaker
Correct, because the severity of the lung inflammation is such that it's unlikely that if you were to use methylprednisolone, let's say for three to five days, that you would see a dramatic response
00:43:02
Speaker
And so these patients generally tend to require a longer period, in which case if you're stopping them during a longer period, you probably should be tapering them to be on the safe side.
00:43:13
Speaker
Whereas if you're using it for shock reversal, if they're now longer in shock and you're using hydrocortisone and you're trying to discontinue it, stopping it over a day five or day six really does not
00:43:29
Speaker
does not have much of an issue because it's for that shock reversal indication as compared to ARDS where you need a much longer period of time for really lung inflammation to get attenuated.
00:43:46
Speaker
Excellent.
00:43:47
Speaker
So I think that in terms of the last population that I have interest in, I know that the guidelines do address this, and this might be a short commentary.
00:43:56
Speaker
What about patients with trauma?
00:43:58
Speaker
Yeah, here we felt that corticosteroids should not be used in patients with major trauma.
Corticosteroids in Major Trauma
00:44:07
Speaker
However, with that said, the recommendation is, again, conditional, and we judged the quality of the evidence to be on the low side.
00:44:20
Speaker
And there were issues regarding the trial design, risk of bias,
00:44:29
Speaker
the different doses that were used.
00:44:32
Speaker
And there was just so many types of corticosteroids, different durations, formulations, and imprecision in the pooled results.
00:44:45
Speaker
And we mentioned this in the paper.
00:44:48
Speaker
But it all seemed to point in the direction that corticosteroids were not really
00:44:56
Speaker
associated with a significant enough benefit and in some patients actually may have caused even harm.
00:45:06
Speaker
Okay, excellent.
00:45:07
Speaker
Well, I think that, Steve, that this is obviously a topic that, as you mentioned, is very dynamic and still evolving.
Evolving Nature of Critical Care Research
00:45:14
Speaker
We'll look forward to new data as these large trials that you mentioned get published, and hopefully we'll be able to have you to come in and give us your commentary and your expertise.
00:45:27
Speaker
One of the things that we try to do also in critical matters is tap into the wisdom of our guest and just talk about other aspects that I think are also relevant to the practice of critical care.
00:45:37
Speaker
So if it's okay with you, I'd like to ask you just a couple of rapid-fire questions outside of the topic of CIRCY.
00:45:46
Speaker
Sure.
00:45:48
Speaker
So is there a book or books that have influenced you the most or what book have you gifted most often to others?
00:45:55
Speaker
You know, as I was growing up, I used to read a lot of finance books and management books thinking that I was going to be an investor.
00:46:07
Speaker
What happened?
00:46:09
Speaker
Was going to run a company.
00:46:11
Speaker
I don't know if my uncle in Bayside, Queens, New York,
00:46:16
Speaker
I may have had that influence because he was always looking at his stocks and he sort of like was giving me financial advice.
00:46:24
Speaker
So I ended up reading a lot of finance books.
00:46:29
Speaker
As I was getting older, I began to venture mostly into, you know, spy novel kind of books.
00:46:39
Speaker
But more recently, I was at a...
00:46:43
Speaker
at a burnout summit of the Critical Care Society's collaborative.
00:46:48
Speaker
And one of the invited guests there is a self-described medical musician, Sergio.
00:46:56
Speaker
And he gave me a book.
00:46:57
Speaker
His name is Andrew Shulman.
00:47:00
Speaker
And he has a bestseller.
00:47:02
Speaker
I've started to read it.
00:47:03
Speaker
I haven't finished the whole book.
00:47:05
Speaker
I don't know if you've heard about it.
00:47:07
Speaker
It's called Waking the Spirit.
00:47:09
Speaker
I have not heard about it, but it sounds interesting.
00:47:12
Speaker
Yes, this was a patient who had what was thought initially coming into surgery thought that he had pancreatic cancer and they were going to do a Whipple procedure.
00:47:26
Speaker
Luckily for him, it wasn't a cancer.
00:47:28
Speaker
But nevertheless, he developed postoperative complications and actually had a cardiac arrest and post-op and basically...
00:47:38
Speaker
was in the surgical ICU here in New York City.
00:47:41
Speaker
And the bottom line is he survived that episode.
00:47:44
Speaker
And one of the tools that he really subscribes to have turned his life around and made him get better was the introduction of music into his ears, which his wife kind of insisted that the clinicians do.
00:47:59
Speaker
This was at a time when, you know, we thought that giving headphones and playing music in a patient that's resting and sedated and whatnot, you know, may not
00:48:08
Speaker
necessarily be a good idea.
00:48:09
Speaker
Well, he felt that really helped him because as that music was being played in his ears, the book seems to suggest and his surgical intensivist, which also helped him write the book, tells us like all his vital signs started improving, his lactate, which started at 17, fell.
00:48:28
Speaker
And the bottom line is he got better.
00:48:31
Speaker
And so I'm reading through this and I think it's a very inspiring book.
00:48:35
Speaker
Waking the spirit.
00:48:37
Speaker
Absolutely.
00:48:37
Speaker
So we'll share that with people.
00:48:39
Speaker
It sounds very interesting, Reid.
00:48:42
Speaker
So going along, is there something that you believe either in life or in critical care to be true that most people don't believe?
00:48:51
Speaker
One of the things that I think sometimes is like, you know, people can assume or even patients and their family members can assume that a patient is well, looks well.
00:49:03
Speaker
but at the same time really can be very, very sick.
00:49:06
Speaker
And I think we learn that every day in our practice when we confront, you know, a patient or a family member of a patient who's very sick in the ICU and they're really just wondering how sick the patient is and he looks so well last week or the other day and how can he be so sick and now you're telling me he's dying in the ICU.
00:49:27
Speaker
And so sometimes navigating through that, you know, where you could look well
00:49:32
Speaker
but can be very sick inside.
00:49:34
Speaker
And I think we all have to sometimes stop and reflect at that, and that can actually happen.
00:49:41
Speaker
You could look well, but actually be sick, and that applies to us, as well as to patients that we care for.
00:49:51
Speaker
And I think that that's a great point.
00:49:53
Speaker
And once somebody told me when I was training that sometimes the most difficult task is to identify who's sick and who's not.
00:50:00
Speaker
And I think it kind of falls in that realm that even critical care physicians sometimes can be fooled.
00:50:06
Speaker
But also, I mean, as family members, that is something that I think is sometimes very difficult to navigate.
00:50:12
Speaker
And we try to teach this to our fellows.
00:50:16
Speaker
Absolutely.
00:50:17
Speaker
And the last question, and I want to be very respectful of your time, but the last question is, is there anything that you would want every intensivist or every sound critical care intensivist who's going to listen to this to know?
Balancing Aggressive Treatment and Limitations
00:50:30
Speaker
Yes, I think, you know, we, as intensivists, we like numbers.
00:50:35
Speaker
We like to reverse abnormal physiology.
00:50:39
Speaker
You know, we like to do procedures and try to apply our knowledge of various techniques.
00:50:45
Speaker
But I think, and that's certainly great and noble to do.
00:50:51
Speaker
But I think for some patients who clearly are not responding to what we would expect
00:51:00
Speaker
for the amount of aggressive interventions that we're doing to them that we realize and reflect that maybe there comes a point where we just have to realize our limitations and that as much as science is advanced in some of the things that we do, there are just some patients that simply are not getting help and we should know in that time point
00:51:27
Speaker
comes and switch gears and go more into the compassionate, palliative side of things and know our limits.
00:51:35
Speaker
And I think, you know, when I was younger, you know, I was so much into, I went into critical care with the mindset of reversing abnormal physiology and doing procedures.
00:51:47
Speaker
And I realized, you know, 25 plus years later that, you know, there were times I would have been more aggressive if this was 25 years ago.
00:51:55
Speaker
But now I know my limits and
00:51:57
Speaker
I know when it's time to shift gears from being a doctor that can treat critical illness to a doctor that maybe should be more compassionate and realize that this patient is dying and better end of life rather than my intensivist skills of doing procedures is what this patient needs.
00:52:14
Speaker
And I think that's a great place to stop.
00:52:16
Speaker
I think it's a very powerful message.
00:52:19
Speaker
And it's a message that I've heard with other of our guests as well.
00:52:22
Speaker
And I think very well said.
00:52:25
Speaker
Steve, I want to thank you enormously for the generosity with your time and your expertise.
00:52:30
Speaker
I definitely look forward to having you back when we have more data to discuss.
00:52:36
Speaker
But also, I know that there are many other topics that you're passionate about and you can tell us a lot about.
00:52:43
Speaker
So hopefully, we'll have you back.
00:52:45
Speaker
Thank you very much for being our guest.
00:52:48
Speaker
My pleasure.
00:52:48
Speaker
And thank you all for listening.
00:52:52
Speaker
Thanks again for listening to Critical Matters.
00:52:55
Speaker
Make sure to subscribe to this podcast on iTunes or Google Play.