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Towards Personalized Vasopressor Support
12 Plays5 years ago
In this episode of Critical Matters, we will discuss hypotension and new data on Angiotensin II within the context of our path towards personalized vasopressor support.
Our guest is Dr. Ashish K. Khanna. Dr. Khanna is an anesthesia and critical care practicing physician. He is Associate Professor, and Section Head for Research, in the Department of Anesthesiology, Section on Critical Care Medicine of the Wake Forest School of Medicine, in Winston-Salem, North Carolina. He is a prolific author and researcher and was the lead author of the ATHOS-3 study in the New England Journal of Medicine. The results of which led to the approval of Angiotensin II as a vasopressor for the treatment of refractory hypotension in adults with septic or other types of distributive shock.
Links:
The Relationship Between ICU Hypotension and In-Hospital Mortality and Morbidity in Septic Patients: https://bit.ly/2D1epJQ
Association between Mean Arterial Pressure and Acute Kidney Injury and a Composite of Myocardial Injury and Mortality in Postoperative Critically Ill Patients: A Retrospective Cohort Analysis: https://bit.ly/2QuyStz
Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3 Trial): https://bit.ly/2G27hhB
Survival After Shock Requiring High-Dose Vasopressor Therapy: https://bit.ly/2EkLm4P
Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients: https://bit.ly/3jiKT1L
Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock: https://bit.ly/2G1tZGB
Additional Content Related to Angiotensin II:
Angiotensin II for Vasodilatory Shock: 2019 Update: https://bit.ly/3hvVkyA
Personalization of Vasopressor Therapy in the Treatment of Vasodilatory Shock: https://bit.ly/3hy7wyD
Recommended
Transcript
Introduction to Critical Matters
00:00:06
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Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
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Sound Critical Care provides comprehensive critical care programs to hospitals across the country.
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To learn more about our programs and career opportunities, visit www.soundphysicians.com.
00:00:27
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And now, your host, Dr. Sergio Zanotti.
Understanding Hypotension and Vasopressor Support
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Hypotension is a defining hemodynamic marker of shock.
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It is a common clinical problem in critically ill patients and is a frequent target of therapeutic interventions in the ICU.
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The aim of these interventions are to restore blood to a level that is sufficient to maintain vital organ perfusion while we identify and correct the underlying causes.
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Fluids and vasopressors are commonly utilized in these cases.
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In today's episode of the podcast, we will discuss emerging data leading the way towards a personalized approach in vasopressor support.
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We will discuss angiotensin II, physiology,
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Renin, among other important concepts.
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We are honored to have Dr. Ashish Khanna as our guest today.
00:01:12
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Dr. Khanna is an anesthesia and critical care physician.
00:01:15
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He is associate professor and section head for research in the Department of Anesthesiology, section on critical care medicine of the Wake Forest School of Medicine in Winston-Salem, North Carolina.
00:01:25
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Dr. Khanna is a prolific author and researcher.
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His areas of interest include hemodynamics, outcomes, base suppressors, and septic shock.
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Dr. Khanna has
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was a lead author for the Athos III paper in the New England Journal of Medicine that led to the approval of Agitensin II as a vape suppressor for the treatment of refractory hypotension in adults with septic or other types of distributive shock.
00:01:47
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Ashish, welcome to Critical Matters.
00:01:50
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Thank you, Sergio.
00:01:51
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It's a pleasure to be here today.
00:01:54
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So I think that we're going to take a departure from a lot of the recent episodes on Critical Matters where we were focusing a lot on COVID topics and talk about a topic that I think is
00:02:05
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very, very interesting, but also very relevant to our practices because it really centers around the use of vasopressors for hemodynamic support in hypotension shock, especially distributive shock.
Exploring Hypotension Management and Research
00:02:17
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So I think that as an introduction, maybe we can start, Ashish, with just your general take on hypotension.
00:02:24
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I know that you've done a lot of studies looking at the effect of hypotension in outcomes of patients both in shock and not in shock.
00:02:31
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Maybe we can start with a general overview to introduce the topic.
00:02:36
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Sure, thank you, Sergio.
00:02:38
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Again, it's a pleasure to be here and talk about something that's very near and dear to me, which is hypotension.
00:02:47
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And hypotension is something that we as intensivists and perioperative physicians, perioperative medicine physicians, when we talk about anesthesiologists or even surgeons or internists or
00:03:05
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or nearly every specialty of medicine sees hypotension in some way, shape, or the other, whether it be in the operating room, the ICU, the post-anesthesia care unit, or in the inpatient wards in a hospital.
00:03:19
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It is also one of those things that is very easily controllable and manageable.
00:03:28
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However,
00:03:30
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If you look across the hospital on any given day and just, you know, just do a snapshot of data, you will see that at least a half of all patients in the hospital at any one given time are hypotensive.
00:03:50
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And sometimes they're hypotensive because they're really sick.
00:03:54
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And sometimes they're hypotensive because their hypotension is going under monitored or unmonitored.
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And sometimes they're hypotensive despite our best efforts to correct their hypotension with fluids, vasopressors, and so on.
00:04:09
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So that, you know, when I started working on hypotension, I really thought about it as the one thing that we see all the time.
00:04:19
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It's probably present in every single patient who is sick in one way, shape or the other in a hospital.
00:04:28
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And yet we're, and knowing that we feel empowered as a lot of different specialists to correct hypotension, still we don't seem to be doing a great job with hypotension correction.
00:04:46
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And that's what sort of started me on this hypotensive journey, as I call it.
00:04:52
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And that's where I got very interested specifically in the critical ill population.
00:04:58
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Very quickly, a story comes to me when I talk about hypotension in the ICU.
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And this was my early career.
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I was doing one of my night shifts in the ICU.
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And I had a medical student, I believe, who was sitting with me and said,
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and just talking about things.
00:05:18
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And I was putting in orders on a patient in the ICU and putting in an order for norepinephrine.
00:05:24
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And when the order set popped up, it automatically said, titrate to a map of 65.
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And it gave me the option to change that, but the default was a map of 65.
00:05:38
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And the medical student turned around and asked me, why do we titrate all our pressers to a map of 65?
00:05:46
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I turned around and started talking about the surviving sepsis campaign guidelines and this and that.
00:05:52
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But then he said, well, why not a map of 75?
00:05:56
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Why not 85?
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Why not 55?
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Are all patients alike?
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Do we know at what blood pressure our patients in the ICU have organ system failure?
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And I looked at him and I sort of diverted the conversation because no one wants to
00:06:15
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really admit in front of a medical student that you don't know your literature.
00:06:19
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But then I went back to my office and I started searching and I came up with nothing.
00:06:24
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We really never really knew.
00:06:26
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We did have surviving sepsis telling us that you're supposed to target to a MAPA 65 when you titrate vasopressors.
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But we didn't really know in terms of hypotensive thresholds when patients have organ system injury.
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critical yield patients specifically in the ICU.
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We specifically didn't know anything about myocardial injury.
00:06:51
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That is, again, an area of great personal interest for me.
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And so I started on the journey of investigating hypotension more.
Challenging Traditional MAP Targets in Hypotension
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And that's why all of that has come off of it.
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We've done a lot of work in large retrospective data sets
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And we've been able to establish some thresholds of hypotension that are sort of unconventional, but are definitely backed by some data and signals.
00:07:22
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And I think that before we dive into some of those findings, which I think are fascinating, it's a great point you made, is that we've taken almost like a dogma 65 of MAP as a target.
00:07:35
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And even though it might be based on best available data,
00:07:40
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by no means is it something that is conclusive and that is full of studies.
00:07:46
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And some of the studies probably that we need are very difficult to do.
00:07:49
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But could you maybe start, before we dive into your findings and your studies, Ashish, just saying, how do you define hypotension?
00:07:57
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That's a great question, Sergio.
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I define hypotension as the best blood pressure that will
00:08:08
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prevent organ system injury in my critically ill patient.
00:08:14
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If you're going to ask me a number, I will say I don't have a precise number for you.
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I don't want the world to go off one single number.
00:08:26
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I will still say that 65 has stood the test of time because, you know, if you go back to the history of
00:08:37
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randomized controlled trials in hypotension and septic shock.
00:08:41
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The work of Pierre Aasfar and colleagues, way back in 2014, I believe, the Sepsis Bam Group published their work in the New England Journal where they looked at, you know, high blood pressure target and a low blood pressure target in patients with septic shock.
00:08:56
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And they compared a map of 80 to 85 versus a map of 70 to 75.
00:09:02
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And overall, they did not find a mortality difference.
00:09:05
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However, they did have subtle differences.
00:09:09
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For example, they did see that in patients with chronic hypertension who were randomized to a lower MAP target, that was 70 to 75, there was more kidney injury.
00:09:21
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Similarly, in their higher blood pressure target group, there was more arrhythmias.
00:09:26
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Now, I can go on and dissect their work into many pieces and sort of look at their work under the microscope,
00:09:35
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But I will say that randomized controlled trial data is the best data that's out there.
00:09:42
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However, if I were to do that trial again today, I would do it differently.
00:09:48
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I would look at things like myocardial injury defined by a troponin increase and not necessarily a full blown myocardial infarction.
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I would look at a different sample size.
00:10:02
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I would have looked at different thresholds of blood pressure and so on.
00:10:08
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That's discussion for another day, but coming back to your question, I will say that hypotension is a pressure that best prevents organ system injury in my critically ill patient.
00:10:23
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It is governed by the patient's pre-morbid status, the age of the patient, patient's
00:10:30
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pre-existing blood pressure.
00:10:32
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I think that's a very common problem.
00:10:35
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We don't really know what our patient's baseline blood pressures are.
00:10:38
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And that's also governed by what kind of vasopressor support my patient is on.
00:10:45
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So what I have done is that I definitely don't choose 65 for all my patients.
00:10:53
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I still choose 65 for some of them, but I do lean on higher
00:11:01
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It's not uncommon for me to try to create my vasopressor to a map of 80 to 85.
00:11:09
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The topic of today is personalizing vasopressor use.
00:11:13
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And from what I'm hearing, Ashish, 65 might be an okay starting point if you have to use a general number based on what we know so far.
00:11:22
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But really, like many other things I will talk about today, the right number might be a personal number.
00:11:29
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number for each patient and understanding that and trying to understand what are the factors that can impact that number for each individual patient that we're treating are going to be very important at the bedside.
00:11:41
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And even in the clinical trial that you mentioned where they randomized one MAP versus another, they did find out that in those who are chronically hypertensive when we know that, higher MAPs might be associated with less renal failure and other problems.
00:11:55
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So clearly, it sounds like
00:11:57
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The message here is that 65 is the starting point that people have recommended based on the data that we have that it's not all conclusive, but it shouldn't be taken as dogma as this is the one number that fits all.
00:12:13
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And you should always be trying to figure out for that individual patient what else is going on or what is the patient telling you in terms of the best blood pressure for that patient.
00:12:24
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Absolutely.
00:12:24
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It's the era of precision medicine.
00:12:27
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And I think in general, a one size fits all approach is out and we have to practice precision medicine, individualized therapeutic targets for every patient in the ICU.
00:12:41
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You mentioned the impact that blood pressure or trying to avoid organ dysfunction, obviously the ultimate outcome that we measure in many trials
00:12:50
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is mortality and we wanna avoid that as much as possible.
00:12:53
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But in critically ill patients, we also know that avoiding or mitigating organ dysfunction is critical.
00:13:00
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Could you share with us some of the studies that you've done?
00:13:02
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I know that you've looked at general shock critical care populations and also post-op populations, specifically trying to understand a little bit better the impact of different blood pressures or time-weighted averages of a specific map.
00:13:19
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over time in terms of outcomes but also organ dysfunction?
00:13:24
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Sure, yes, gladly.
00:13:26
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So all of this work was published early to mid 2018 and we've been moving on further from that point and we're still looking at some other outcomes.
00:13:39
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But the largest data set was 10,000 patients with all kinds of shock, mostly
00:13:49
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medical septic shock from a large electronic data set in the United States.
00:13:56
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And what we saw in that patient population was, number one, we were able to establish the threshold of 65 and the amount of damage associated with blood pressure when it goes less than that threshold of a MAPO 65.
00:14:15
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So what we saw was that for every one unit of time-weighted average MAP less than 65, there was a 7 to 11 percent increase in acute kidney injury and myocardial injury for patients who would experience that kind of blood pressure drop over time.
00:14:45
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all this basically just reinforced what we knew although we took myocardial injury as an outcome which we defined as a troponin rise with or without symptoms we excluded patients with non-ischemic causes of atroponin increase what we were
00:15:07
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excited with in the same data set was when we did a when we looked at different thresholds of MAP we saw that the earliest increase in the risk of myocardial injury mortality and acute kidney injury is at a MAP of 85 and as the blood pressure dropped from 85 a MAP of 85 down to a MAP of 55
00:15:35
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the risk of myocardial injury, acute kidney injury, and mortality went up in a near stepwise manner.
00:15:46
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So this was interesting.
00:15:47
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We were now saying that a MAP of 85 may be that blood pressure where your patient is first exposed to the risk of organ system failure and mortality.
00:16:00
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In fact, right after this paper was published in intensive care medicine, Pierre Asfar himself wrote an editorial for this paper.
00:16:08
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And that editorial was titled Map of 65, Target of the Past with a big question mark at the end.
00:16:17
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And obviously that excited us because coming from Pierre himself, it meant a lot.
00:16:23
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um you know and but the point he made in that editorial was you know he talked about his own work and his own large randomized trial which is truly the only landmark trial when we look at blood pressure targets and septic shock and then he talked about our work and you know he he made the comment that you know randomized controlled trial data will always be better than large retrospective data sets there is obviously
00:16:50
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hidden confounding in large retrospective data sets.
00:16:55
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He was all praise for us, for our best efforts at trying to make the data set as granular as possible by excluding all kinds of patients and controlling for all kinds of confounders.
00:17:12
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However, he made some very important points.
00:17:14
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He said that this is a message to all of us in critical care medicine to
00:17:20
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rethink blood pressure targets to rethink the next randomized trial of high and low blood pressures, what outcomes you want to study, how we want to study them, how we want to randomize our patients, and also a message to all of us specifically who are interested in large data sets in the ICU that we need more granular data coming from our bedside monitors.
00:17:44
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We simply cannot have blood pressure data that's recorded every once in a half an hour.
00:17:51
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Because when we do large retrospective analyses, the more granular we can have data packed together, the better it is for us to see a clearer signal.
00:18:01
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So he made some great points.
00:18:03
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Anyway, around that time, we also looked at specifically a post-surgical population.
00:18:09
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So a population that really interests a lot of us who practice anesthesia critical care, because a lot of us work in the typical SICU or the surgical ICU,
00:18:20
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where you get sicker patients from the operating room as direct admissions.
00:18:24
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So we looked at about 3,000 patients who were direct admissions from the operating room to the surgical ICU.
00:18:31
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And we almost replicated our findings with the other data set that we had just published.
00:18:40
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We saw that in our patient population and overall population median blood pressure was a map of 87.
00:18:50
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comparing any two patients who who were at a map of less than 87 for about every 10 millimeters drop in in map there was a nearly 30 to 35 percent increased risk of myocardial injury and or mortality and similar outcomes in patients with acute kidney injury and again this
00:19:17
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This obviously was exciting.
00:19:20
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It reinforced two data sets that are speaking exactly the same language.
00:19:25
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However, we also did see that post-operative ICU outcomes depended on intraoperative hypotension.
00:19:33
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So despite our best efforts to control for intraoperative hypotension, post-operative adverse events were dependent on
00:19:44
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hypotension that happened in the operating room made sense because we all know that patients who have prolonged courses in the operating room with long exposures to hypotension, when they end up in the surgical ICU, that hypotension is simply a continuation of the hypotension they're seeing in the operating room.
00:20:03
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But it also made a point to all of us that resuscitation probably starts in the operating room.
00:20:09
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That's where we really need to be strong about defending a blood pressure because the damage starts then and not when your patient ends up in the surgical ICU.
00:20:18
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So this was really the two large pillars of data that we published.
00:20:25
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And then we followed it up with, we've also looked at delirium, for example, in the surgical ICU.
00:20:34
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And we've seen that at a map of about 75 is that that is that threshold point where patients who were below a map of 75 have had about a 30% increased risk of ICU delirium.
00:20:48
Speaker
And then our future work in this area will be looking specifically at blood pressure components.
00:20:56
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So specifically looking at systolic, diastolic, and pulse pressure.
00:21:01
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to see if there is a difference in blood pressure components and their effect on outcomes.
00:21:08
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And someday I also want to look at the effect of cardiac output and things of that nature with more and more continuous cardiac output being used in our ICU population.
Multimodal Vasopressor Approach in ICU Care
00:21:17
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So really lots of large data and data sets and lots of numbers, but I
00:21:25
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That sort of reinforces my belief in the fact that 65 is definitely not that one religiously followed number.
00:21:34
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There is more to it.
00:21:35
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There is a lot of signals out there.
00:21:38
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And we need to do more in this area.
00:21:40
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And we need to treat each patient slightly differently.
00:21:46
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So clearly, it's important for our listeners to understand that there are clear implications for our patients in
00:21:55
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of being hypotensive, of having mean arterial pressures below what's normal in terms not only of increased risk of mortality, but increased risk of myocardial dysfunction or myocardial injury as measured by troponin, acute kidney injury.
00:22:10
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One of the things that I think has been embedded in people's mind is that 65 milligrams of mercury MAP as dogma.
00:22:18
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And I think that
00:22:19
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It's an okay starting point, but there's a lot more to it, like you said, and that probably is one of the first things that we recognize when we're talking about personalizing our approach to hemodynamic support to our individual patient who's at our bedside.
00:22:33
Speaker
One question I wanted to ask you about these studies before we move on to a different area, Ashish, you mentioned that in the post-op patients, intra-op hypotension obviously had a greater impact than hypotension in the ICU and for the
00:22:49
Speaker
and you mentioned the reasons, was there any data or any findings that would suggest in those critically ill patients that are not, or maybe in both groups, is it the degree of hypotension or is it the duration that matters most, or it's the combination of those that ultimately determines the outcomes?
00:23:09
Speaker
Yes, great question.
00:23:10
Speaker
Again, I always say hypotension should never be defined by just a degree without a duration.
00:23:19
Speaker
So it's both the amount and duration of hypotension always.
00:23:22
Speaker
So not only did we see the thresholds that I just talked about, but we also looked at the time dependent effect of hypotension that you just talked about.
00:23:34
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So for example, we saw that for every one hour that was spent at a MAP less than 85, there was a significantly increased risk of organ system failure.
00:23:46
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Similarly, for any duration of time at a MAP less than 75, there was a significant increase in organ system failure.
00:23:55
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So yes, there was a definite duration associated with it.
00:23:59
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Clearly the duration of time was more at higher maps and as you went to relatively lower maps, even a minute of time at a lower map was associated with organ system failure.
00:24:11
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Now again, remember, retrospective data will show you lots of odds ratios and risks
00:24:20
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but you have to keep it in clinical context.
00:24:23
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And clinical context would also mean that, yes, if your patient's bleeding, you need to fix the bleeding quickly.
00:24:29
Speaker
If your patient needs source control, go back to the operating room first.
00:24:34
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If you don't do that, then correcting hypotension in the ICU will probably not make a difference in outcomes.
00:24:40
Speaker
Absolutely.
00:24:42
Speaker
So we talked about defending the map and trying to
00:24:47
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individualize that for what our patient and the particular organs in that patient require.
00:24:52
Speaker
And obviously there's still a lot that we need to learn there, but I think that that's a great starting point.
00:24:57
Speaker
Can we talk a little bit about just in general terms, the approach people have to using vasopressors?
Classes and Roles of Vasopressors
00:25:04
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We obviously have three categories of vasopressors now available, but I think that it's not uncommon for people to keep increasing the dose and keep adding catecholamines to a patient.
00:25:16
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where maybe, I mean, there is a more of a multimodal approach that might make sense in physiology.
00:25:22
Speaker
And obviously, as we gain data in this area, we'll learn a lot more.
00:25:27
Speaker
But I think just from a kind of a teleological standpoint, it just makes sense to understand physiology a little bit better, like we do with other diseases.
00:25:36
Speaker
Can you share with us your thoughts on that, Ashish?
00:25:39
Speaker
Sure.
00:25:40
Speaker
Yeah, again, you know, for years together, you know, the vasopressor toolbox,
00:25:47
Speaker
as a lot of my learned friends call it, only had catecholamines.
00:25:52
Speaker
So all kinds of catecholamines, right from, you know, dopamine, phenylephrine, or norepinephrine, epinephrine.
00:25:59
Speaker
And some people would also include inotropes like dobutamine in that.
00:26:03
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And that's what we played with.
00:26:05
Speaker
We heavily relied on norepinephrine as our single presser.
00:26:09
Speaker
We kept escalating it, you know, till our patients got, you know, black fingertips and so on.
00:26:17
Speaker
But I guess the best way of looking at it is like we do early antibiotics in critical care resuscitation.
00:26:27
Speaker
We should be looking at a early multimodal vasopressor therapy.
00:26:34
Speaker
And the reason for that is that you don't really know.
00:26:37
Speaker
We talked about individualized care for our critical heal patients.
00:26:42
Speaker
So like we don't know what that magic number for blood pressure is, it's hopefully more than 65.
00:26:47
Speaker
Similarly, we don't know whether a patient is a catecholamine responder, a vasopressin responder, or, you know, while we talk about the newer class, the angiotensin and related agents responder.
00:27:03
Speaker
And because we don't know that today, the way we approach it where, you know, we usually put a patient on a catecholamine,
00:27:12
Speaker
wait for a day or two, the amount of catecholamine goes on increasing, 10, 20, 30, 40, 50 mikes or so of norepinephrine.
00:27:24
Speaker
And then we think about, oh, now it's the catecholamine failure.
00:27:28
Speaker
We'll go to add some vasopressin.
00:27:31
Speaker
And then three days later, then we think about XYZ magic drug downstream.
00:27:38
Speaker
That stepwise approach to
00:27:41
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to escalating a pressor, waiting for it to fail, and then getting to the next pressor.
00:27:46
Speaker
While it sounds theoretically appealing, what we don't realize is in the background, there is a progressive multisystem organ failure.
00:27:55
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And with every organ system that fails, we know that ICU mortality goes up several fold.
00:28:00
Speaker
So you're not doing justice to your pressor number two or pressor number three, because by the time you bring around pressor number three, the patient's already, you know, has a lactate of 20.
00:28:11
Speaker
and is severely acidotic and is dying.
00:28:14
Speaker
Then your present number three gets a bad name because you feel, oh, it's not working.
00:28:21
Speaker
So I think our whole approach of managing this needs to be different.
00:28:26
Speaker
I often tell my trainees, if patient comes into the ICU, now is your time to intervene the first six to 12 hours.
00:28:35
Speaker
If you have any bright ideas, if you want to do anything differently,
00:28:39
Speaker
Now is your time, not seven days later.
00:28:43
Speaker
Seven days later is probably time to talk to the family and say, you know, your loved one's not doing well.
00:28:48
Speaker
Let's be realistic.
00:28:50
Speaker
Now is the time to actually do something.
00:28:52
Speaker
And that's where I think our approach has to change.
00:28:55
Speaker
The whole multi-class approach, Sergio, is also, I mean, this is not me saying it.
00:29:00
Speaker
I mean, if you, there is ample literature that talks about, um,
00:29:06
Speaker
high dose vasopressor therapy and poor outcomes.
00:29:10
Speaker
And the one paper I love to cite in my work, and I really swear by that work, is the work of Samuel Brown and colleagues from Intermountain Health.
00:29:22
Speaker
And I believe this paper came out in chest at least six or seven years ago and simply looked at exposure to high dose vasopressors
00:29:33
Speaker
And I believe it was 30 and 90-day mortality in critically ill patients with shock.
00:29:38
Speaker
And what those investigators very nicely showed in a retrospective analysis was that as the norepinephrine equivalence of a high-dose presser goes beyond 0.6 to 0.8 mics per kilo per minute and anything beyond that, then you're looking at upwards of 80% 30 to 90-day mortality.
00:30:03
Speaker
um mortality for these patients so that that really means that once you're on those high dose pressors irrespective of whether you whether your primary problem is fixed or not most of your patients are not going to make it out alive out of the icu and that is that is huge plus there is ample data that talks about uh the the the arrhythmias the atrial arrhythmias the
00:30:30
Speaker
the vascular problems associated with high-dose catecholamines and so on and so forth, does not mean that catecholamines don't have a place.
00:30:39
Speaker
I think they have a very, very important place in management of septic shock.
00:30:45
Speaker
However, monotherapy with catecholamines and delaying initiation of a balanced vasopressor approach
00:30:53
Speaker
is the biggest problem.
00:30:55
Speaker
And that is what has to change if we're really going to look at better outcomes for our patients.
00:31:02
Speaker
So in terms of a balanced approach, just to remind our listeners, what are the other two classes that we have available, Ashish?
00:31:12
Speaker
And how do you think about them in general terms before we go into more specifics on angiotensin II?
00:31:18
Speaker
Sure.
00:31:19
Speaker
So a common...
00:31:22
Speaker
Second friend for us in the ICU has been vasopressin.
00:31:26
Speaker
It's been around for more than a decade or so.
00:31:31
Speaker
And the premise there being that there's a vasopressin deficiency in septic shock.
00:31:36
Speaker
There's been lots of landmark trials comparing vasopressin and norepinephrine and some of the work by Tony Gordon and colleagues from England and more recently, specifically the VANISH trial.
00:31:52
Speaker
I think vasopressin has a very important role.
00:31:55
Speaker
There is definitely a vasopressin deficiency that has been shown in septic shock.
00:32:00
Speaker
I think it's a very good, relatively safe vasopressor.
00:32:08
Speaker
There is definitely data that suggests harm at higher doses, and higher, I say, more than 0.06, 0.08.
00:32:16
Speaker
The threat of mesenteric ischemia comes in.
00:32:18
Speaker
So it's not really a very titratable presser.
00:32:23
Speaker
However, it's great for vasoplegia.
00:32:27
Speaker
It's great for preventing atrial arrhythmias.
00:32:30
Speaker
Patient with atrial fibrillation and septic shock, I'd like to use vasopressin ahead of norepinephrine if I could.
00:32:37
Speaker
So a proven place and works very well with norepinephrine.
00:32:41
Speaker
Once you're getting to that 20 mics per minute of norepinephrine, even about
00:32:46
Speaker
10 to 15 mics of norepinephrine and you see an upward trajectory, vasopressin should be there to allow you to deescalate your catecholamines.
00:32:56
Speaker
And then, you know, celepresin has also been tried.
00:32:59
Speaker
It's a part of that vasopressin family.
00:33:03
Speaker
However, not approved by the US FDA yet, so I'm not going to go into celepresin today.
00:33:08
Speaker
Just stick to vasopressin.
00:33:12
Speaker
Angiotensin II,
00:33:14
Speaker
Again, we can talk a lot about angiotensin II, but specifically angiotensin II then works on the third leg of this three-legged stool of management of blood pressure, where one leg is catecholamines and the adrenal medulla and so on, the sympathetic pathway.
00:33:33
Speaker
The other leg is vasopressin, the V1 and V2 receptors.
00:33:38
Speaker
with the posterior pituitary and vasopressin pathway.
00:33:42
Speaker
And the third leg is the renin-angiotensin-aldosterone axis where the angiotensin II is going to work.
00:33:51
Speaker
And really, that is the role of angiotensin II to provide that balance, to deescalate catecholamines, hopefully deescalate vasopressin as well.
00:34:02
Speaker
And as we'll talk today, it probably has a specific place
00:34:08
Speaker
in certain shock biotypes.
00:34:14
Speaker
One of the things that I enjoy when I'm not doing medicine is fountain pens and old and new fountain pens.
00:34:20
Speaker
And there's a term, Ashish, in the fountain pen collecting world that's NOS, which is new old stock, which is a very unique finding of you find a fountain pen that is brand new, but it's 30, 40 years old and has never been sold.
00:34:36
Speaker
So it's a new old stock.
00:34:38
Speaker
So it seems that in some respect, angiotensin 2 is new old stock.
00:34:42
Speaker
Can you tell us a little bit about angiotensin, how it works, where it comes from, and share with us your experience with Athos 3 as lead author, and that was a study that obviously propelled the FDA approval and the reintroduction of angiotensin 2 in our world.
Development and Impact of Angiotensin II Trial
00:34:57
Speaker
And then we can dive into some of the newer data that's emerging, and like you said, on specific phenotypes of shock that might be of interest for us.
00:35:06
Speaker
sure yes i i love the analogy new old stock by the way it's that's great i love it um so the story of angiotensin 2 actually goes all the way back to the 1950s where a gentleman by the name of irvine page at cleveland clinic was doing a lot of research on angiotensin 2 and at the same time there was investigators in latin america
00:35:33
Speaker
And we're also looking at angiotensin 2.
00:35:35
Speaker
And interestingly, it was not called angiotensin 2 back then.
00:35:38
Speaker
It was called hypertension because it was a hormone that was known to be associated with intractable hypertension.
00:35:48
Speaker
And a lot of work that was being done and is still being done was an attempt to block this hormone.
00:35:54
Speaker
So modern analogy of that is all the ACE inhibitors and ARBs that were developing.
00:35:59
Speaker
But no one was really...
00:36:02
Speaker
thinking of trying to use it in shock then if you look at for example JAMA in the in the early 1960s i believe there was you know a report of 20 patients who received with all kinds of shock who received angiotensin 2 that was bovine angiotensin 2 by the way and and angiotensin 2 rescued them from from shock and hypotension and there were several case reports
00:36:28
Speaker
in the years to follow a case report here, a case report there of where angiotensin II had been used as a rescue and someone was dying with ACE inhibitor poisoning and a rescue and someone had really bad anaphylaxis and so on and so forth.
00:36:44
Speaker
So it was there in the background where people were using sort of off label to sort of rescue them in crisis situations.
00:36:53
Speaker
But,
00:36:54
Speaker
It had not been developed.
00:36:56
Speaker
There was no formal trials.
00:36:58
Speaker
There was no real production of angiotensin, so to speak.
00:37:04
Speaker
And then it was not until the group at George Washington, led by Lakmir Chawla and joined by Larry Bussey,
00:37:17
Speaker
and other colleagues, they got a hold of Angiotensin II and there's a backstory to that as well, which I'll stay away from that backstory or how they got a hold of Angiotensin II.
00:37:30
Speaker
It's a very complicated story that goes all the way to Australia and then comes back to the United States to connect everyone.
00:37:36
Speaker
But anyway,
00:37:38
Speaker
They got the molecule and they did a 20-patient pilot trial on patients with shock in the ICU with high-output shock.
00:37:48
Speaker
And what they saw in that trial was the real ATHOS trial, the angiotensin-doin high-output shock trial.
00:37:57
Speaker
In 20 patients, they saw a significant blood pressure and a catecholamine sparing effect.
00:38:03
Speaker
And the results were pretty dramatic.
00:38:07
Speaker
In fact, if you read more about the trial, there is letters to the editor that have been published around the trial and editorials where there were some patients who just had an absolutely dramatic response to the angiotensin that they were given.
00:38:24
Speaker
And, you know, Dr. Chawla Mink actually thought that those patients were on ACE inhibitors.
00:38:31
Speaker
And as it turns out, those patients probably had really bad ARDS.
00:38:37
Speaker
And angiotensin II is related to ARDS because the angiotensin-converting enzyme is a pulmonary capillary endothelial enzyme.
00:38:51
Speaker
And knowing that ARDS would destroy the ability of the lungs to produce angiotensin-converting enzyme, thus leading to low endogenous angiotensin II, that is sort of the backstory to the physiology there, which
00:39:06
Speaker
sort of in made this group more interested in how and why this was an endogenous substance that was that was really low in a class of patients with septic shock and how synthetic angiotensin 2 could then help them out in a very exquisite manner and that happened they they armed with that pilot data
00:39:30
Speaker
um you know dr chavla and colleagues then uh went to the fda and and and then worked with us in in designing the ethos 3 trial the angiotensin 2 in high output shock 3. and um
00:39:50
Speaker
And really the important part as I talk about this trial is the fact that it was a phase three trial.
00:39:57
Speaker
That's where the three comes from.
00:39:58
Speaker
And that's where people sometimes ask me, oh, there's ATHOS and ATHOS three.
00:40:01
Speaker
There's no ATHOS two.
00:40:02
Speaker
Well, it was a phase three trial.
00:40:05
Speaker
That's where the ATHOS three comes from.
00:40:07
Speaker
It was a pre-FDA trial where the FDA was
00:40:15
Speaker
hand in hand with us in trying to design the trial protocol.
00:40:19
Speaker
So we had something called a special protocol assessment agreement with the US FDA, which really meant that the FDA was in complete agreement with the way the study had been designed.
00:40:32
Speaker
And if the drug did show what we proposed it would show, then the FDA in a special protocol assessment agreement would not go back and question the trial design.
00:40:45
Speaker
And so what the FDA wanted the investigative teams to prove was that number one, the vasopressor did what it's supposed to do, which is increase blood pressure.
00:40:56
Speaker
So our primary outcome was getting to a mean arterial pressure of 75 or 10 more than baseline.
00:41:05
Speaker
And number two, our secondary outcomes were a difference in SOFA scores, Sequential Organ Failure Assessment scores,
00:41:15
Speaker
and achieving a catecholamine sparing effect.
00:41:20
Speaker
And finally, because it was a pre-FTA approval trial, we also looked at a series of adverse events, serious adverse events, and so on and so forth.
00:41:30
Speaker
And really the way the trial was designed was it was a massive undertaking.
00:41:34
Speaker
There was 80 plus sites, three continents, North America, and includes US and Canada.
00:41:43
Speaker
a number of sites in Europe, and then Australia and New Zealand.
00:41:48
Speaker
And over a period of two years, we were able to start and finish the trial and publish the data, which I feel is a testimony to my co-investigators on the trial and all the colleagues and everyone was involved in this because a septic shock or a shock trial like ATHOS-3 is a lot of work.
00:42:10
Speaker
And we randomized about 340-odd patients to receive either placebo or angiotensin II.
00:42:17
Speaker
Our basic randomization criteria were patients who were on more than 0.2 miks per kilo per minute of norepinephrine equivalents.
00:42:27
Speaker
So norepinephrine equivalents here would mean about, say, 10 to 15 miks per minute, micrograms per minute of norepinephrine.
00:42:37
Speaker
with about 0.02 of vasopressin.
00:42:41
Speaker
That would then translate into a norepinephrine equivalence of 0.2 micrograms per kilo per minute.
00:42:49
Speaker
That concept of norepinephrine equivalence was given to standardize all the different vasopressors that a patient could be on with high output shock.
00:42:59
Speaker
The important point I want to make here as I talk about randomization is that all of our patients in ethos-3
00:43:06
Speaker
were volume replete.
00:43:09
Speaker
Trial criteria demanded that all of our patients receive at least 25 cc per kilo of initial resuscitation and that we are able to show that the patient does not have either hemorrhagic or low output shock or cardiogenic shock or is under resuscitated.
00:43:26
Speaker
So we had to show a mixed venous oxygenation of more than 70%, a normal to high CVP and a normal
00:43:36
Speaker
cardiac index at least 2.1.
00:43:39
Speaker
So based on that, we knew that our patients were not volume behind.
00:43:45
Speaker
They did not have cardiogenic shock.
00:43:47
Speaker
They did not have hypovolemic shock at the time of randomization.
00:43:51
Speaker
They were simply hypotensive, a map less than 65 in the presence of significant, that is more than 0.2 mics per kilo per minute of norepinephrine equivalent vasopressors.
00:44:05
Speaker
At that point, patients were randomized to either get angiotensin II or placebo.
00:44:10
Speaker
The trial itself ran to 48 hours and then up to seven days.
00:44:17
Speaker
So for the 48 hours, patients were then divided into time zero to time at hour three and then hour three to hour 48.
00:44:28
Speaker
In the first three hours, background standard of care pressures were kept constant.
00:44:34
Speaker
and the study drug was up titrated from 20 nanograms per kilo per minute all the way to 200 nanograms per kilo per minute to see if a map of 75 could be achieved our three onwards to our 48 the investigators were allowed to titrate background pressers and the study drug this time to achieve maps between 65 and 75
00:45:01
Speaker
And then hour 48, the study drug was titrated off in a protocolized manner.
00:45:07
Speaker
If the patient became really unstable, the investigator had the option of restarting the study drug again, make it run all the way up to one week.
00:45:15
Speaker
Now, when I talk about the trial, I'll tell you the first three hours was the time where we looked at the potency of angiotensin II and did it make it to a map of 75?
00:45:28
Speaker
So did it behave like a potent vasopressor?
00:45:31
Speaker
And then from hour 3 to hour 48, we looked at the overall catecholamine sparing effect of angiotensin II.
00:45:38
Speaker
And obviously, we looked at adverse events all the way through.
00:45:41
Speaker
We looked at mortality data, even though the trial wasn't powered for mortality.
00:45:46
Speaker
So very quickly, if I talk about outcomes, we're all familiar with outcomes.
00:45:51
Speaker
There was, as far as the primary outcome is concerned, angiotensin II achieved a MAPA-75 in a large majority of patients, more than 70% of our patients, in fact.
00:46:03
Speaker
And there was a highly statistically significant outcome, achieved catecholamine sparing, achieved better cardiovascular SOFA scores.
00:46:14
Speaker
Did not show a mortality difference, though the trend line was encouraging.
00:46:18
Speaker
But with a sample size of about 340, we were not powered for mortality.
00:46:24
Speaker
And then, you know, there was overall no difference in adverse events, although there was some data to suggest that there was increased incidence of thrombotic complications in patients who received angiotensin II.
00:46:40
Speaker
Now that's where we stood after we finished the ATHOS-3 trial.
00:46:44
Speaker
And that really very quickly then led the FDA to first allow angiotensin to be used in a compassionate use form.
00:46:56
Speaker
And then I believe in December of 2018,
00:47:00
Speaker
we achieved formal FDA approval for the drug to be used to increase blood pressure in adults with septic or other distributive shock.
00:47:09
Speaker
And then further, the EMA in Europe approved the drug as well in early summer of 2019.
00:47:19
Speaker
So that's sort of the long and short history of angiotensin II.
00:47:24
Speaker
Clearly, there's a lot of
00:47:26
Speaker
side stories and so on and so forth attached to the trial.
00:47:30
Speaker
It was a huge undertaking.
00:47:32
Speaker
And personally speaking, you know, I was very, very, very engaged in this trial.
00:47:37
Speaker
I was, my wife was pregnant with our twins at that time.
00:47:42
Speaker
The trial was happening and my pager was going off all through the night.
00:47:45
Speaker
And it was a battle on a lot of different fronts, but we got to our end point and we were all very happy with the outcome.
00:47:57
Speaker
And just as a trivia, I guess, the first episode of Critical Matters, which is in December of 2018, was with a dear friend of mine, Steve Treziak, who wrote the editorial for the Atheros III trial in the New England Journal of Medicine with Phil Dellinger.
00:48:15
Speaker
And we talked about angiotensin II and just to update on base suppressors.
00:48:20
Speaker
So I think that clearly we're tied, I mean, to angiotensin II.
00:48:24
Speaker
three, I just did two in that respect as well with the podcast.
00:48:29
Speaker
Since AtherS III was published, like you said, it was FDA approved and now approved in Europe and being utilized as a drug for vasopressor support in adult patients with a septic shock and other types of distributive shock.
Renin Levels and Personalized Shock Therapy
00:48:45
Speaker
But there's also been a lot of emerging data, mostly from additional studies that kind of derived from data from
00:48:53
Speaker
from the large clinical trial.
00:48:55
Speaker
And I would like to maybe explore some of those areas, because I think they're of great interest and help define further the potential role of Androtensin II, but also I think that it pushes us in the direction of what we were talking about at the beginning, which is personalizing vasopressor use and trying to identify the right phenotypes, at least, in terms of where we think it might be most useful and have the highest impact.
00:49:20
Speaker
So the first thing I wanted to ask you about is
00:49:24
Speaker
low-dose responders.
00:49:26
Speaker
So one of the phenomenon that I've seen at the bedside, but also I think was described in clinical trials, is those patients that with a very small dose of angiotensin 2 have a remarkable response in their blood pressure.
00:49:39
Speaker
I know that originally, correct me if I'm wrong, the initial dose that was utilized to start the trial was 20 nanograms per kilogram per minute as a drip.
00:49:50
Speaker
The current range that's recommended is anyway from five to 40 nanograms per kilogram per minute.
00:49:55
Speaker
But I do understand that there's some interesting data on these low responders that go beyond just the clinical phenomenon of serving once in a while at the bedside.
00:50:07
Speaker
Yeah, I think, Sergio, you bring up some really, really important points over there.
00:50:14
Speaker
And I have to tell you that even when I was doing the trial,
00:50:20
Speaker
as the one person who enrolled more patients in this trial than anyone else in the world, I saw all kinds of responses.
00:50:29
Speaker
And I have to say, it's a perfectly double-blinded, well-done trial.
00:50:35
Speaker
But I saw some patients who were really sick at the time we enrolled them.
00:50:44
Speaker
A very famous story to that one is I remember calling the
00:50:50
Speaker
the trial headquarters one time saying, hey, this is a really sick patient, I'm enrolling.
00:50:55
Speaker
The family is on the verge of calling it a day.
00:51:00
Speaker
I'm sort of conflicted in my head, but I'm still going ahead and doing this, and I don't know what's going to happen.
00:51:08
Speaker
I'm a little worried, this patient's really sick.
00:51:11
Speaker
And within 24 hours, that patient went from being on like four pressers to nothing,
00:51:19
Speaker
and you know starts making urine and oxygenation improves and almost looks like a different person the family changes their mind doesn't want to talk about end-of-life care anymore and and i i will say that that happened at least in one or two patients and i was intrigued and this is sort of a similar story to what uh you know dr chawla and colleagues had at gw where there's these patients who yes they were
00:51:48
Speaker
this particular patient was not necessarily a low-dose responder, was a responder even though he or she was really, really sick.
00:51:58
Speaker
Now, we're talking about the low-dose responders.
00:52:01
Speaker
So in an a priori fashion, the trial steering committee had decided that if patients respond to less than 5 nanograms per kilo per hour,
00:52:17
Speaker
minute at before 30 minutes of drug initiation.
00:52:24
Speaker
So you initiate the drug.
00:52:25
Speaker
You were supposed to initiate the drug at 20 nanograms per kilo per minute and then up titrate.
00:52:30
Speaker
But there was patients where you started at 20, their blood pressure skyrocketed.
00:52:36
Speaker
You actually had to down titrate all the way to five or less nanograms per kilo per minute at less than 30 minutes.
00:52:45
Speaker
And these patients were just exquisite responders.
00:52:48
Speaker
So we looked at them.
00:52:50
Speaker
We said, okay, let's look at these patients who are super responders.
00:52:56
Speaker
And what we found in these patients who responded at less than five nanograms per kilo per minute was that they had significantly higher MAP or blood pressure versus the other group.
00:53:12
Speaker
The other group would mean the usual,
00:53:15
Speaker
responders.
00:53:17
Speaker
Plus, we saw that day 28 survival was also higher in these patients who were responding at very, very low doses of angiotensin II.
00:53:28
Speaker
We controlled for all kinds of confounders in a multivariate analysis, but still our survival benefit came through.
00:53:38
Speaker
And not only that, these patients had a very favorable safety profile, and these patients did not discontinue
00:53:45
Speaker
treatment at all compared to patients who either did not respond or responded at very high doses where there was high chances of treatment discontinuation before getting to 48 hours.
00:53:56
Speaker
So this was really exciting, Sergio.
00:53:58
Speaker
This was totally in line with what Lakmir Chawla had reported before.
00:54:03
Speaker
It sort of made us feel that there is definitely an inherent physiology that we're hitting and there needs to be more investigation as to why some patients are
00:54:14
Speaker
just behaving this way with angiotensin II.
00:54:18
Speaker
And the goal, obviously, of personalized medicine is identifying which patients will benefit from individual therapies and making sure that we prioritize for those types of therapies for these patients.
00:54:30
Speaker
So I think we're going to start to go down that pathway.
00:54:32
Speaker
But before we get into the RAS physiology and some of, I think, interesting topics, could you comment, Ashish, on just a clinical phenotype of acute kidney injury and its relationship
00:54:44
Speaker
to the effects of angiotensin II and the response to angiotensin II?
00:54:49
Speaker
Sure, sure.
00:54:50
Speaker
So when I talk about the phenotype of acute kidney injury, it also builds into the RAS pathway where we know that renin is closely related to the juxtagromedular apparatus in the kidneys.
00:55:07
Speaker
So when the GJ cells are
00:55:10
Speaker
sense hypotension or afferent arterial dilation and hypotension in the GJ cells or decreased sodium delivery or increased sympathetic tone, then the kidney is stimulated to produce renin.
00:55:29
Speaker
And that renin then takes angiotensinogen, which is produced in the liver, and then converts it to angiotensin-1.
00:55:38
Speaker
angiotensin 1 is then converted to angiotensin 2, the angiotensin-converting enzyme, most of which sits in the pulmonary capillary endothelium.
00:55:47
Speaker
So going back to renal injury, we know that in terms of a phenotype, patients with acute kidney injury are the ones that are most likely to have the highest serum renin levels.
00:56:04
Speaker
And that is, in fact, what we have seen.
00:56:06
Speaker
when we have dissected the ATHOS3 data, the highest serum renin levels were in patients with AKI.
00:56:14
Speaker
Higher serum renin levels were also in patients with ARDS, but definitely in patients with acute kidney injury.
00:56:19
Speaker
So high renin shock associated with acute kidney injury is definitely that phenotype that is a focus of our investigation now.
00:56:33
Speaker
And we have seen it.
00:56:35
Speaker
In fact, we did a post hoc analysis in our ATHOS III population where we looked at patients who had developed acute kidney injury after randomization into the trial.
00:56:51
Speaker
And we looked at outcomes in that population, whether they were exposed to angiotensin II or placebo.
00:56:58
Speaker
And we saw that patients who were exposed to angiotensin II had faster liberation from renal replacement therapy
00:57:04
Speaker
had higher blood pressures, and had a mortality benefit compared to patients who received placebo.
00:57:11
Speaker
So clearly, AKI was a segment of population, and then now we know that high renin shock in the setting of AKI is that segment of population which should probably receive exogenous angiotensin II.
00:57:28
Speaker
And I think that from a value perspective,
00:57:31
Speaker
Clearly, whenever you introduce a new drug that has a price differential with drugs such as catecholamines, there's going to be pushback at the hospital level or at the PNT committee level to use the drug in an appropriate way.
00:57:43
Speaker
But when you look at overall cost of care, if you can avoid or you can shorten the duration of renal replacement therapy, that is definitely something that needs to be a part of that equation and I think can be a way of thinking of adding value to our support of hemodynamic instability
00:58:00
Speaker
with new drugs such as angiotensin II, correct?
00:58:04
Speaker
Yeah, correct, absolutely.
00:58:05
Speaker
I mean, we can talk about this at length, but I'll stay away from long discussion.
00:58:10
Speaker
I will say that this is the cost bias to the way we treat our patients in the ICU.
00:58:17
Speaker
We're very excited with things that, you know, come to the institution at low cost.
00:58:22
Speaker
We experiment with them a lot, but when we come to slightly more expensive interventions,
00:58:28
Speaker
We tend to look at vasopressors as an intervention based on the healthcare dollars that are spent at that minute or within those 24 hours.
00:58:38
Speaker
But what we don't look at is long-term patient outcomes.
00:58:43
Speaker
For example, if you can rescue a patient from going on dialysis and save a day or two of dialysis and get the patient out of the ICU faster, that is way more money saved than a vial of an expensive vasopressor.
00:58:57
Speaker
So the value proposition, we need to look at the big picture rather than narrow our focus and look at, oh, a presser A versus B versus C and just look at the amount of dollars spent then.
00:59:11
Speaker
Absolutely.
00:59:12
Speaker
You mentioned renin, and I think that this is going to be kind of the key in the near future towards a more personalized approach, it seems, to use of a suppressor such as angiotensin II.
00:59:25
Speaker
So let's talk a little bit about renin.
00:59:27
Speaker
And I would like to start maybe with a super basic one-on-one review of the renin-angiotensin-algosterone system kind of pathway and why renin might be of relevance for us just in terms of when it's high in these patients.
00:59:43
Speaker
And then maybe we can start talking about what are some of the findings related to renin and some of the studies that have emerged over the last couple of months.
00:59:51
Speaker
Sure.
00:59:52
Speaker
Yeah.
00:59:52
Speaker
So I, you know,
00:59:55
Speaker
Five minutes ago, I just went over it really quickly, but you know, renin is produced in the kidneys and it's produced in the kidneys in response to hypotension or low sodium delivery.
01:00:05
Speaker
And then, you know, it starts the cascade off where it, angiotensinogen, renin acts on angiotensinogen and renin then go to angiotensin one.
01:00:16
Speaker
And then in the presence of angiotensin converting enzyme, angiotensin one goes to angiotensin two.
01:00:21
Speaker
which then has downstream effects of increased aldosterone release, increased antidiuretic hormone release, which together increase blood volume and then increase retention of sodium at the level of the kidneys.
01:00:36
Speaker
Angiotensin II also then directly increases systemic vascular resistance to increase arterial pressure.
01:00:43
Speaker
So renin is that key regulator in this whole cascade.
01:00:51
Speaker
when we do things to the angiotensin converting enzyme and when i say do things either we make it pharmacologically non-functional by giving a patient years and years of ace inhibitors or dysfunctional because of byproducts of septic shock or dysfunctional because of acute respiratory distress syndrome because angiotensin converting enzyme is produced in the pulmonary capillary endothelium
01:01:18
Speaker
acute respiratory distress syndrome will will destroy the ability of angiotensin converting enzyme production and other interventions as well such as prolonged cardiopulmonary bypass and so on whatever whenever we do something to the angiotensin converting enzyme both renin and angiotensin 1 will increase because of biofeedback in the reverse direction so
01:01:45
Speaker
You know, it's like you put a stop to a downstream process and everything upstream starts building up.
01:01:51
Speaker
Now, there was very interesting work that was published out of a group in Brussels, Belgium, led by Gleason and colleagues.
01:02:04
Speaker
And I had the pleasure of writing an editorial to that work.
01:02:09
Speaker
And I labeled my editorial, Is Renin the New Lactate?
01:02:14
Speaker
And the reason I did that was because Gleason and colleagues, and it included some great investigators on that group, including the great Jean-Louis Vincent, demonstrated in about, you know, it's about 120 samples they took from patients in their ICUs with all kinds of shock.
01:02:35
Speaker
They demonstrated in that single center prospective observational study that their patients, number one,
01:02:43
Speaker
had stable renin levels, largely unaffected by diurnal variation, the use of continuous renal replacement therapy, or other drugs known to influence the RAS axis.
01:02:54
Speaker
That was great.
01:02:56
Speaker
And number two, that renin outperformed lactate as a predictor of mortality in these patients with a heterogeneous etiology of shock.
01:03:08
Speaker
So specifically, the rate of increase of plasma renin over time in non-survivors versus survivors was significantly greater compared with lactate.
01:03:20
Speaker
And that maximum renin appeared to be a much stronger and significant predictor of ICU mortality with a better AUC ROC compared to lactate.
01:03:30
Speaker
And this was great.
01:03:32
Speaker
This made perfect sense with the dysfunctional ACE
01:03:38
Speaker
renin that's built up, and then renin that is a predictor of mortality.
01:03:43
Speaker
The other part of this interesting thing is that if you look at ATHOS-3 data and renin, and we compare lactate, lactate traditionally has been a marker of poor perfusion, inadequate resuscitation, poor perfusion, anaerobic metabolism.
01:04:03
Speaker
Patients in ATHOS-3 were absolutely adequately resuscitated
01:04:07
Speaker
had in fact largely normal lactates as well.
01:04:12
Speaker
Their lactates were not sky high.
01:04:14
Speaker
So in adequately resuscitated patients, Gleason and colleagues also adequately resuscitated patients.
01:04:22
Speaker
So renin is a marker in adequately resuscitated patients of poor outcomes in shock.
01:04:30
Speaker
This also becomes really interesting because a big problem with lactate is that
01:04:35
Speaker
There are a lot of different things that determine high lactate.
01:04:39
Speaker
We all know that all high lactates are not the same.
01:04:43
Speaker
There is a lot of high lactates that mean nothing and are still treated as septic shock and given tons of volume and they should not be given.
01:04:50
Speaker
But anyway, that discussion aside, all of this data was was really, really interesting.
01:04:56
Speaker
So we then went back into the ethos three data and we said, OK, if renin is
01:05:05
Speaker
really that focal point of where this this whole axis pivots then look let's look at renin let's look at angiotensin 1 and angiotensin 2 the downstream products now i also want to tell the listeners at this moment that it's not as simple as renin angiotensinogen angiotensin 1 ace enzyme and angiotensin 2. there's also an alternative pathway
01:05:34
Speaker
which where the ACE2 enzyme acts on angiotensin 1 and converts it into angiotensin 1 to 7 and angiotensin 2 to 9.
01:05:44
Speaker
And these angiotensin byproducts are actually vasodilatory.
01:05:51
Speaker
In fact, more and more literature suggests that it is the harmful effect of these byproducts that causes all the hypotension,
01:05:59
Speaker
in patients who take ACE inhibitors and in patients whose main ACE enzyme is dysfunctional rather than the all of it being the going away of angiotensin 2.
01:06:09
Speaker
So keeping that in mind, the first experiment we did was we looked at angiotensin 1 to angiotensin ratios in our entire ATOS 3 population.
01:06:21
Speaker
We chose a population median of 1.63.
01:06:27
Speaker
normal angiotensin 1, angiotensin 2 ratios are 0.5.
01:06:31
Speaker
So our population in general in ethos 3 had a much higher angiotensin 1 to angiotensin 2 ratio, which meant that most of our patients in shock were high renin, high angiotensin 1, low angiotensin 2 patients.
01:06:47
Speaker
And we saw in this post-talk analysis that patients who had a high angiotensin 1 to angiotensin 2 ratio
01:06:56
Speaker
had a greater incidence of prior exposure to ace inhibitors and greater much higher incidence of catecholamine resistant vasodilatory shock that then needed high dose norepinephrine equivalents and also these patients when they were given synthetic angiotensin 2 had a survival benefit
01:07:24
Speaker
this data was very interesting.
01:07:26
Speaker
And that has really been the trigger point for our recent work where we have now focused on renin as a marker for survival in vasodilatory shock.
01:07:38
Speaker
Before we talk about renin as a marker for survival in vasodilatory shock, could you just clarify for our audience the advantage of renin as a bioessay over measuring the ratio of angiotensin 1 to angiotensin 2?
01:07:55
Speaker
Yeah, so I think the biggest advantage of using renin as a bioassay is the fact that it's a cheap and inexpensive bioassay.
01:08:09
Speaker
It's easily available.
01:08:11
Speaker
And like I just said, there's data now to show that serum renin levels are largely unaltered by a lot of interventions that we do in the intensive care unit.
01:08:21
Speaker
And really,
01:08:23
Speaker
rather than doing a complex angiotensin 1-angiotensin 2 ratio, which will then be dependent on other factors as well, a singular value from the serum renin level that could be titrated over time, same way as we do with lactate, would be way, way, way easier.
01:08:43
Speaker
So, Ashish, can you share with us, you mentioned this recent study, which is, I presume, the Blue Journal study that was published ahead of print in
01:08:52
Speaker
recently, can you share with us kind of the nuts and bolts and the findings of that paper, the renin and survival and basal terratory shock?
01:09:02
Speaker
Sure, definitely.
01:09:03
Speaker
So, you know, like I just said, we had a lot of data to support the hypothesis that renin is a key marker of survival.
01:09:14
Speaker
So what we basically did was we looked at serum samples from patients who were enrolled in the ATHOS-3 trial.
01:09:20
Speaker
We looked at renin, angiotensin I, and angiotensin II prior to the start of the giving of angiotensin II or placebo, and then at after three hours of the giving of angiotensin II or placebo.
01:09:38
Speaker
And there was some key results.
01:09:40
Speaker
The first thing was that our baseline serum renin concentration in about 80% of our patients was
01:09:51
Speaker
nearly three times that of the normal range.
01:09:55
Speaker
The normal range for serum renin is anywhere from two to 60 picograms per cc.
01:10:02
Speaker
Our median renin concentration was nearly 170 picograms per cc.
01:10:09
Speaker
And some of our renins were as high as 6,000.
01:10:13
Speaker
Most of our renins were in the 300s.
01:10:15
Speaker
And like I said, highest in AKI and ARDS subgroups.
01:10:20
Speaker
And then we also saw that these renin levels correlated positively with angiotensin 1 to angiotensin 2 ratios, meaning thereby that if you had high renin, then you had a high angiotensin 1 to angiotensin 2 ratio.
01:10:37
Speaker
At three hours after the initiation of angiotensin 2 therapy, there was a more than 50% reduction, a huge reduction in renin levels
01:10:48
Speaker
compared with patients who received placebo, where the reduction was about 15%.
01:10:52
Speaker
Furthermore, in patients with renin concentrations that were above that population median that I just said was 170 picograms per cc.
01:11:08
Speaker
So if we looked at patients who achieved more than that 170,
01:11:13
Speaker
and then got exogenous angiotensin 2, there was a significant reduction of 28-day mortality, a difference of about 20%.
01:11:23
Speaker
So about 50% of patients in that subgroup died versus 70% of patients treated with placebo.
01:11:32
Speaker
And this outcome was statistically very significant.
01:11:37
Speaker
And there was several multivariate analyses controlling for other
01:11:41
Speaker
covariates and confounders and the outcome steward the test of those analyses so all sort of then fits into that puzzle of the renin angiotensin aldosterone axis and why high serum renin is a marker for poor outcomes and shock and here we have a biomarker that we can specifically target angiotensin 2 therapy too in fact
01:12:10
Speaker
I say this and I practice this, I do get serum renin levels checked in a whole slew of patients with shock in my daily practice now to see how my patients are behaving and whether or not they need angiotensin II.
01:12:24
Speaker
And also, I think it's a great way to narrow also and identify those patients who have the highest likelihood of first responding with a, I would imagine that high renin levels, not only when we use angiotensin II, are associated with better outcomes, like you mentioned, and that
01:12:40
Speaker
post-hoc analysis, but also probably the response in the blood pressure is much more dramatic because the brain would serve as the identifier that that pathway that we're trying to correct is actually altered in these patients.
01:12:53
Speaker
Oh, absolutely.
01:12:54
Speaker
I mean, we have a pathway, and with the work that we just published in the Blue Journal, I think we are happy that we have a
01:13:06
Speaker
mechanistic pathway to know how angiotensin 2 is giving our patients a benefit.
01:13:12
Speaker
Quite often we use vasopressors in a sort of, you know, throw the kitchen sink at the patient, don't know what will act.
01:13:21
Speaker
But here we have a mechanistic pathway where we can actually use a presser for a reason and then also gauge its response.
01:13:33
Speaker
Now I will say that this is post hoc
01:13:36
Speaker
retrospective data, and it will need prospective validation.
Advocating Personalized Vasopressor Strategies
01:13:42
Speaker
And really, I would love to be a part of that randomized trial where we do prospective validation of this.
01:13:49
Speaker
But while we await prospective validation, I think it is not wrong to check serum remnants on your patients and see if there is indeed a pattern that is identifiable.
01:14:02
Speaker
So I think that
01:14:04
Speaker
From what I'm hearing, Ashish, a couple of things, I mean, come to mind as we try to close this together and try to give some advice for the clinicians at the bedside.
01:14:13
Speaker
Number one is that where personalization of vasopressor support starts by understanding that each patient might have a different perfusion to MAP curve for each, for their organs, and really identifying the right MAP for those patients might take more than just starting with one number that fits all, which is 65.
01:14:34
Speaker
I think that very important also what you mentioned with the idea that there are three different pathways that can cause or perpetuate or exacerbate hypotension and vasodiretory shock and using approaches that are multimodal makes sense from a physiological perspective.
01:14:54
Speaker
The thing that I think that we talked a lot about was the role of adjutantin-2 as part of that trifecta
01:15:00
Speaker
of catecholamines, vasopressin, and now adding angiotensin II.
01:15:05
Speaker
And the real question is, as this is a new drug, is when do you add that?
01:15:10
Speaker
And it seems that earlier is better than later in general terms, in terms of improving outcomes.
01:15:16
Speaker
But it also seems that there might be phenotypes and biotypes, let's call them, that might be of great interest for us with angiotensin II.
01:15:24
Speaker
And specifically what you mentioned was acute kidney injury as a marker probably
01:15:30
Speaker
of patients who and whom you might want to use angiotensin II earlier than later as an adjunct to your face therapy support.
01:15:39
Speaker
And also what you're mentioning now with the renin data as a marker of increased and worse outcomes, but also as a marker of who might respond to angiotensin II and even maybe have a survival benefit.
01:15:53
Speaker
Could you just, for septic shock first, kind of summarize how you would apply this at the bedside?
01:16:01
Speaker
I think, Sergio, you summarized this really well.
01:16:07
Speaker
I think the main thing to understand in septic shock is that there is no going away from things like norepinephrine.
01:16:15
Speaker
Every patient with septic shock should not get angiotensin II.
01:16:20
Speaker
However, I will say that we need a culture change where we need to look at every patient slightly differently.
01:16:28
Speaker
No two patients with septic shock are the same.
01:16:31
Speaker
So I'm hoping for a day where a patient will roll into the ICU and you will check markers like serum berenin.
01:16:39
Speaker
You will check markers like maybe an angiotensin 1, angiotensin 2 ratio, a lactate, you know, maybe a marker for vasopressin responsiveness, and then choose a presser accordingly.
01:16:50
Speaker
Now, run-of-the-mill septic shock, say, you know, UTI, under-resuscitated, norepinephrine is definitely the first-line agent for patients.
01:17:00
Speaker
for a variety of good reasons.
01:17:03
Speaker
But think about adding your second vasopressor sooner rather than later.
01:17:10
Speaker
Do not wait for 24 hours later when your patient is on 20 micrograms of norepinephrine per minute and has been on it for two days.
01:17:19
Speaker
That is a sign of failure.
01:17:21
Speaker
You should not have to wait till failure because then you're just using a drug when there's no receptors for the drug to act on.
01:17:28
Speaker
So
01:17:29
Speaker
early multimodal vasopressor therapy early checking of markers and then if you identify high renin in a patient with septic shock who has acute kidney injury or who has ards knowing this data it is it would it would be common sense to start angiotensin too early definitely in conjunction with norepinephrine but but yes started early don't wait till the patient is
01:17:56
Speaker
into advanced ARDS and on a peep of 20 and dying because of respiratory failure.
01:18:01
Speaker
Start it early.
01:18:03
Speaker
That is the biggest message I want to give my audience today.
01:18:09
Speaker
And similarly, I want to extend this to beyond just septic shock.
01:18:13
Speaker
I talked briefly about the general concept of dysfunctional ACE.
01:18:17
Speaker
We do know that patients who are on prolonged cardiopulmonary bypass, and in fact, not just prolonged cardiopulmonary bypass, patients who are on extracorporeal circuits to support oxygenation, their blood is not traversing the pulmonary capillaries as in a normal patient.
01:18:35
Speaker
They have dysfunctional ACE activity.
01:18:38
Speaker
Even though I don't have the data today to show you angiotensin I and angiotensin II levels in patients on prolonged cardiopulmonary bypass, I will say
01:18:47
Speaker
that these are the patients where it makes a lot of theoretical sense because they are on a lot of ACE inhibition coming into cardiac surgery.
01:18:56
Speaker
Then they get six hours of a bypass run.
01:18:59
Speaker
Then they come out vasoplegic.
01:19:01
Speaker
Then they're put on tons of what we call voodoo medicines, as some of my friends say, vitamin so-and-so, vitamin so-and-so, methylene blue, and this and that.
01:19:13
Speaker
Nothing works.
01:19:15
Speaker
that's not supported by data and patient stays in the ICU three days longer, those patients need to be on angiotensin II early because there is a physiological rationale to give them angiotensin II.
01:19:29
Speaker
And I personally practice that in my cardiac surgical ICU.
01:19:34
Speaker
And I have so far in results that are being published as we speak, I've shown good results in
01:19:42
Speaker
not just patients with coronary artery bypass grafts, but also patients who have received heart transplants and patients who have had renal failure because of other reasons and then received heart transplants.
01:19:54
Speaker
Excellent.
01:19:55
Speaker
And I was going to ask you about cardiac surgery, but I think that that covers everything very well.
01:19:58
Speaker
And we definitely will be looking forward to more of the data being published and more studies to come down the line.
01:20:06
Speaker
I think it's always exciting where physiology matches what we see at the bedside.
01:20:11
Speaker
And like you said, the pieces of the puzzle fall in the right place and it all makes sense.
01:20:15
Speaker
So that's all very, very exciting, I think, for intensivists in general.
01:20:20
Speaker
Ashish, this has been a wonderful conversation about vasopressors, about personalizing vasopressor support, about angiotensin II physiology.
01:20:29
Speaker
And I think that we could probably keep on going.
01:20:33
Speaker
But I want to be respectful of your time and want to kind of
01:20:38
Speaker
close the conversation here.
01:20:40
Speaker
One of the things that we usually do on the podcast is close with some questions that are unrelated to the topic.
01:20:46
Speaker
So if that's okay, if you're game for that, I would like to go in that direction.
01:20:50
Speaker
Oh, sure.
01:20:51
Speaker
Fire away.
01:20:53
Speaker
So the first question relates to books or people who have influenced you the most and how so?
01:21:00
Speaker
Well, I will take people because that's easier when you suddenly put that question in front of me.
01:21:07
Speaker
um so with people i will say my parents my dad is a vascular surgeon who trained in the united states in the late 60s and then went back to india and and truly set up vascular surgery in india and sort of known as the father of vascular surgery in india and i grew up with a discussion of aortic aneurysms around the dining table and he's uh he's my inspiration the person i've always looked up to uh always um looking at him i
01:21:37
Speaker
And he still tells me that even though he's 81 years of age, that there is no end to the amount of hard work you can put into something.
01:21:46
Speaker
And every time I come back from a rough ICU shift and I put on FaceTime and I call him in India, he'll be like, you know, just stop, stop the drama and get back to work.
01:21:57
Speaker
So he always pushes me to work harder.
01:22:01
Speaker
And I'm so grateful for him inspiring me.
01:22:05
Speaker
My mom who kept the family together while my dad was lost in his blood vessels and show in the operating room.
01:22:15
Speaker
Without her, you know, these kids wouldn't have been where they are today.
01:22:20
Speaker
So my big salutations to them and my teachers in anesthesiology and critical care.
01:22:27
Speaker
So I trained initially in anesthesia and critical care in India.
01:22:31
Speaker
And then I came back to the U.S. and I trained again.
01:22:33
Speaker
And both of
01:22:34
Speaker
places some of my teachers were my absolute inspirations to do critical care critical care is never an easy option after doing anesthesia there's a lot of very nicer lifestyle fellowships after anesthesia i chose to do critical care because my mentors both in india and the us were some of the best of the best in critical care anesthesia and and clearly i wouldn't have been anywhere close to where i am today had they not and even today continue to hold my hand
01:23:04
Speaker
and show me how to do things the right way in both academics and life.
01:23:13
Speaker
And definitely, I think always, I mean, recognizing our parents and our mentors is very important.
Personal Reflections and Life Philosophy
01:23:20
Speaker
But also, I think that it really ultimately boils down to when you become a parent or you become a mentor and realizing how hard it is
01:23:28
Speaker
and how amazing the job the people who came before you did in that respect.
01:23:33
Speaker
So I think it's definitely something that is worth, I mean, remembering.
01:23:38
Speaker
The second question, Ashish, relates to what do you believe to be true in medicine or in life that most people don't believe or at least don't act like they believe it?
01:23:50
Speaker
Wow, this is a slightly difficult one, but I will say that most people take
01:23:56
Speaker
life and medicine for granted and they believe that they can in the icu for example predict patient trajectories you know predict when an end-of-life discussion should happen and similarly people can predict human behavior in real life but i feel that the real truth in both medicine and life is a lack of predictability we sometimes have plans for our life for the next two years five years ten years life is
01:24:25
Speaker
supremely unpredictable, life changes, people you know change, colleagues and friends, they behave differently to you, respond to you in different fashions.
01:24:35
Speaker
And similarly, patients are unpredictable in the ICU.
01:24:39
Speaker
Things can change any time.
01:24:42
Speaker
So the message there being that believe that life and medicine are both unpredictable, but stay focused, keep doing what you know how to do the best.
01:24:54
Speaker
Keep focusing on your positive points and keep doing your best every single day in life.
01:25:00
Speaker
Life will find a way.
01:25:02
Speaker
Well said.
01:25:03
Speaker
The final question is, what would you want every intensivist to know?
01:25:06
Speaker
Could be a quote or a fact.
01:25:10
Speaker
Yeah, so my very favorite quote of all times.
01:25:13
Speaker
is a from a guy that I look up to a lot in terms of facing hardship and still being brilliant and getting to what he did in life is Stephen Hawking, the famous physicist with amyotrophic lateral sclerosis who recently passed away.
01:25:33
Speaker
And there's I am quoting him and I will say that
01:25:39
Speaker
Remember to look up at the stars and not down at your feet Try to make sense of what you see and wonder about what makes the universe exist Be curious and however difficult life may seem there is always something you can do and succeed at it It matters that you don't just give up and that Sergio I feel is a quote that I repeat to myself after a long day in the ICU and
01:26:10
Speaker
after I've worked one week on a paper or after a peer reviewer has sent me a nasty peer review where I'm like, how am I going to get through this?
01:26:19
Speaker
And through several other situations in life.
01:26:21
Speaker
And that's why it really inspires me.
01:26:23
Speaker
And it's a brilliant quote, obviously from a brilliant man.
01:26:26
Speaker
And thanks for sharing.
01:26:27
Speaker
It was beautiful.
01:26:27
Speaker
And I think that that's a perfect place to stop.
01:26:31
Speaker
Ashish, thank you so much for sharing your expertise and your time with us.
01:26:35
Speaker
And I look forward to having you back on the podcast soon.
01:26:38
Speaker
Absolutely, Sergio.
01:26:39
Speaker
It was my pleasure.
01:26:40
Speaker
Thanks a lot.
01:26:43
Speaker
Thank you for listening to Critical Matters, a Sound Critical Care podcast.
01:26:47
Speaker
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01:26:53
Speaker
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01:26:58
Speaker
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