Transcript
Speaker: Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now your host, Dr. Sergio Zanotti.
Speaker: Septic shock causes a wide range of pathophysiological changes in critically ill patients.
Speaker: Hemodynamic resuscitation is a key component of therapy for patients with septic shock.
Speaker: Research in septic shock has focused on identifying the best resuscitation strategy to improve patient outcomes.
Speaker: In today's episode of the podcast, we will discuss the assessment of peripheral perfusion as a tool to guide treatment in septic shock.
Speaker: Specifically, we will discuss capillary refilled time.
Speaker: Our guest is Dr. Eduardo Catan, a critical care and anesthesia physician.
Speaker: Dr. Catan is an assistant professor at the Pontificia Catholic University of Chile, where he also serves as adult critical care program director and director of research and academics in the Department of Critical Care Medicine.
Speaker: A prolific investigator, he focuses his research on septic shock in medical education.
Speaker: Dr. Rattan is a co-principal investigator of the recently published Andromeda Shock 2 clinical trial.
Speaker: Eduardo, welcome to Critical Matters.
Speaker: Thank you, Sergio.
Speaker: It's such an honor to be here.
Speaker: And I'm eager to spend this time talking about research, life, and our study.
Speaker: Awesome, man.
Speaker: Really a privilege to have you on.
Speaker: And I would like to start with the first question is, why do you think intensivists should care about this topic?
Speaker: So I think that, like...
Speaker: behind when we're facing a patient with septic shock or shock, what we're trying to do is, let's say, try to manipulate macromodynamics to finally improve tissue perfusion.
Speaker: The issue is, the main issue is that assessing tissue perfusion is an imperfect, let's say,
Speaker: area, we do not have, let's say, beyond research practice where we can see the microcirculation with these handheld microscopes, we have surrogates to assess tissue perfusion or the adequacy of tissue perfusion, which can be a two-edged sword because it can tell us when not only to keep doing resuscitation, giving fluids, vasopressor, rhinocopes, and on the other hand, when to stop and avoid the atrogenic harm.
Speaker: One of the windows that Professor Max Harry Weil already 30 years ago had shown or exposed was to assess the skin as one of the territories that could tell us about the adequacy of tissue perfusion of other organs that are quite more important as the liver, the intestines, etc.
Speaker: So it's one of our key windows in which we can assess the perfusion and the adequacy of flow with other organs.
Speaker: And as we talk about flow, especially in septic shock, which is obviously the focus of the Andromeda shock trial, could you give us an overview of the basics of pathophysiology in terms of shunting and why assessing the peripheral tissue might be of value?
Speaker: Of course.
Speaker: So even though we usually learn, let's say, in medical school that septic shock is a, let's say, high-cardic output vasoplegic shock, there is more beyond that, and there are a few researchers in the last few years that show quite heterogenic patterns on the macromodynamic side.
Speaker: Let's say there are patients that go with, let's say, persistent hypovolemia, other that have left or right ventricular dysfunction, and other, like,
Speaker: the usual clinical hyperkinetic septic shock.
Speaker: However, these macro-hemodynamic patterns is not the only thing that's, let's say,
Speaker: determining an inability to deliver oxygen to the tissues.
Speaker: There's also microcirculatory derangements, and there's heterogeneity of flow, microtrombosis of the microcirculation, there's a component of venous congestion in some cases.
Speaker: So there's two pathophysiological processes that are intertwined, are coexisting in this, let's say, in this difficult phases of septic shock, in which we do not have only to resuscitate the macro, but
Speaker: consider its coupling and the hemodynamic coherence with the micro-stimulation.
Speaker: In terms of assessing the peripheral perfusion, I had many years ago been part of some studies that were looking at sublingual capillary microflow.
Speaker: That didn't really translate useful tools at the bedside, but I understand that a lot of your research has been focused on trying to find tools that actually bedside clinicians can utilize.
Speaker: What are some of the tools that are available for evaluation of peripheral perfusion today?
Speaker: So the skin is one of the largest organs, let's say, and there are many tools that can help us assess the peripheral perfusion.
Speaker: Some are technological, for example, you can use temperature gradients from the periphery to the central temperature with skin thermistors, like the peripheral perfusion index that's derived from the platysmography.
Speaker: It's also another tool that's been consistently used in critical care and anesthesia.
Speaker: There are some other techniques such as the laser Doppler, which measures the skin blood flow with a small non-invasive sensor that you can place it anywhere in the skin.
Speaker: and there are non-technological, let's say, clearly clinical methods like the mottling score which uses this semi-quantitative ordinal scale to address the extension of the mottling from the kneecaps to the groin or capillary ratio time that
Speaker: when it's done, let's say, in a standardized or semi-standardized way, can help us not only identify a problem, but also to quantify it as well with degrees of severity.
Speaker: We'll dive into more details with the capillary refill time, Eduardo, in a second.
Speaker: But in terms of the modeling score and some of the other devices that you have mentioned, my understanding is that mostly the literature suggests that they are very good prognostic factors.
Speaker: Is that correct?
Speaker: Yes.
Speaker: Yes, yes, I think especially for the modeling score, there's a big bunch of evidence and even meta-analysis led by Professor Hafidah Tufela in Paris, where the modeling score, let's say, the persistence of an abnormal modeling score during early resuscitation has been consistently associated with worse outcomes.
Speaker: It has a prognostic value, especially 14 or 28-day mortality.
Speaker: So when you see an abnormal Motley score, it's a linear relationship with mortality.
Speaker: Before we move on to capital refilled time, could you just give our audience a brief description of what the Motley score is?
Speaker: Of course, of course, of course.
Speaker: So the mottling score, let's say, you can, it's a visual scale in which goes from one to five, and it covers the extent of, let's say, this mottled skin on the kneecap.
Speaker: So one is just a small area over the kneecap.
Speaker: Number two goes the full area of the kneecap.
Speaker: Score number three goes halfway through the femur, let's say.
Speaker: Number four almost reaches the inguinal ligament.
Speaker: And over the inguinal ligament goes the most severe one.
Speaker: That's number five.
Speaker: So it's a visual scale that you can apply at the bedside at no cost.
Speaker: And you can...
Speaker: try to quantify the extent and the severity of the motul skin of the patient.
Speaker: Perfect.
Speaker: And I believe it's a good reminder to our critical care colleagues that there is value in the physical exam.
Speaker: There is value in looking at our patients.
Speaker: And the modeling score is a perfect example of how you can try to be more objective with what you're observing.
Speaker: And studies have shown that it can tell you a little bit more about the direction your patient is headed.
Speaker: So something for people to maybe read a little bit about it.
Speaker: They're not using it at this time.
Speaker: Let's talk about... Yeah, there's no cost, only just lifting the sheets to see the kneecaps from the patient.
Speaker: So that's the only investment.
Speaker: It's a two-second test that can give you a lot of valuable information.
Speaker: Absolutely.
Speaker: Let's talk about capital refill time, which is obviously an important focus of the Andromeda shock industry.
Speaker: number one and number two clinical trials that we'll discuss in a second.
Speaker: But could you tell us a little bit about capillary refill time?
Speaker: And let's start with the proper technique to measure CRT.
Speaker: Perfect.
Speaker: So capillary refill time is a test that you can do at the bedside.
Speaker: How we standardized it in the Andromeda studies was to use a glass or plastic probe that generates a compression on the ventral side of the index finger.
Speaker: just to avoid the side, the hand that has an arc line, just to avoid, let's say, arterial flow disruptions due to the arterial line.
Speaker: But we compress for 10 seconds until the finger is blanched, and then it comes with a chronometer, the time it takes to visually recolorate to the color level that was beforehand.
Speaker: So this is the technique that we standardize for the Andromeda-Sherst 2.
Speaker: Other researchers have used other techniques.
Speaker: For example, Matias Jaquet-Lagres used a syringe to compress.
Speaker: So he standardized, let's say, the pressure with the syringe into the sternum.
Speaker: And there are others that have used more or less time.
Speaker: But the idea is to...
Speaker: whenever you're using it to try to do it objectively in the amount of pressure we use just the amount of pressure necessary to blanch the skin and to take the time with a chronometer and counting let's say mississippi's that could be for a way to do it what is considered a normal refill time in adults we we we have considered it as a
Speaker: Below three seconds.
Speaker: That's what we consider three or less seconds as a normal CRT.
Speaker: Over three seconds, we consider it abnormal and it prompts us or trigger us to do a clinical intervention.
Speaker: Okay, perfect.
Speaker: And in terms of interpreting the capillary refill time, Eduardo, it's basically a dichotomy, right?
Speaker: Abnormal or normal.
Speaker: It doesn't matter if it's, once it's above three seconds, it's abnormal.
Speaker: And if it's below three seconds, it's normal.
Speaker: Is that correct?
Speaker: In the studies, we did it like that.
Speaker: However, you know that a patient with 9 seconds is probably way sicker than a patient with 3.5.
Speaker: Also, the time can also give you information on the kinetics.
Speaker: Let's say a patient had 9 seconds, you give him 500 mL of fluid, and then it's 4.
Speaker: We're moving in the right direction.
Speaker: So I think the value itself is also...
Speaker: relevant because it gives you a sense of trajectory.
Speaker: Yet for the study, we used this dichotomy to, let's say, patient was okay or not to continue or not pushing registration.
Speaker: Okay, perfect.
Speaker: And is there any caveats for skin color or other patient characteristics that a clinician should be aware of?
Speaker: Yeah, there are some patients that you have some issues measuring.
Speaker: For example, I don't know, Raynaud disease or severe vasculopathy.
Speaker: There's also another very interesting group that I think there's lack of research gone.
Speaker: That's cirrhotic patients because you know cirrhotic patients live in this vasodilated state.
Speaker: So we're running actually an observational study to try to find the best cutoff or if CRT or skin flow can actually measure or measure
Speaker: assessivity in this subset of patients.
Speaker: So I think there are other, let's say, limitations to its use.
Speaker: The skin color, it's kind of difficult sometimes in patients with darker skin.
Speaker: Other researchers have used other sites to measure, even there's some research in the tip of the nose or the ear lobel, but it's still in validation phase.
Speaker: In terms of the pathophysiological determinants of CRT, could you give us an overview of how sympathetic tone, endothelial and coagulation dysregulation, we talked about the microcirculation abnormalities and also at a microhemodynamic level.
Speaker: What are we seeing?
Speaker: What are we trying to interpret?
Speaker: Yeah, this is a great question.
Speaker: I love it because it's been one of our research areas the last five to ten years because CRT,
Speaker: Let's say we all know that the skin is, let's say there's a huge sympathetic tone innervation and in a stress or a fight or flight mode, the sympathetic tone will be activated and the flow of the skin will be diverted to, let's say, more noble organs.
Speaker: And from 300, 400 mL per minute, that's the part of the cardiac output that goes to the skin, it will be almost all diverted.
Speaker: into the other organs.
Speaker: And we did a lot of studies with the laser Doppler device to assess the relationship between CRT and skin blood flow.
Speaker: We did one here in Santiago and one in Paris, and we found a tight relationship with skin blood flow and capillary refill time.
Speaker: The capillary refill time moved in an almost asymptotic way when, sorry, skin blood flow moved almost asymptotically when CRT increased.
Speaker: Yet, other of our collaborations with Professor Gustavo Spina in Cali, he has also assessed...
Speaker: let's say, the components of a cup refill time in a way that they're not only vascular flow, but also adrenergic stress or microvascular reactivity.
Speaker: Because when we compress and decompress the finger, we're also looking at, let's say, it's like a small vascular occlusion test, like the ones we did with this ischemia reperfusion with
Speaker: these studies for the NEERS device.
Speaker: So there must be also a component of, let's say, capacity of the microcirculation to adapt.
Speaker: And we might be testing it, especially when we do a 10-second compression.
Speaker: So this is like uncharted territory still for some of the research, but it's also really interesting to understand all the determinants of this territory, not only the macro circulatory determinant, but also the micro circulatory determinant.
Speaker: There is one study led by Professor Swan in China that assessed like almost 300 patients, and there was a nice correlation between sublingual microcirculatory etiogenity and flow measured by the mean flow index and an abnormal capillary refill plan.
Speaker: Yet it was not perfect.
Speaker: So probably there are two territories that are converging in some part, but not perfect.
Speaker: completely.
Speaker: Probably there's different vascular, probably the tongue is more central flow rather than the peripheral in the skin, etc.
Speaker: Also, there's another study that showed that the capillary refill time also correlates tightly.
Speaker: It was done by Andreas Grunauer in Austria with visceral organ flow.
Speaker: They measured the
Speaker: hepatic, splenic, and intestinal renal arteries flow, and these are patients with abnormal capillary refill time had ultrasonographic patterns of more resistance.
Speaker: So, how I interpret this corpus of evidence is probably that refill time is a window that's more accessible, cheaper, to other territories, and it's probably moving in the same directions, as you mentioned.
Speaker: Da Vinci said that simplicity is the ultimate sophistication.
Speaker: So instead of using all these fancy devices, maybe all we should use is the tip of a fingertip, right?
Speaker: Yeah, that's the attractiveness.
Speaker: I think that's one of the great added values.
Speaker: That's just costless and you don't have to do this.
Speaker: cumbersome techniques to assess an organ proficient.
Speaker: Excellent.
Speaker: Let's dive into the evidence behind the application of CRT at the bedside.
Speaker: And obviously there's a body of literature that has looked at CRT.
Speaker: You measured Professor Max Weil, who I mean was pioneered I think in the 70s looking at toe temperature and other parameters in the skin for sure.
Speaker: But in terms of specifically what I wanted to focus on was on Andromeda Shock and Andromeda Shock 2 recently published in JAMA.
Speaker: So maybe we can start with Andromeda Shock and you could give us a little bit, an overview of the study, the hypothesis and what you found and what it means.
Speaker: Perfect.
Speaker: So I'll start with, let's say, something that's similar to the Motley core.
Speaker: There's a meta-analysis by Matthieu Jaquette-Lagrèce that shows that an abnormal cap ratio time is associated with worse outcomes.
Speaker: So it's also a prognostic...
Speaker: the value technique with a NUTs ratio of 4 or 5, but when the technique is done properly, it increases over 10.
Speaker: So we have a very nice clinical tool that can help us identify patients at risk of death.
Speaker: But also, one of the beauties of capillary refill time is that it has a fast kinetic response,
Speaker: in which patients that are adequately resuscitated or with macromodynamic interventions, patients respond in less than 15 or 20 minutes by improving cap refill time.
Speaker: There's a study by Lisa Raya that showed that after a fluid bolus, the patients that responded responded in 15 minutes.
Speaker: They measured every two minutes and they noticed that CRT was super fast compared to other, let's say, perfusion parameters.
Speaker: And we had a paper in 2014
Speaker: that we tracked 100 survivors of septic shock, and every four hours we did lactate, microcirculation, sublingual microcirculation, cap refill time, and other derived, let's say, perfusion variables.
Speaker: And we saw that patients that survived normalized cap refill time at two hours, 70% of them, while 50% of them had an abnormal lactate,
Speaker: let's say, after 24 hours.
Speaker: So lactate presented like a B-facic kinetic, and it had a rapid normalization, but then it was slower to normalize.
Speaker: And that was the basis for the Andromeda shock one.
Speaker: They basically compared a resuscitation strategy following cap refill time,
Speaker: versus a recitation strategy following lactate decrease or normalization.
Speaker: And this study was done in five countries in Latin America.
Speaker: It involved 424 patients and it was published in JAMA in 2019.
Speaker: And both recitation strategies were the same.
Speaker: Let's say fluid responsiveness tested first, if the patient was not a fluid responder or had a or
Speaker: or became non-fluoresponder but still had an abnormal value of the perfusion target, came a MAP challenge and then a 9-0 probe challenge.
Speaker: So it was the same strategy but with a different target.
Speaker: And the study showed that patients that were randomized to cap refill time had a
Speaker: It had an 8% absolute decrease in mortality, that even though it had a p-value of 0.06, a Bayesian reanalysis after published by Fernando Sampieri showed that it had a very, let's say, high chance of being positive for clinical practice.
Speaker: But also, patients received less fluid and had less organ dysfunction.
Speaker: So this study came to challenge, let's say, the standard of care that was pursuing lactate normalization or decrease by using bed-safe techniques such as capillary refill time.
Speaker: That was the Andromeda-SHOQ1 trial, and it made a lot of, let's say, positive noise in the sense that capillary refill time that was, let's say, sometimes looked...
Speaker: over the shoulder because it's a technique that's at the bedside.
Speaker: It appeared in the guidelines.
Speaker: The 2021 Surviving Sepsis Campaign brought it up and it boomed a lot of research and clinical translation of this technique.
Speaker: That was Andromeda Strap I.
Speaker: Perfect.
Speaker: And just to put some perspective, right?
Speaker: Capitaly refill time is something that has been investigated and there were small studies looking at its prognostic factor for decades.
Speaker: And Andromeda...
Speaker: Andromeda Shock 1 brought it back to the forefront, like you said, and really started a new wave of interest in applying a very simple bedside intervention to guide therapy that is a lot more accessible to clinicians in terms of time, in terms of cost, in terms of availability.
Speaker: And that led, I presume, to Andromeda Shock 2, which we'll talk about now.
Speaker: Yeah, yeah, and what's nice is that also the philosophy behind the study was to put the tissue perfusion as a hierarchical target, you know?
Speaker: It was not to normalize macromodynamics, a cardiac index, a minor arterial pressure, or no, it was we manipulated the macromodynamics in order to restore tissue perfusion.
Speaker: I think that was very nice, and following probably the reverse study, then the lactate trial published in the Blue Journal, so it's a change of the pendulum of focusing solely from the macro,
Speaker: to following to the tissue proficient.
Speaker: That's our end goal.
Speaker: Perfect.
Speaker: So let's, let's go ahead.
Speaker: Perfect.
Speaker: So after we finished 2019, we all suffered the pandemics, so we had this two-year gap.
Speaker: And in 2021, we started thinking of how can we push this further?
Speaker: Can we test?
Speaker: How can we still keep improving hemodynamic resuscitation of septic shock patients?
Speaker: And after months of discussion, we came with the idea
Speaker: We have one side of the face of the coin, that's the capillary refill time.
Speaker: That's simple, it's, let's say, easy to do, and we've already brought up this corpus of evidence.
Speaker: But what about the macromodynamics?
Speaker: Can we try to do something as simple as capillary refill time, but in order to personalize resuscitation?
Speaker: At that time, we had some nice papers by Guillaume Guiri and Anton Vilevarón that showed that there was...
Speaker: hemodynamic clusters, and there were quite heterogenic patterns of hemodynamic clusters or cardiovascular clusters in patients.
Speaker: So we started thinking, iterating ideas, and we came, okay, we need to perform an algorithm that's able to
Speaker: individualized care, not go like one step at a time, but let's do like more branching in the algorithm, but using simple tools.
Speaker: And that's where we came with, let's use pulse pressure and diastolic arterial pressure to identify patients that have a low stroke volume, either by low cardiac,
Speaker: right or left ventricular failure or hypovolemia, and the astolic blood pressure as a surrogate for, let's say, vascular tone.
Speaker: So that's how we started building this, always aiming at caperitial time, formalization.
Speaker: And we also said...
Speaker: we must include a cardiac evaluation with ECHO, but reserved for those that do not resolve the hyperperfusion or do not normalize capricutin with the simple interventions.
Speaker: And that's where the main changes from andromedal stroke 1 to 2, which we use pulse pressure and the esthetic blood pressure to, let's say, try to divide patients that have predominant vasoclycia or pulmonary
Speaker: low stroke volume, and we integrated a cardiac echo at the start of Tier 2.
Speaker: And the other pillars are just the same, that's fluid responsiveness before every fluid challenge, and the tests, let's say the mean arterial pressure test and the inodulator test, that are reversible tests that allow us to type-take hemodynamic interventions to normalize cap refute.
Speaker: So this trial, we started recruiting patients in 2022, and it was super nice because we grew beyond Latin America.
Speaker: We had centers in North America, Western Europe, and Asia, and it's finalized with a drug community of researchers and clinicians,
Speaker: that participated in the study.
Speaker: And we recruited 1,500 patients in the span of three years.
Speaker: And we did the study with no financing at all.
Speaker: It was super nice.
Speaker: Everyone that wanted to participate had to find their own financing if they're required.
Speaker: But I think the sense of community and the sense of building this together was the main driver that allowed us to complete
Speaker: the recruitment of the study in a record time of three years for 1,500 patients.
Speaker: And this was the study design and the, let's say, the people involved.
Speaker: And we had such a collaboration from whole research groups, not only here in Latin America, but in Spain, there was this anesthesia society that
Speaker: went in a block together, and they were super inspirational.
Speaker: The French team also won a grant, and they started computing.
Speaker: And we had some... There's a very nice human story behind the Andromeda structure.
Speaker: But coming back to the study, sorry I diverged.
Speaker: Now we have this protocol, we developed this algorithm, and we wanted to compare to what we were going to compare to.
Speaker: And that's when we decided, okay, we cannot give another, let's say, protocol, like it was the Andromeda 1 that we compared to lactate, so we chose to compare to usual care.
Speaker: And we were discussing the outcomes, our statistical genius, that's Alexandre Biasica-Valcanti from Brazil, said, I guess I want to propose to use a composite primary outcome, but not in a composite like in an old-fashioned way where every component of the composite outcome weighs the same.
Speaker: There's a rather new way to process.
Speaker: To use these composite outcomes, it's called the win ratio, which we use a hierarchy on the outcomes and the highest of the hierarchy have more way into the final metric.
Speaker: So that's when we say, okay, let's do it this way.
Speaker: And we involved three outcomes.
Speaker: There was mortality, length of organ support, and hospital length of step.
Speaker: So we use this hierarchical outcome to address our research question.
Speaker: And as I told you, it was 1,500 patients and
Speaker: The primary outcome was positive.
Speaker: We had a 1.16 win ratio that was mainly driven by duration of organ support.
Speaker: That was our second tier outcome.
Speaker: So we were super happy on this, not only on the results, but in the process itself.
Speaker: There was human growth.
Speaker: We made bonds with people around the world and w as a researcher-led study.
Speaker: And I think it's worth taking a second to really appreciate the unique nature of Andromeda Shock 2, which is, like you mentioned, was 100% investigator-driven and did not have any external funding and was really a...
Speaker: a work of passion and true curiosity and finding better ways of treating our patients.
Speaker: So kudos to you and the whole team.
Speaker: Really a phenomenal testament to what we can achieve when we really have a will.
Speaker: So congratulations.
Speaker: And what I wanted to ask you, Eduardo, was could you talk a little bit more about the primary outcome?
Speaker: Because like you mentioned, composite outcomes over the last couple of years have become more common in critical care, clinical trials.
Speaker: But the idea of using a hierarchical composite outcome is a little bit more novel.
Speaker: It's not as common.
Speaker: And if I recall from reading the paper, the primary outcome was basically an order of importance mortality,
Speaker: duration of vital support, which included vasoactive drugs, mechanical ventilation, and kidney replacement therapy, and then finally, the length of hospital stay, and all that measure at 28 days.
Speaker: Is that correct?
Speaker: That's correct.
Speaker: So the idea of this outcome is just to give a higher value to those that are on the top of the hierarchy.
Speaker: So in the practical way, how do you do it?
Speaker: You compare each patient...
Speaker: from the intervention group to each patient to the control group.
Speaker: So patient one, you compare to patient one of the control group, patient one, you compare to patient two, then patient three, and that makes you a number of comparisons.
Speaker: That's basically the number of patients in one group multiplied by the number of patients in the other group.
Speaker: And in each comparison, you compare either a win,
Speaker: a tie or a lose.
Speaker: So, for example, if the patient on the intervention lived and in the control died, it's a win to the intervention.
Speaker: If the patient of the control group lives and the patient in the intervention group dies, it's a win to the control.
Speaker: And if both patients survive, it's a tie, and then you go to the next hierarchy.
Speaker: You compare the duration of organ support only to those that survived in the first one.
Speaker: And then you do the same.
Speaker: So if in the Tier 2 or in the outcome number 2, there's 20 days and then it has 19 days of duration of organ support, it's a win for control.
Speaker: But if both have 20 days, you tie, and then you compare all in those that tie,
Speaker: the third outcome.
Speaker: So that way you give a higher value to the most relevant outcome, first mortality, then duration of organ, and then a hospital length of stay.
Speaker: Okay, that's perfect.
Speaker: Now I understand a bit better.
Speaker: And that means that at the end, I mean, you basically had 700 plus times 700 plus comparisons, so a large number of comparisons.
Speaker: Yeah, it was one, like 200, let me open the paper to give you the exact number, because we did it stratified by Apache, so it changed a bit, but the idea is that it's thousands, hundreds of thousands of comparisons to find this.
Speaker: this difference, you know, to make this the indicator.
Speaker: And I want to dive a little bit more into the protocol itself in one second.
Speaker: But in terms of the study itself, so 1,500 patients with septic shock, all adults, were there any major exclusion criteria that are relevant to
Speaker: You mentioned earlier questions about cirrhosis in terms of CRT, so I presume that was included.
Speaker: But what are some of the patients that were excluded from the study?
Speaker: Yeah, so yeah, it's a really bad point.
Speaker: I didn't highlight this.
Speaker: There's some exclusion criteria, for example, patients that had more than four hours since diagnosis.
Speaker: So we had a small time frame because we wanted to focus on early septic shock.
Speaker: Also, if patients were going to go to surgery and we could not continue the six-hour, let's say,
Speaker: the time span of the study, or patients that had, let's say, severe ARDS, DNR, or pregnancy, that these are like usual exclusive criteria for septic shock studies.
Speaker: I think those are the major ones, let's say.
Speaker: Perfect.
Speaker: And in terms of the actual protocol or the intervention, one important aspect I want to emphasize is that as the title says, the idea here was to personalize hemodynamic treatment based on CRT as part of a protocol.
Speaker: So this was not like one protocol that is applied to everybody the same way, but you tried to identify different phenotypes, let's call it, or different categories of patients based on the response to shock.
Speaker: So you did mention earlier that in the personalized hemodynamic recitation protocol that was targeting CRT, there was a Tier 1 and Tier 2.
Speaker: Could you explain that in more detail?
Speaker: Yes, of course.
Speaker: So our idea was to handle atherogenity,
Speaker: within the protocol itself, because patients are quite heterogeneic.
Speaker: So we started with a two-tiered approach.
Speaker: So tier one is the simpler interventions, and the first assessment was cap refill time.
Speaker: If cap refill time was normal, we did not do any further intervention, just observe hourly.
Speaker: Of course, during the six-hour patient deteriorated, we intervened.
Speaker: But let's say a patient with a normal cap refill time had...
Speaker: Then if the patient had an abnormal cap refill time, we assess pulse pressure as our first, let's say, branching tool.
Speaker: If the patient had a low pulse pressure, we check fluid responsiveness with the technique that the clinician had at the moment and according to the patient characteristics.
Speaker: And if the patient was food responsive, we gave food challenges up to 1,000 mLs.
Speaker: If the patient had a normal pulse pressure and a low diastolic blood pressure, less than 50, we say, wait, here's an issue here.
Speaker: It's probably done by predominant vasoplegia.
Speaker: So we titrated norepinephrine to increase diastolic blood pressure over 50.
Speaker: As you know, the main determinants of diastolic blood pressure is vascular tone and the heart rate.
Speaker: So if neither of these interventions, either fluids or the diastolic test, let's say, increased or normalized cab refill time, we went to Tier 2.
Speaker: It was a bit more labor-intensive, and it started with echo to check for right ventricular or left ventricular failure.
Speaker: If we found those, we treated them according to the local clinician guidance.
Speaker: If there was no cardiac echo, we checked again for fluid responsiveness to assess if further fluids could make the trick and improve capillary ratio time.
Speaker: if even though there's no fluids where the or patient was not fluid responder or whatnot, we did the same as sending Andromeda 1.
Speaker: We did a test to in those patients that were previously hypertensive to transiently increase mean arterial pressure to 80-85 and checking one hour.
Speaker: If the CRT normalized,
Speaker: we kept these high targets.
Speaker: If the CRT was not normal, we went back to 65, there was a previous baseline level, and did a low dose of vitamin test with 5 micrograms per key.
Speaker: For one hour as well, to check if in a reversible fashion we could improve cap refill time.
Speaker: So this was like the overview of the protocol, but our idea behind it was to, let's say, stratify interventions with Tier 1 and Tier 2, and to try to address heterogeneity according to the determinant phenotype, as you mentioned, or let's say, cardiovascular cluster of patterns.
Speaker: Excellent.
Speaker: But it started with CRT as the first determination.
Speaker: And even if you had no access, and we'll talk about the practical implications to echo, Tier 1 probably involved a large proportion of patients, right?
Speaker: So you can start with Tier 1.
Speaker: Go ahead.
Speaker: Sorry, sorry.
Speaker: So actually, in the supplement, we added one figure with the individual predictors of patients, and 65% of patients normalize cap refill time with Tier 1.
Speaker: So only one in three had to go to Tier 2.
Speaker: And of course, echo could be a limiting factor.
Speaker: In fact, there's a study done in the UK where less than 7% of patients admitted to the ICU receive an echo during the first hour.
Speaker: So when we designed this algorithm, we were conscious about this, especially because most of the patients, or many patients, were randomized in research constraint settings.
Speaker: So we have to put echo as a second level, let's say,
Speaker: strategy because or else it won't be practical.
Speaker: So in summary, both Andromeda shock one and shock two were positive studies.
Speaker: It seems that in Andromeda shock one, the comparison to using what at that time was recommended, which was lactose clearance was equivalent.
Speaker: And when you did post hoc analysis with Bayesian approaches, there was an increased probability of improved mortality and a clear signal to a lower utilization of fluids and basal active drugs.
Speaker: Correct.
Speaker: And in shock two, what you demonstrated was that with a composite hierarchical primary outcome, there was a positive signal or positive finding that was statistically significant with using CRT to personalize your hemodynamic result in terms of that outcome.
Speaker: And that was driven mostly to the use of life support or vasoactive renal support and mechanical ventilation treatments.
Speaker: Correct.
Speaker: Yeah, correct.
Speaker: So in terms of... I will say that, yeah.
Speaker: In terms of moving on to practical considerations, so we have two... We have a body of literature suggesting the prognostic value.
Speaker: We now have two wonderful studies showing its applicability at the bedside.
Speaker: But we always have to translate from clinical trials, which are very motivated, very controlled settings, to...
Speaker: using it in the wild, right?
Speaker: And applying it at the bedside.
Speaker: So my question, my question for you, Eduardo, is practical considerations.
Speaker: What are some of the challenges of incorporating CRT into your resuscitation as a clinician?
Speaker: I think, let's say, one of the barriers I found is to do it in a standardized fashion.
Speaker: And maybe for the clinical practice, you can do it like
Speaker: without a glass probe or maybe you can compress with your finger, you know, that's beyond the clinical research scenario.
Speaker: It's probably an easier way to bring the CRT to the bedside.
Speaker: Also regarding, let's say, there have been some criticism to this algorithm, saying that it's kind of labor-intensive and branches out.
Speaker: And for me, and I'm speaking personally now, I think
Speaker: Probably maybe in five to ten years, this is not the last algorithm.
Speaker: But what I think what we showed here, super humbly, I think, is that...
Speaker: Personalizing therapy matters, you know, giving fluids to those with high probability of fluid responsiveness.
Speaker: If the patient has a vasoplegic tone, let's try to address that first.
Speaker: Let's check for cardiovascular dysfunction.
Speaker: And maybe this algorithm will not be the final algorithm, you know, and maybe to adapt it to your clinical scenario, you have to do, or if you are an echocardiography lover, you will do echocardiography.
Speaker: But the value I think is,
Speaker: to bring together the hemodynamic resuscitation in a personalized fashion with a tissue perfusion.
Speaker: As well, we're not always looking only at capillary field time.
Speaker: We have to create context, and we are checking the lactate, the simple venous saturation, CO2 gap.
Speaker: So in the clinical, every day, we're looking at a broader movie, let's say.
Speaker: But the important thing is that we can mix this work together and try to give our patients what they require.
Speaker: Yeah.
Speaker: I also believe after reading this and thinking about the results that there is no question in my mind that any intervention that brings us to the bedside and forces us to think about that individual patient is probably positive.
Speaker: And really that being the route of personalization, right?
Speaker: That to think about in this particular patient, what is the right answer?
Speaker: And we might be wrong sometimes, but on average, if we spend more time thinking about the individual patient, we're more likely to have a better process and that would lead to better outcomes.
Speaker: So that is also very valuable to really apply this at the bedside and really try to find the best answer for that individual patient.
Speaker: And the value to, as you mentioned, to do something, intervene, and then reassess and be there.
Speaker: You know, just like be there with the patient and close this loop.
Speaker: Like, okay, I'm giving an increasing MAP, and I'm not doing it like flipping a coin and say high MAP versus low MAP, because that could work in an RCP.
Speaker: But in the daily clinical practice, you can increase MAP and then check the
Speaker: I didn't work out, so I'll avoid exposing the patient to more of a tract.
Speaker: So I think this closing the loops and testing, I think at the end of the day, as you say, brings us closer and allows us to individualize.
Speaker: Absolutely.
Speaker: And after all the research that has been done over the last 20 years on hemodynamic monitoring, what has been clear from my perspective is that dynamic is better than static.
Speaker: And this is a dynamic application of a hemodynamic monitoring tool.
Speaker: And like you said, it really helps us personalize better our interventions.
Speaker: You mentioned earlier, Eduardo, the sepsis guidelines and how after Andromeda 1, it got included into the recommendations for CRT.
Speaker: What do the guidelines say right now?
Speaker: And obviously, that last iteration of the guideline was published prior to Andromeda Shock 2, but I'm just curious to see where the guidelines stand today.
Speaker: Yeah.
Speaker: Today they say that, I'm paraphrasing now, but they say to use lactate and its clearance as guiding, let's say, resuscitation, and also that capillary time can be used as an agent measure to guide resuscitation.
Speaker: How would you... Go ahead.
Speaker: Yeah, and there was a ESICM, let's say,
Speaker: Telphi panel, published this year on how to conduct with subject-socure resuscitation on resource constraint settings, and they recommended a capillary full-time to guide resuscitation as well.
Speaker: And since you mentioned that, I know ESAM also had a panel recently on the later phases of resuscitation, which is de-resuscitation or what we do when we've stabilized the patient and now have perhaps fluid overload.
Speaker: Is there value in using CRT in that de-resuscitation phase or evacuation phase?
Speaker: I love this question because it's also one of the uncharted territories and it's also been part of the ongoing research by many groups.
Speaker: There's a paper by the group of Fabio Silvio Taconi that assessed the laser doppler when patients were connected to ultrafiltration
Speaker: and the laser Doppler, let's say skin blood flow, decreased earlier than the, let's say, ultrafiltration intolerance with macro-hemodynamic instability.
Speaker: So it could also serve as a guide to the unresuscitate patients and integrate tissue perfusion as well.
Speaker: There's also some data
Speaker: but it's also very, very, let's say, from the research arena, that the microcirculation can also be affected by venous congestion.
Speaker: So if a patient is fluid overloaded with a high CVP, with, let's say, a high VEXO score, it would be interesting to address as well and assess if this impacts, let's say, or if there is a following of the capillary result time abnormality.
Speaker: But this is also in the research.
Speaker: still in the research context and I could not provide certain evidence.
Speaker: But I think as we're doing it and doing the resuscitation in which we're taking only, not only, macromodynamics to guide resuscitation but also tissue perfusion, I think that in the next years we will see a bunch of literature addressing tissue perfusion as well in the deregistative phase to avoid second and third hits.
Speaker: And it makes sense, right?
Speaker: If it's useful on the way up, it should be useful on the way down.
Speaker: Yeah.
Speaker: Yeah, absolutely.
Speaker: We have to create the literature as well.
Speaker: Perfect.
Speaker: How would you recommend CRT be utilized today in clinical practice?
Speaker: I think one of the beauties, let's say, of caprifield time is that it's simple, it's costless, and it can be done almost anywhere.
Speaker: So I think that...
Speaker: Cap-refill time can be used in the emergency room.
Speaker: There's some nice papers using as a triage, admission criteria, also to assess patients.
Speaker: We did a study in Mexico in critically ill-obstetric patients, and we saw that even though most of them have preeclampsia, patients with abnormal cap-refill time were usually admitted to the ICU.
Speaker: There's a study by Mergy et al.
Speaker: that used capillary refill time in cardiogenic shock.
Speaker: So I think there's a broader growth of CRT to other critically ill diseases beyond septic shock.
Speaker: And of course, pediatricians and pediatric intensivists have used capillary refill time for many years as a daily clinical practice.
Speaker: So I think it's a prognostic tool.
Speaker: can help us to guide resuscitation during a septic shock.
Speaker: And also, I hope that we can see some value on, as you mentioned, on the de-resuscitation phase.
Speaker: Any common pitfalls to avoid and pros for practical success you want to share as we close?
Speaker: Yeah.
Speaker: Sometimes I, I, uh, there are some literature to support these to do more than one measurement than have an average just to increase, uh, to avoid, uh, let's say, um, heterogeneity in the measurements.
Speaker: Uh, if you can use a chronometer, use a chronometer to, to, to, to make it more objective in the measurement.
Speaker: And, um, I think.
Speaker: that as with any complex disease and any complex scenario, don't take decisions only based on one parameter, but look at the global picture and assess in the clinical practice all other signals that are talking about the cardiovascular deficiency and tissue perfusion.
Speaker: Let's say if the patient is awake, he's peeing, and he's, let's say, with a little bit of norepinephrine, you say, hopefully this patient that is warm, awake, and peeing is probably okay.
Speaker: And with the same vasoactive drug dose, if the patient has a motiline score, lactate is rising, and the patient is anemic, probably you have an issue.
Speaker: So not focusing only one thing, but let's say build a broader picture.
Speaker: What are some developments that you are anticipating and are most excited about in the future?
Speaker: I hope that, well, you know the story of the reverse trial that later was tried again in three other big trials.
Speaker: So I hope there's a new interest on doing something similar.
Speaker: that testing an hypothesis with a broader spectrum or a clinical, I don't know, maybe in the US, they will start an Andromeda US study, something like that.
Speaker: And I hope to see it validated by different groups or tested at least the hypothesis by different groups.
Speaker: I think that there will be a renowned interest by industries to
Speaker: make, I don't know, semi-automatic or automatic monitors addressing capital and refill time.
Speaker: And for me, what are my research agenda, at least personally, is I'm very interested in venous congestion and see how this can affect organ and tissue perfusion.
Speaker: And
Speaker: how can we guide this, let's say, resource more gently with this, let's say, trying to improve tissue perfusion without inducing venous congestive.
Speaker: I think this would be nice.
Speaker: And also one of my interests is this great concept of refractory shock, what it is.
Speaker: Each one of us has a definition of its own, so I think it would be nice to come to Common Grounds.
Speaker: So we can also...
Speaker: start doing research on this area.
Speaker: That is the beauty of having great questions.
Speaker: It just leads to more great questions, right?
Speaker: Yeah.
Speaker: Yeah, yeah.
Speaker: Sometimes it's like an Everest, but I think with a nice team and good friends, you can always try to bring them to the most.
Speaker: Absolutely.
Speaker: Eduardo, we'd like to close the podcast with a couple of questions that are unrelated to the clinical topic.
Speaker: Would that be okay?
Speaker: Yes, of course.
Speaker: I'd love to.
Speaker: The first question relates to books.
Speaker: Is there a book or books that have influenced you significantly or a book that you have gifted often to other people?
Speaker: Yes, yes.
Speaker: For me, it's like a story book that I read and now I'm reading to my children, The Little Prince by Antoine de Saint-Exupéry.
Speaker: It's been a... It's come with me at different stages of my life and every time you read it, it brings new...
Speaker: let's say, ideas or messages.
Speaker: And the book that I'm reading now is called The Autumn Ghost by Hannah Wunsch.
Speaker: I don't know if you had the opportunity to read it.
Speaker: It's about the polio pandemics.
Speaker: I'm really enjoying it.
Speaker: I'm reading it now, and I'm really enjoying it.
Speaker: And for our listeners who have not read The Little Prince, it is a quick read.
Speaker: But like you said, Eduardo, every time you read it, you learn new things and you think about different aspects of life.
Speaker: But truly an enduring and wonderful book that is highly recommended.
Speaker: The Autumn Ghost is...
Speaker: a book about the polio epidemic, which really is the birth of critical care, right?
Speaker: So it's really where our specialty started.
Speaker: So highly recommended by one of our wonderful colleagues.
Speaker: And I will link both of them in the show notes.
Speaker: So thanks for sharing those.
Speaker: The second question relates to changing your mind.
Speaker: And could you share with us something you changed your mind about recently?
Speaker: Yeah.
Speaker: Yeah, yeah, I think I would like to, well, we could talk about many things over here, but for me, what I'd like to share is the journey of doing research.
Speaker: So for me, at the beginning, you wanted to get to the answers, and you hoped that your hypothesis was correct, and I think
Speaker: after finishing the Andromeda SHOEK-2 trial, it's the journey itself that's the most beautiful, you know?
Speaker: It's getting to know such nice and beautiful people along the way, how to do it properly, and independent of the result, I think the journey itself has been so enriching, and it's been
Speaker: Such a, let's say, a wonderful ride.
Speaker: It has its drawbacks, its sour moments as well.
Speaker: But it's been so nice that I think for me the lesson or what I've changed my mind about is not just focusing on the goal.
Speaker: but on the journey and that applies to everything in life.
Speaker: I think it's a great analogy for life and which really the lesson that over and over has been learned, I think in different traditions has been that the real value lies in the journey.
Speaker: And we definitely will have to talk more about that and would love to have you back to talk about new developments soon.
Speaker: But to close, I would like to ask you one final question.
Speaker: What would you want every listener to know?
Speaker: Oh, this is a tough one, but I think that it's okay to be wrong sometimes.
Speaker: It's in an argument with a family member.
Speaker: It's in a clinical scenario that you have a mindset and you're answering with your own biases.
Speaker: It could be with, let's say, I don't know.
Speaker: Discussing with a friend, but it's okay to be wrong.
Speaker: It's difficult sometimes not to be super, let's say, exigente.
Speaker: How do you say it in English?
Speaker: Let's say... Demanding.
Speaker: Demanding with yourself.
Speaker: So it's okay sometimes to cut a bit of slack and be, let's say...
Speaker: We're humans, you know?
Speaker: Failure is what makes us humans.
Speaker: I agree.
Speaker: So embracing failure and learning from it, I think.
Speaker: And I think one way to summarize, and it's a beautiful thought, is don't aim to be right, aim to learn.
Speaker: Yeah.
Speaker: And in order to learn, we have to fail.
Speaker: Right.
Speaker: Yeah.
Speaker: So that should be the path forward.
Speaker: Eduardo, thank you so much for sharing your time and your expertise with us.
Speaker: We definitely would love to have you back in the future to talk about other fascinating topics.
Speaker: And again, congratulations on Andromeda Shock 2.
Speaker: And I look forward to talking with you more.
Speaker: Thank you.
Speaker: Thank you for the opportunity of being here.
Speaker: Again, this is a collective, let's say, milestone with more than 800 researchers involved in this study.
Speaker: And it's such a wonderful opportunity to be sharing it with you and all your team.
Speaker: So thank you very much.
Speaker: Thank you for listening to Critical Matters, a sound podcast.
Speaker: Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network.
Speaker: Sound's transforming the way critical care is provided in hospitals across the country.
Speaker: To learn more, visit www.soundphysicians.com.
