SCCMPod-561: Microcirculation and Shock in Critical Care

Dr. Bulloch: Hello and welcome to the Society of Critical Care Medicine podcast. I'm your host, Marilyn Bulloch. Today, I'm joined by Olfa Hamzaoui, MD, PhD, to discuss her Peter Saffer Honorary Lecture, Tissue Perfusion and Microcirculation and Shock.

Dr. Hamzaoui is a professor of intensive care at the Robert Debris Hospital, University Hospital of Rems at Rems University in Rems, France. Welcome, Dr. Hamzaoui. Before we start, do you have anything to disclose?

Dr. Hamzaoui: Oh yeah, I have some conflicts of interest. I got some honorary lectures from some companies, AOP Healthcare, from Baxter, from Gettinger. I think that's it.

Dr. Bulloch: So a very busy woman. We're glad you're here and thank you so much for being able to join us at Congress here in Orlando and being able to be one of our thought leaders and give such a big honor for me.

Dr. Hamzaoui: I'm really so grateful and I'm very happy to be here. It's my first time actually in the SCCM Congress and it has been always something which is looking for it. So no, it's the honor is for me.

Dr. Bulloch: That's wonderful. So this is a bucket list item for you. That is wonderful.

And I know that Peter Saffer lecture is always a very important one. So that seems went to someone very deserving this year. Oh, thank you so much.

That's so nice. So your research is heavily focused on cardiovascular monitoring, echo, volume status assessment, and use of vasopressors in the critically ill. One thing I love to do when we have guests who are as important as you are and have done so much is to ask them, how did you get here?

What was it like? Tell us about your journey.

Dr. Hamzaoui: Oh, my journey was so, I think not a typical journey. Okay, I like that. Yeah, okay.

It's a long story. It begins in Tunisia because I'm originally from Tunisia and I started my medical studies there. And then I went to France in my residency.

And when I went to France, actually, it was like scholarship with the French ICU teams. It has been like a tradition for the ICU physicians in Tunisia. And when I was moving, I choose to be in Bicet Hospital in Paris because I wanted to be expert in cardiovascular issues as this hospital, Bicet Hospital and the ICU of Bicet Hospital was always the reference of the cardiovascular monitoring and the research around the cardiovascular in the ICU setting.

So I said, I'm an ICU resident, but I want to do some research and to be expert in the cardiovascular. So I traveled to France and I finished my residency there. And then I decided to stay there.

And so I passed a lot of exams and I have a double diploma from Tunisia and from France. For me, it was really when I discovered the research when I arrived in Bicet with the cardiovascular issues. And my first paper, I was actually a resident there about the hemodynamic monitoring.

That's fantastic. You got to start early. Yeah, because for me, it was like a Disney world.

We are in Orlando, but it's like the same thing. Because for me, it was, I was just meeting people that I was reading in their papers. So they were my stars.

These were your celebrities. Yeah, the real celebrities who have been publishing in the cardiovascular monitoring. And so it was for me a great experience.

So I spent there two years in Bicet. And then after, I just decided to stay in Paris and I continued. With the help of the Bicet hospital, I managed to get my own research also around the cardiovascular.

And when I discovered these topics and the research, I was really fascinated by this. Of course, in parallel to taking care of the patients and the clinical work. And I wasn't, at that time, I was not a full professor, of course, resident.

And then I was like a senior consultant in another ICU next to, not in Bicet, from another Beclair hospital. And I continued to have a research around cardiovascular. And it was for me one of the important things that I was doing in my career, of course, in addition to my clinical work.

And then I get there with all this research because I was fascinated by this, passionate about it.

Dr. Bulloch: And that's wonderful. And I think that passion really drills down to productivity and what you can accomplish. Now in medicine, especially intensive care medicine, we have to take care of the whole person.

And so it's sometimes it's hard for us to pick a favorite, but it seems like cardiovascular was very early your favorite. What was it that made you so interested in this particular niche area? Yeah.

You said you went to France for cardiovascular.

Dr. Hamzaoui: Yeah. Yeah. Yeah.

It was really, I think in the very young years in my residency that I discovered the cardiovascular research. And I said that I want to be really expert in that field. I know.

Yeah. You're right. You're totally right that the ICU physician must have a lot of competencies.

That means a lot of skills and knowledge about all the organs. But if you want to focus on research anyway, and I think it was unconsciously also my idea also to just begin some research, you need to define one of the topics and you cannot have a research of all the organs anyway. So you cannot be expert in all.

So it was something that was really fascinating me very, very early in the residency. I wanted to learn how to do echocardiography. I wanted to learn about blood pressure, about heart rate, about cardiovascular physiology.

This was something when I was resident, I went also in for six months in cardiac ICU care in order to get some more skills about the cardiac issues and cardiac patients. So yeah, it's something that was really a passion for me, the cardiovascular topics.

Dr. Bulloch: You really love the heart and our listeners can't see, but you're wearing red, which I feel is so fitting to your talk today.

Dr. Hamzaoui: This is what, you know, Professor Steve Olinberg was telling me just before my honorary lecture. He said, you know, in the cardiac congresses, the women are in red because it indicates the heart, but it was not really.

Dr. Bulloch: It wasn't planned.

Dr. Hamzaoui: Yeah, it was not planned, but it is.

Dr. Bulloch: So for our listeners who maybe didn't get a chance to come to Orlando and hear your talk this afternoon, can you maybe just summarize what you told our attendees today?

Dr. Hamzaoui: You know, it's difficult to summarize 100 slides, but I'm trying to. I know, just the Cliff Notes version. Yeah.

Actually, I was talking about the microcirculation and tissue perfusion, and I was telling that, yeah, we know from research that there are a lot of disturbances in microcirculation during shock, especially a lot frequently described in septic shock, but also in cartogenic shock. There is, of course, a physiopathological rational that explains this with an inflammatory factor that will induce this dysregulation of the vasomotor tone and the decrease of the capillary recruitment, but also endothelial dysfunction that will create all the microcirculatory disturbances. We know also that it may occur early.

We know also that it may be correlated to the outcome of the patients. This was my introduction, my introduction slides, and I was wondering if that given all this information, should we routinely monitor microcirculation? And I just also went through the tools that we have to monitor microcirculation.

I talked a lot about the handheld video microscopy with the HVMS, which is a portable device to explore by video microscopy the sublungual area, which I talked a lot about it because it was extensively really studied, and the main research of microcirculation was using this technology. The problem of this technology is, although there is a lot of research around it, it is not yet recommended at the bedside because there are some technical issues. There is a lot of artifacts.

It is costly. It is not available.

Dr. Bulloch: It's not very practical, it sounds.

Dr. Hamzaoui: Yeah, it's not very practical, and it is time-consuming because the analyses are offline and you need a lot of expertise, and this is why even the experts of microcirculation in their consensus published in 2018 do not recommend it at the bedside for the moment because we need developing more the algorithm and the software in order to be more accurate and very rapidly automated. There is more automation and reliable, even though during these years, the technology had evolved because there are different video microscopies that have been developed three years from the OPS, the first one, until what we call the IDF, the last one. Probably there is now, recently, that has been developed by Chan-In Chi, who's one of the masters of microcirculation in the Netherlands.

He's developing a micro tool. He is just promoting this as a point-of-care device, but we need more data, actually. But I'm saying why we have these tools, we have this research, and we don't use it because of this technical, but we have also some controversy in the data, in the research data.

For example, we have some data showing that the sublungal microcirculation do not correlate, for example, with other organ microcirculation. It's interesting. Example, the intestinal.

And there are some studies showing that these two microcirculations do not correlate. So that means that if you are concentrating on the sublungal, probably you are missing other parts, and it's not reflecting all the microcirculation of all the organs. There are also other issues because there are some cohorts with mortality, moderate mortality, or even high mortality of 28%.

And when you look at a cohort of 500 patients, there is only 18% with real sublungal microcirculatory disturbances, which means that probably it's not so relevant. And sometimes even in these data, when you compare survival and non-survival, there is no difference between the microcirculatory parameters. There are another also important point is that it may occur early, frequently it may occur early, the microcirculatory disturbance, but when it occurs early, frequently it is correlated to macrocirculation.

And so if you correct microcirculation, you correct microcirculation. So what is the benefit? To have a costy tool to monitor microcirculation as you are correcting it by only correcting microcirculation, which is easily, of course, monitored.

Some papers say that, yeah, but you know, there are some remaining patients with later phases microcirculatory disturbances. So for these patients, we need to monitor microcirculation. Yeah, we need to monitor microcirculation, but for what?

What we will do? Do we have any specific treatment for this microcirculatory remaining disturbances? For the moment, no, we don't have any specific treatment.

We have only treatments for microcirculation. This is very academic right now. Yeah, it is for research.

And after I talked about another tool, which unfortunately, and I say unfortunately, because I used it in my research, which is the NIRS, the Near Inferred Video Microscopy, which is like a sensor on the thinner eminence, and it gives oxygen saturation. It actually visualizes the muscle at 15 millimeters of depth on the eminence thinner. And actually, it is based on the absorption of the deoxyomoglobin and the oxyomoglobin of the red light, two different waves.

And then there are two probes, one with the illumination and the other one detecting the reflected light, and will be displayed on the monitor as a value of STO2, which is a tissue oxygen saturation, was developed in the 2005 and 6. The problem is that the only value of this STO2 was not so relevant because it was different from the healthy volunteers and the sickest patients. But what was interesting, it was the dynamic changes of this STO2 and what we call a recovery STO2 slope.

It is induced by a vaso-occlusive test with inflating a pneumatic cuff until you have a drop of the saturation of 40%, which takes three to five minutes. And then after an abrupt release of the pneumatic, so that actually you induce like a ischemic stimulus, and then you release it, and you look at the recovery slope of the STO2 that dropped before due to the inflation of the cuff. And this slope was very interesting because it was different from septic shock patients, from healthy volunteers.

It improved with treatments, and it has a real prognostic and outcome relevance.

Dr. Bulloch: So I'm a pharmacist, and you just said that it improved with treatment, since I love kind of going down those rabbit holes. When you say it improved with treatments, do you mean fluid resuscitation, vasopressor, some other type of therapy? Yeah.

Dr. Hamzaoui: I presented one of my studies that I published a few years ago, and we included patients at the early phase of septic shock. All the patients were hypotensive, very hypotensive, and there was an indication to increase mean arterial pressure by increasing norepinephrine. And we measured this STO2 recovery slope before, and then we measure it after, getting target MAP and increasing norepinephrine.

And on average, the STO2 recovery slope increased significantly and improved significantly. But what was more interesting is that there was some individual variation. When you look at, because you have a nice figure in my presentation, where there is the individual evolution of this recovery slope.

And there are, in some patients, they really benefit from the increase of mean arterial pressure, and the recovery slope like go from lower values to higher values. But in other patients, the recovery slope either did not change with a neutral effect or even deteriorated. That means that even if you think that you improved mean arterial pressure from the patient, this patient, probably with this information, which is further than a macrocirculatory value, they need probably another intervention.

Either they are undertreated, so probably this mean arterial pressure is not sufficient, so you need to go further, or you put it higher than what is normally targeted for this patient, and you need to go lower and to go back. So it's like a real individualization of these patients regarding this parameter.

Dr. Bulloch: I absolutely love that because, you know, we have for so long used a one-size-fits-all approach, and that's how everyone learns, and people don't realize that every person is very different. Even twins are very, very different. You know, a math of 65 may mean something very different for each person, and to have a tool where I think that you can individualize your therapy, I think, could really advance what we're doing in sepsis.

So I really do hope that that does proceed, you know, at least in my career, that we'll be able to see it. It'll be very exciting to say, I remember that when I learned about that in its infancy, and all of you on the podcast, you're hearing about it now, you know, several years from now, we'll be talking about how to titrate our vasopressors to these new endpoints, and I do think that's very exciting.

Dr. Hamzaoui: Yeah. The problem is that, unfortunately, it's no more commercialized, this NIRS technology, actually for this setting, because it is always commercialized for the neurocritical care and the STO2 and the jugular vein, which is not the same thing. This was something which was really disappointing, I think, for this technology.

And after I talked about a simple tool that may be used also to individualize treatment. What is that tool? It's the capillary refill time.

Dr. Bulloch: I am a former EMT. For the audience out there, I'm a pharmacist, but in a past life, I was an EMT, and I loved when the capillary refill data came out originally a few years ago. So tell me about this.

I'm very excited.

Dr. Hamzaoui: So the capillary refill time was actually famous. Yeah, it's famous for pediatric patients. And since 2019, and after the Andromeda shock trial, which was a trial in the Latin American countries led by Glenn Hernandez, who is a Chilean guy, who randomized, it's a big trial published in the JAMA, randomized the patients in two different strategies, either resuscitation septic shock patients and targeting the normalization of the capillary refill time, or resuscitating septic shock patients and targeting normalization of lactate. The main endpoint was not different, but there was a trend in favor of the capillary refill time as the P was of 0.06. And they made Bayesian reanalysis of their data. They published one year after in the Blue Journal, and they found that there was a real significant difference between immortality and less resuscitation in the patients where we targeted capillary refill time in comparison with what the patients were in randomizing the strategy of the normalization of lactate.

And they made a really very interesting also post hoc analysis on an ancillary data. They just included the patients where they had the data at two hours, the patients who normalized their capillary refill time at two hours, regardless of where they were randomized. They found that these patients had a higher mortality survival rate, so a lower day 28 mortality, and the less resuscitation of fluids and the less vasopressors.

That means that these patients were probably more individualized in their resuscitation than with a global strategy normalizing lactate. And the capillary refill time, the problem is that there is a real variability of the measurement. You can measure it three times.

You will have different values. You need to average even for five times in order to have more precision. And I think even for five times, you have a least significant change of 22%.

That means that you need to track the changes of delta capillary refill time. It needs to be more than 22% in order to track it. So the small changes, you cannot.

So I think that it is the beginning of the development, but we need to have a more performant devices to measure very precisely the capillary refill time. And I showed what is the most standardized way to do it. And Glenn in the Andromeda shock trial also used it.

He used in the fingertip a glass slide. And they put a pressure on the glass slide until the fingertip whitens. And then they count for 10 seconds and they release the pressure.

And then they count the seconds for the skin to recolor. And this is the most standardized way to measure the capillary refill time.

Dr. Bulloch: That's so funny. That is exactly how I learned to do it. Okay.

More years ago than I'm going to admit to. And I think that's why I loved this idea because I'm from a very rural area originally of America. And the area of the country that I practice in now is a big community teaching hospital, but it serves several counties that are rural.

It's very practical to me because it's easy to do. You can do it in resource limited settings and you don't have to wait on it like you do with selective. And I think that it just, it's very practical and it's non-invasive as well.

Dr. Hamzaoui: And also it means something because they also, the team of Glenn, they made some data in order to explain what is this capillary refill time. And they explored the skin blood flow by laser Doppler and they found a real correlation between this parameter. And also when they made a dynamic change with the vasoclosive test, they measured the laser Doppler vascular activity.

They showed also correlation. That means something. And it's not correlated really to the macrocirculatory parameters like MAP or cardiac index or CVP.

So it is further than the macro circulation. It is peripheral perfusion. And some people say probably somehow microcirculation.

I say some people because the data for the moment are really controversial. There are some data showing that it is correlated to microcirculation. Some others say that it's probably not exactly microcirculation.

But anyway, it is further than macrocirculation and it is probably the peripheral perfusion. And it may individualize treatment because I showed a study, a small study where the authors, they just examined the evolution of the capillary refill time after fluids. And for the patient who were fluid respondents, that means that the patient or the patient increased their cardiac output.

And we, of course, we define fluid respondents by the increase of cardiac output. And this is what physicians normally look for. But there were 13 patients who responded for fluids in terms of cardiac output.

But there are five from these patients who did not respond on the capillary refill time. There are eight who improved their capillary refill time and there are five who did not improve their capillary refill time. That means that these five patients, despite the increase of cardiac output, either they were undertreated and they need more increase in cardiac output or they didn't benefit from fluids and they probably they were over resuscitated and they don't need.

That means that it goes further than cardiac output and it may individualize some patients with only looking to the changes of capillary refill time.

Dr. Bulloch: And that's something that we keep, we talk about so much in critical care is about we've got at some point get to the where we are individualizing treatment. I have been practicing for a long time, but I felt like I was promised we would be there by now and we still haven't gotten there. One of the things that I love about this opportunity or the potential behind this is that maybe at some point, like we do assume our other conditions, we might be able to introduce treatment into pre-hospital care because we know how important time is and we understand the microcirculation and how that ties into everything and really decrease that time.

I want to come back because you did talk a lot about different tools and techniques for diagnosing microcirculatory abnormalities. One of the things that you have been an advocate for is using echocardiography to manage patients with shock. And if I misstate that, please let me know.

What have you found? And again, I'm at a big teaching hospital, but it's a community hospital. So we don't always have the same resources that some of my peers at big academic medical centers have.

And we talk about that. What have you found has been like the best or the most practical way now that echo is kind of rolling out everywhere, not just at the big facilities. What's the most practical way to integrate this into bedside care?

Dr. Hamzaoui: The echocardiography?

Dr. Bulloch: Yes, in terms of like sepsis or anything else for the microcirculation.

Dr. Hamzaoui: Echocardiography, I think, and now it's not only a thought, but now it is even a recommendation. It needs to be a first-line exam. The same thing with a clinical assessment at the same level, with a clinical assessment.

So when you take the blood pressure of the patient and you assess the patient clinically and you discover that the patient is in shock, I think it is important to have an echocardiography just close to you in order probably not to manage microcirculation. It's not, yeah, not the role.

Dr. Bulloch: We're not here yet.

Dr. Hamzaoui: Yeah, we are not here yet. But it is important for macrocirculation and also for defining the origin of shock in order to rule out some also causes of shock, for example, the cardiac dysfunction or things. So it is really a key exam at the bedside and even at the initial phase of shock, septic, cardiogenic, or whatever. So I will put it at the same level as a clinical assessment at the same time.

Dr. Bulloch: Do you think we're going to be able to use it practically for resuscitation purposes at the bedside? Like, how would you use it in an ideal world?

Dr. Hamzaoui: Yeah, yeah, yeah. Actually, I use it, but probably I'm biased because I'm really a big defender of echocardiography. And also in our unit, all the juniors and the seniors are trained on the echocardiography.

And we make them train when they get in the unit. So I will use it at the initial phase. And in some patients, I can use it really with a set of measurements in order to readapt treatments, to assess fluid responsiveness, to reassess the effect of some treatments like the inotropes or the fluids.

So it depends on the evolution of the patient. But I can use it as a diagnostic. But I can use it, I won't say a monitoring because it's not a continuous monitoring.

But I will say with a really close reassessment of the patient at the bedside. If I have, at the initial phase, the patient arrives shocked, hypotensive, I'm not sure about the mechanism, I will do my echocardiography. I rule out if there is any cardiac dysfunction, any cardiogenic shock.

And then if it is a septic, I will give some fluids. If it is not the case, it's cardiac dysfunction, I will think about the treatment of this cardiogenic shock. If the patient is not improving with my first treatment, I will reassess more advanced parameters.

Because at the first assessment, they can have only some eyeballing of the cardiac function and not measuring the cardiac output or the feeling pressures and all these parameters. And after will be more in details in order to reassess cardiac output and to see preload responsiveness using echocardiography. That means, for example, passive leg raising with a surrogate of cardiac output that we can measure with echocardiography, which is the velocity time integral of subarctic flow, VTI of the subarctic flow.

And I will see during the passive leg raising if there is any changes of this VTI and if the patient is preload responsive. If the patient has a cardiogenic shock and I decided to put some inotropes, I will look at the cardiac function with the Simpson method, with the left ventricular ejection fraction. I have also other parameters like the S, the mitral S wave, or also sometimes I can use also some strain parameters.

So I will go actually with the patient. If it is more and more complicated, I will have more and more advanced exam. Because the echocardiography can be used with simple parameters, but it can give more complicated also parameters, right and left ventricular, and even some pressure.

So it's interesting.

Dr. Bulloch: So you brought up inotropes, and it made me start to think sometimes in clinical practice, we start the vasopressors early and based on what resources we have, we don't realize they need an inotrope until later. And then we either add on to butamine or switch to epinephrine. Do you think either now or maybe even in the future, this might be a tool that we can use to get individualized therapy so we know early on what's going to be the best approach for our patients without having to wait several hours before like they're not getting better.

We're missing...

Dr. Hamzaoui: I totally agree. Of course, I totally agree. And I say that really, this is why I'm saying it is a first line exam.

First line exam, that means that yeah, when the patient arrives at the bedside with shock, you need to give probably fluids, you need to put some blood, some monitoring, but you need to assess the cardiac function with echocardiography in order to rule out if there is any cardiac function. And after to reassess, if the patient is not responding to vasopressors but do not wait for six hours, reassess. Probably he's developing a cardiac dysfunction at that time.

Dr. Bulloch: And six hours can be a long time.

Dr. Hamzaoui: Yeah, of course. And the patient can develop septic cardiomyopathy. And the reason why he's not improving is probably the cardiac dysfunction and not the vasoplesia and not increasing.

And sometimes it is some dangerous action that can be done because if you look at, for example, the guidelines and the patient arrives with a septic shock and you give norepinephrine, but if he's not responding, they will, if you look at the guidelines, they will put some vasopressin.

Dr. Bulloch: Right. And that's not always great in every patient.

Dr. Hamzaoui: Yeah, but the vasopressin, if the patient is not improving because he has a cardiac dysfunction, it will be disaster for your patient. So I think if your resuscitation is not improving your patient, you need to reassess with echocardiography the patient. Really, serial measurements are really needed in echocardiography, with echocardiography in these kind of patients.

Dr. Bulloch: I think that's so important. And it'll be interesting to see in future iterations of the guidelines, like where this comes in. I know that it's changed a lot.

One of the things that we also think about, there's so much attention on dealing with these patients when they first come in. And I'm very excited to see that there's a growing movement now to start looking at them again once we've got them through that initial sick period and we've resuscitated them and they're better. We started to treat their infection and all of that inflammatory, the mediators are going down.

We need to back off. So what do you envision is the role of echocardiography in the de-resuscitation process? Oh, yeah.

Dr. Hamzaoui: Oh, that's a great question. Of course, it may play a big role because the de-resuscitation, it means that the patient is already stabilized. And sometimes it occurs not because we over-resuscitated the patient, but it may occur because of a lot of factors, that the patient will be congested, will have fluid overload and a positive balance of fluid overload.

And we need probably to de-resuscitate the fluids and to try to monitor our de-resuscitation with some tool that we can have with the echocardiography, either, of course, echocardiography or the lung ultrasound also, because the lung ultrasound may give us also an idea about the pulmonary edema that the patient is developing. The echo will give us also some idea about the degree of congestion of the patient. And so giving diuretics and the beginning, the depletion of the patients must be re-evaluated with the echocardiography that you have.

And you have a lot of parameters. I won't talk about the VEXA score because I'm not the expert in this. But I think that in some patients, more importantly, probably the cardiac failure patients, if you have some indicators of a high VEXA score with a congestive, really, profile, you need to give fluids, but to monitor your congestive parameters with echocardiography, with Doppler measurements of the renal, the hepatic, the portal, and the IVC.

So yeah, of course, you can de-resuscitate the patient with this. And also, you can, of course, step down for the inotropes with your echocardiography because you see that the patient is becoming hyperkinetic and the cardiac output is now good enough. And then if you step down for your doses of your inotropes, you need to reassess if this decrease of the doses was not deteriorating your patient in order to go in the same direction or to come back to your first doses.

So yeah, I think it's something which is important from the admission of the patient until discharge of the patient, actually.

Dr. Bulloch: It's like a new way of therapeutic drug monitoring. I'm very excited about this opportunity. I want to shift gears just a little bit.

In 2023, you published an article in the journal Clinical Medicine where you advocated for titrating norepinephrine to an individual target. And I know that you have mentioned that a couple of times in our conversation today. Again, I always love the practical things that we can do at the bedside.

And sometimes when we say we need to individualize it, that's for younger clinicians especially. I think that that's how do we do it. How do you do it?

Not only how do you pick it, how do you adapt as things with the patient change? Yeah, excellent question.

Dr. Hamzaoui: And actually, it's a talk of 100 slides or so, but I can try to summarize. But it's an exciting topic because it's one of my favorite topics of research, the vasopressors and norepinephrine and the effects of norepinephrine. Because I, with Jean-Louis Tabun, in Bisset Hospital, and I was a resident, it was one of my first papers.

And it was one of the first papers suggesting that the early introduction of norepinephrine in patients with septic shock is not deleterious, but in contrary, it is relevant because it has other physiological mechanism on cardiac output. And it increases preload, it increases contractility, and it is beneficial for the patient. And comparison to a strategy where you go fluids, fluids, fluids, and then after you get the vasopressors after flooding the patient with the fluids.

So how can I do? One simple way to see if your patient needs the norepinephrine at that time is to look to your diastolic arterial pressure. The diastolic arterial pressure, and this is physiology, is a reflection of the vasomotor tone.

And if the patient arrives in the ward or in the ICU very quickly, and he just had some fluids, and even though the hypovolemia is not already resolved, and you have a low diastolic arterial pressure, that means that your patient has mainly vasopressure. Vasopressure cannot be corrected with fluids. You know that even if you give 10 liters of fluids, you won't correct hypotension.

So this patient, you need to introduce norepinephrine very early in comparison to another patient who is coming with septic shock but with not a very low diastolic arterial pressure. This is one way to titrate, to individualize the introduction and the timing of the introduction of norepinephrine. The second way also to do is to titrate the goal, your mean arterial pressure.

And you were talking about the 65 is not the magic number for all the patients. And this is also physiology because the curves of the autoregulation of the organ blood flow is different from a patient, for example, with hypotension from a patient with no hypotension. So a 65 may be good for a patient with no hypotension, but it's not enough for a patient with hypertensive comorbidities.

So you need to titrate also your goal. So if you have a patient with comorbidities, hypertension, or an increased value of CVP. Why?

Because actually, the perfusion pressure of the organ is the upstream pressure minus the downstream pressure. The upstream pressure of the majority of the organs is the mean arterial pressure. But the downstream pressure, it is estimated to be the central venous pressure.

Of course, if you have, for example, in the abdomen, if you have an intra-abdominal hypotension, it will be the abdominal pressure. But in a setting without any abdominal pressure or any intracranial hypotension, it is estimated to be the CVP. So if you have a 65 with a very low value of CVP, your perfusion pressure is OK for your kidney or for your brain.

But if you have a downstream pressure of CVP, which is high, your perfusion pressure will be low with this 65. So you need probably more than the 65 to have the same perfusion pressure for this patient. There is not a lot of research about this, but there is a nice paper by Marley-Sosterman, published in 2017, that showed that this mean perfusion pressure, which is calculated as mean arterial pressure minus the CVP, was an independent factor for the progression of the acute kidney injury in comparison to the mean arterial pressure by itself.

And she defined a cut-off value of 60 millimeters of mercury. So if you have a patient and you monitor his CVP, and he has 20 millimeters of mercury or some meters of water of CVP, and he has a 65 of mean arterial pressure, his mean perfusion pressure is a 45, which is far lower than the 60, which is normally the cut-off for the kidney, for example. This is also how to individualize, to titrate your dose of norepinephrine to your target of mean arterial pressure.

Dr. Bulloch: This is absolutely fascinating to me, because when I was younger, CVP was one of the things that we did measure. It was right when the surviving sepsis was launching. And throughout my career, I have watched this tug of war among my colleagues about CVP.

And it's not even in the current edition of the guidelines. But we were using it very different than what you just described. And sometimes I always think about the things we used to do, and will they ever come back?

And what you're telling me is maybe. Maybe CVP is not so bad. It's just we weren't using it in the right way.

We were using it for fluids, and we weren't thinking about it. Same thing with the diastolic pressure. I feel like so much in sepsis, we ignore that pressure clinically.

We focus on systolic or the MAP, and it's almost like diastolic doesn't exist.

Would you agree? 

Dr. Hamzaoui: Oh, yeah. The two missing things in the surviving sepsis campaign, I would say the SSCM podcast, and I will say probably I will get some enemies, but I don't know.

We're here to open conversation. Yeah, yeah, yeah. I think it is something which is missing, and I think it's probably something which is important, and it has been missing in the recent surviving sepsis campaign, which was not the case in 2012.

If you remember that surviving sepsis campaign in 2012, there was a recommendation about the early introduction of norepinephrine. And the recommendation says that you need to introduce early norepinephrine if you have a threatened life, how it was written, like a very severe hypotension. And in the rationale, they explain what is this threatening hypotension.

What is it? It is written that when diastolic arterial pressure is low. This was in the version 2012 of the surviving sepsis campaign, but unfortunately disappeared in the other versions, which is probably disappointing.

And I think it's probably something which is neglected, and it's not recognized with its real physiological value, because septic shock is mainly vasoplegia. And diastolic arterial pressure, but this is physiology, is a reflection of vasomotor tone. So actually, it's not a target, but you can titrate, and you can trigger the introduction of norepinephrine when looking at your diastolic arterial pressure, because you can diagnose at the bedside of vasoplegia and vasoplegic mechanism for your shock.

Dr. Bulloch: So we're going to look to see what future additions, because it will again be one of those things, I think sometimes we find what we did in the past wasn't so wrong.

Dr. Hamzaoui: Yeah, no, the CVP neither, and you're right, the CVP neither. The problem is that we focused on CVP for the fluid management, which is not the right thing to do. The CVP cannot be used to assess preload responsiveness.

This is not, because it is a static measurement of preload, and static measurements of preload cannot assess preload responsiveness. But it is so important for other things. It can, of course, give us an idea about the right ventricular filling pressures.

Of course, when you have a patient with ARDS, and you don't have any, you know, you cannot have a continuous monitoring of the right ventricle with the echocardiography. But if you have a continuous monitoring of CVP, and if you are looking and you are titrating your PEEP, for example, and you are looking your CVP, if it goes high, that means that there's something with the right ventricle going wrong. At that time, take your probe, and you look at your right ventricle to see if there is a real dilation of your right ventricle, and probably you are worsening your right ventricle with your PEEP, and you need to rearrange your strategy regarding the PEEP.

It is important for targeting mean arterial pressure because it is the downstream pressure of the majority of the organs. And so you may titrate your perfusion pressure. The mean perfusion pressure of your organs.

So you can calculate the MAP minus CVP. So it is valuable. It is something which is really very important in my unit.

And now I recommend, and I have it in all my patients, the CVP.

Dr. Bulloch: It's so easy to get to because all of these patients have central lines, and it's just very easy. And that's a great segue to my last question for you. A lot of times we get a lot of really good bench research, and I've seen several in some of my colleagues just at this Congress that have presented amazing data, but it's not practical yet.

But I want it to be. I really want. And some of it is very challenging to our traditional views.

So how do we close those gaps between bench research and bedside application and encourage this dialogue that challenges the traditional views and promotes innovative approaches to health care?

Dr. Hamzaoui: Yeah, great point. And I'm also, with your opinion, I'm also trying to bring from the bench to the bedside the research. Because I think, yeah, of course, sometimes we cannot have the perfect setting to lead a perfect research at the bedside, but we need always to think that, what is the relevance of this parameter in my patient, in my care, the routine care of the patients?

And this is what actually I was taught when I was resident, when I was in Bissette Hospital with one of my mentors, Jean-Louis Tabut. Actually, he begins by a physiology, so the bench. And then after we make it, we bring it to the patient.

And how can we use it to the patient? So I think we need to communicate between really fundamental researchers and clinical physicians and clinical researchers. Because there are, of course, excellent ideas at the bench, but we need to bring them a little bit to your patients.

For example, I was in my hospital. I'm interested, of course, in vascular dysfunction. And we have a, I hope it will be published very soon.

We developed a new ratio for vasoplegia, which is a clinically ratio to evaluate the vascular responsiveness to norepinephrine in patients with subject shock. And it is a ratio that is using DAP, so diastereotropic pressure, divided by the heart rate and the dose of norepinephrine. And so we try to validate this ratio as a ratio for vascular responsiveness.

And how can we use it at the bedside? That means that if your patient has a higher ratio of this DAP divided by norepinephrine, that means that the patient has no vascular dysfunction, but it is a lower ratio. That means that he has vascular dysfunction and probably is not responding to norepinephrine.

And you may probably think to change and to add another vasopressor. So this is what we are trying to see. And we were talking with colleagues in the lab.

And she was telling me that she has developed new methods and new biomarkers using really very innovative techniques, which is the proteomics, in order to see the vascular responsiveness. And she said, if you are interested, we can make a research together. And I said, oh, that's a great idea.

We can measure these parameters that are developed in the lab, actually, just on the lab, and try to validate it and to associate it to this clinical ratio that we measure it at the bedside for all the patients. So we think it is really important to have this discussion between these two types of research. The clinical research needs to have some fundamental research, but the fundamental research needs to have some clinical application.

Otherwise, we don't do any positive care, any positive effect for our patients. And I think, in my opinion, my aim is to improve the care for our patients.

Dr. Bulloch: I have learned so much in our conversation today. This has been so enlightening to me as someone who loves sepsis and who teaches it to several different types of trainees. Unfortunately, our time is winding down.

We could go on all day. Yeah. Before we leave, I just want to give you a final opportunity.

Is there anything we haven't discussed today that you'd like to share with our audience before we go?

Dr. Hamzaoui: Oh, we have such things, but I think we discussed a lot of things. And you, I think, addressed a lot, a lot of important questions and important issues here for the ICU physicians and septic patients.

Dr. Bulloch: For those of you listening, whether you were able to attend this SAFR lecture or not here at Congress, I encourage you to go on Congress Digital and listen to it again. Available. I think you'll learn a lot of information.

So this concludes another episode of the Society of Critical Care Medicine podcast. If you're listening on your favorite podcast app and you liked what you heard, consider writing and leaving a review for the Society of Critical Care Medicine podcast. I'm Marilyn Bullock and thank you for listening.

Announcer: Marilyn N. Bullock, PharmD, BCPS, FCCM, is an associate clinical professor and director of strategic operations at Auburn University Harrison School of Pharmacy. She is also an adjunct associate professor in the Department of Family, Internal and Rural Medicine at the University of Alabama in Tuscaloosa, Alabama, USA and the University of Alabama Birmingham School of Medicine.

Join or renew your membership with SCCM, the only multiprofessional society dedicated exclusively to the advancement of critical care. Contact a customer service representative at 847-827-6888 or visit sccm.org/membership for more information. The SCCM Podcast is the copyrighted material of the Society of Critical Care Medicine and all rights are reserved. Find more episodes at sccm.org/podcast. This podcast is for educational purposes only.

The material presented is intended to represent an approach, view, statement, or opinion of the presenter that may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned.