In this video, anesthesiologist
Dr. Audrey Spelde outlines the function and importance of microcirculation while describing the methods for monitoring the microcirculatory function. She discusses the association between microcirculatory dysfunction and its outcomes, along with sharing the considered areas for future advances.
@PennMDForum Won't be talking so much about my own research today but kind of just giving a broad overview of kind of where we are in studying um the microcirculation for patients that are on M CS. So for our objectives, we'll be talking about the function and the importance of the microcirculation. Describe methods for monitoring, micro circulatory function, outline the association between micro circulatory dysfunction and outcomes and then consider areas for future advances. Um So I don't know if anybody else saw the bodies exhibit when it was going around in the early two thousands, I think a picture is worth 1000 words. And this picture I think truly is worth 1000 words. Uh There was maybe some controversy surrounding this exhibit, but I went and saw it in Saint Louis when it was there. I was an undergrad at the time kind of applying for medical schools and this in particular was really impactful to me. Um They created this mold of the vascular system by injecting resins into the blood vessels and creating this model. And I think about this on a regular basis when I'm taking care of my patients and we're gonna talk about today, kind of how we can really drill down to this level to process at this very complex and very tiny level when for the most part, it's not something that we're necessarily thinking about. Um But it's been increasingly being recognized for its importance and I think will continue to be pushed to the forefront as Joyce already kind of alluded to earlier today. Um And so that's, you know, I'll, I'll be talking about why that is. So what is the microcirculation? Well, it's the smallest subset of vessels that's responsible for providing oxygen and nutrient exchange to tissues. Its importance is being increasingly recognized for its role in maintaining perfusion and basically keeping organs functioning, feeding our organs in multiple shock states, micro circulatory dysfunction has been shown to predict mortality and in cardiogenic shock dysfunction has been shown to be a core component of organ failure. So I'm sure you've all seen the diagram in the top right corner at some point in the past kind of showing that spiral of death of myocardial ischemia and dysfunction and the spiral of death is kind of focusing more on the macro circulatory components of the vascular system. But we can create a similar cycle for factors leading to micro circulatory dysfunction as well. So in the bottom right hand corner, you see that we have cardiac dysfunction leading to poor forward flow, increased venus pressures, tissue edema. We have a systemic inflammatory response and basal dilation leading to micro circulatory collapse and poor tissue perfusion. Institution of mechanical support can improve our systemic perfusion can help prevent secondary organ failure and potentially reverse shock if we institute it early enough. Uh But there's a subset of patients where this shock persists and despite instituting mechanical support and restoring blood flow. Um And so, in the subset where abnormal perfusion persists, this portends a poor prognosis and then uh organ recovery is a no as possible. So we have to pause here for a moment. And as we've been talking about all day, just think about how we typically manage our patients in shock. And we talked about this earlier in one of our first sessions today. How we're really thinking more about pressure and less about perfusion wet treat our vasoactive medications to a map of 60. We target a mixed venus saturation of greater than 50-60% and we guide our management based on macro hemodynamics. But these are really surrogate markers for what we care about, which is cellular organ perfusion. So this is just an excerpt from up to date. And while I'll grant you all that up to date is not necessarily the end all be all of shock management. Uh The guidance that they provide under the ECMO section is here. So following cation patients are connected to the ECMO circuit, blood flow is increased until respiratory and hemodynamic parameters are satisfactory And reasonable targets include an arterial saturation, greater than 90 a venous saturation, 20-25% lower than arterial saturation and adequate tissue perfusion. As evidence, for example, by arterial blood pressure, uh our venous oxygen saturation and blood lactate levels. So the problem with this guidance again is that these are all surrogates for what's happening at the cellular level. And what's the big deal with using surrogates? Well, the big deal is that these macro surrogates don't really give us the whole picture. There's a phenomenon known as loss of human dynamic coherence, which is the terminology that we use to describe the disconnect or an uncoupling between the macro and the micro circulations. While the majority of our focus is really spent on correcting systemic human dynamics. Ever increasingly, we're realizing that this is only half the picture and that a high percentage of our patients may have ongoing derangements at the micro circulatory level. Despite normalization of these systemic human dynamics, just having a normal blood pressure doesn't tell us or guarantee us anything about what's really happening at the micro level. Um and persistent impairments in micro circulatory function may be due to an imbalance in the vasodilators and vasoconstrictor mediators, maybe due to endothelial dysfunction, tissue edema, perhaps microvascular thrombosis. But again, our macro does not predict the micro. So how do we really uh drill down and visualize the microcirculation? Well, there's a lot of different methods that have been looked at some of them indirect things like capillary, refill our lactate levels, urine output as a marker of organ perfusion. More direct methods include things like handheld video microscopy contrast and enhanced ultrasound. Uh neur infrared spectroscopy, laser Doppler perfusion imaging. Just to name a few of them looking at our indirect markers for the microcirculation. Uh This was a study done in a cardiogenic shock population using cap refill time as an indirect marker of perfusion. And they found that capillary refill time greater than three seconds correlated with 90 day mortality or a need for B A A with a hazard ratio. They found of 12.38. Also capillary refill time was poorly correlated with systemic hemodynamics. But what about our more direct measurements? Surely that gives us more information than our indirect measurements. Uh Well, one of the techniques that's commonly being used in a research setting is handheld video microscopy and is the type of technology that I've been looking at. And this is really an overarching term for using a magnified camera to look at the microcirculation. They use a green wavelength of light that's absorbed by hemoglobin. So we can produce a direct real time image of the moving microcirculation. Most commonly we measure this under the tongue. So it's a sublingual measurement which means that it's relatively non-invasive. It's just like taking a temperature under the tongue. Uh and videos can be quantified using software to give us measurable variables that can describe both vessel density and vessel flow or perfusion. So these are some of the terms that we use to describe these quantitative variables, things like perfused capillary, density or perfu vessel density and uh pro proportion of profused vessels. So this was a substu of the culprit shock trial which randomized patients with A Q M I complicated by cardiogenic shock and multivessel disease to either culprit lesion only or multivessel re vascularization. And in a subset of these patients, they used handheld video microscopy to measure sublingual microcirculation immediately post PC I. And then they correlated these measurements with a combined end point of death or severe renal dysfunction requiring renal replacement therapy at 30 days. Looking at their combined end point, there was a significant difference in outcomes for patients with decreased micro circulatory uh flow and density. Uh So these patients with micro circulatory dysfunction had worse outcomes. This difference by the way was driven by uh by death and not by renal failure. And in the figure on the right, they took that subset of patients that had normal systolic blood pressures greater than 90 and abnormal micro circulatory parameters again was generally associated with adverse outcomes. Our takeaways from this study are the following. So, cardiogenic shock involves perfusion abnormalities both at the macro and the micro circulatory levels. There's a significant association between micro circulatory parameters in cardiogenic shock and the end points of death and end organ failure. And importantly, micro circulatory parameters have a dominant prognostic value over our hemodynamics. So, what was happening at the micro circulatory level was really a better predictor of outcomes than the macro circulation. And this significantly calls into question our management of patients with pot invasive pressure medications like epinephrine. Um and this is particularly a poignant question in light of data, like a meta analysis showing a threefold increase in mortality associated with epinephrine in patients with cardiogenic shock. Other studies have also demonstrated the negative effect of vasopressors. So this was an animal study of cardiac arrest and they induced ventricular fibrillation for five minutes, then performed CPR for five minutes before de fibrillating and obtaining ROS. If you look at the graph on the right with initiation of V F, we have an acute drop in our microcircuit toy blood flow. We have partial restoration of blood flow with CPR and then improvement to almost near baseline uh with ROS. But in a subset of animals, they gave epinephrine during CPR. And you know, just as we would in line with our AC L S uh and patients that received epinephrine had a significant reduction in their micro micro circulatory blood flow which persisted into the period after ROS. So again, this is really calling into question our management of cardiogenic shock with potent bas pressors and inotropes. And so the next question becomes, what is the effect of mechanical support? Only a few studies have really looked at this question of looking at the sublingual microcirculation in a va ECMO population. A study of 24 patients on va ECMO for cardiogenic shock showed that despite no difference in hemodynamics at ECMO initiation perfused vessel density of the microcirculation was predictive of survival. This lends credence to the concept that success of resuscitation from circulatory shock is the normalization of the microcirculation and of tissue perfusion. Another study of 48 patients placed on B A ECMO for cardiogenic shock found that sublingual microcirculation 12 hours after initiation of ECMO was predictive of 28 day survival. Despite no difference in heart rate, math inotropic score or lactate and that the subgroup with the lowest micro circulatory parameters had comparatively worse survival. Another study, uh a small study of VA ECMO patients for cardiogenic shock uh showed that the inability to restore microcirculation during the 1st 24 hours of ACMA despite normal Hedy NAMS was associated with mortality. And finally, in an ECMO weaning study, sublingual microcirculation was a better predictor of successful ECMO weaning than ECMO parameters. So now the next question becomes, is this modifiable? Can we impact micro circulatory function with changes in ECMO management or with our management at all? This was a study published in 2021 looked at the effect of changing VA ECMO pump flows on sublingual microcirculation. They measured sublingual microcirculation before and after changing pump flows according to the treatment plan that was dictated by their E C O team And what they found was that there was a somewhat unpredictable response to changes in flows with increasing pump flows. 60% of patients had increases in their perfused vessel density, whereas 40% had a decrease. And similarly, when they were decreasing pump flows, 57% of patients had an increase in their perfused vessel density and 43% had a decrease. They did find that patients with low perfused vessel density to begin with had a much higher probability of improving um their perfused vessel density with increases in pump flows. But without measuring the microcirculation beforehand, certainly can't predict a micro circulatory response to changes in pump flows based on what the study found. Importantly, I think this really highlights the role for measuring the microcirculation before and after pump changes in order to really target optimal micro circulatory function. So where do we go from here? Well, we've already seen that we can impact micro circulatory function with ECMO titration. And similarly, we can have a negative impact on function with vasopressor therapy. Other therapeutics that are being investigated more closely are are vasodilators and nitric oxide donors. Uh the figure on the right is from a study of 20 patients with acute heart failure where nitroglycerin was given out a fixed dose. And after 15 minutes, they had a modest decrease in CVP and wedge pressure and they had an increase in perfused vessel density in the majority of their patients. And then after stopping the nitroglycerine, these parameters returned to baseline. So despite all the previous work that's been done, we're really still in the infancy of kind of understanding the microcirculation and how to harness it. Um It's generally accepted that the sublingual microcirculation is an acceptable surrogate for regional micro circulations. But we don't really have a truly good understanding of these relationships. So how does the sublingual microcirculation correlate with the brain or with the kidney? How does regional auto regulation factor into global micro circulatory function? And how does uh sublingual microcirculation compare to other methods of measurement? And what's the optimal method that can be incorporated as a routine bedside measurement or monitor? And finally, how can we direct our management to target the microcirculation and does modifying our treatments impact outcomes? So, just to summarize what we've learned is that by improving systemic human dynamics, we don't always cause an improvement in our micro circulatory perfusion because of this phenomenon known as loss of coherence. In fact, therapies aimed at treating the microcirculation may have no or even adverse effects on the microcirculation and in circumstances where loss of coherence exists when we have normal macro human dynamics. But abnormal microcirculation microvascular perfusion is really the predominant prognostic factor. Incorporation of our micro circulatory monitoring into management may help us to enhance risk stratification for patients with cardiogenic shock, may also help us to direct appropriate treatment with the ultimate goal of improving our outcomes Um but the optimal approach to achieving hemodynamic coherence and improving our micro circulatory function is really currently unknown. And finally, more studies are needed investigating what therapeutics can improve our micro circulation and whether these treatments are really effective at, at improving our survival.