Thank you so much for that introduction. My objectives for today are to go further into the importance of the microcirculation in sepsis, to identify methods of assessing the microcirculation, and to discuss the impact of fluids on the microcirculation in sepsis. I have no financial conflicts of interest to disclose. I will disclose that as a clinical pharmacist, I'm really not an expert in some of these methods that I'll be discussing, but my hope for today is that for anyone in the audience that may be less familiar with this topic, I can provide more of a basic overview for you. So the microcirculation represents about 10% of the circulating blood volume, and it includes arterioles, capillaries, and venules with diameters less than 20 micrometers. It's considered the final destination of the cardiovascular system, and is ultimately responsible for tissue perfusion and oxygen delivery. Microcirculation acts as a gatekeeper to tissue oxygenation, and therefore should be a priority during resuscitation. There have been numerous studies evaluating the impact of sepsis on the microcirculation, and together these really tell a story of why microcirculation is important in patients with sepsis. First, it's been demonstrated that microvascular alterations are present in patients with sepsis, and these include a decrease in total vascular density, a decrease in proportion of perfused capillaries, as well as heterogeneity between areas. It's also been demonstrated that the severity of microvascular alterations is associated with poor patient outcomes, including mortality. More so, survivors of sepsis have shown progressive improvement in their microcirculation, while non-survivors have failed to improve their microcirculation or even further deteriorate it. And this gives more evidence that there is this relationship between microcirculation and outcomes in sepsis. The response of the microcirculation to interventions, such as fluid administration, has been shown to be associated with the evolution of organ function. In one retrospective analysis, increased microcirculatory flow during the initial stages of resuscitation and septic shock was associated with improvement in SOFA score at 24 hours, while patients that did not have improvement in microcirculation did not improve their SOFA scores. So this gives us some evidence that the microcirculation can be manipulated by our clinical interventions and that that can improve outcomes. This is complicated, however, by the fact that alterations in microcirculation are not always related to systemic hemodynamics. And this really brings us to the concept of hemodynamic coherence, which we'll discuss next. So hemodynamic coherence is the theory that changes in the macrocirculation are reflective of changes in microcirculation. Our typical targets for resuscitation are macrocirculatory variables, but really what we're trying to do is to ensure tissue perfusion, and the microcirculation is ultimately largely responsible for that. A lack of hemodynamic occurs in states of shock, inflammation, and infection. And in these instances, targeting normalization of macrocirculatory variables is not effective in restoring tissue perfusion. So when this occurs, targeting our normal endpoints, like a map over 65, won't necessarily result in tissue oxygenation. Currently, there aren't really well-established methods for routinely and reliably assessing microcirculation at the bedside, but the methods that are available can be classified as indirect and direct techniques. The indirect techniques measure tissue oxygenation as a surrogate for microcirculation and include parameters like tissue partial pressure of oxygen and venous oxygen saturation. Microcirculation can be inferred by elevated lactate levels as an indicator of tissue hypoxia, but this really isn't an ideal marker of microcirculation since there's so many other factors that can result in elevated lactate as well. Inter-infrared spectroscopy is another method of indirectly measuring the microcirculation, and this is done through non-invasive continuous assessment of tissue oxygen saturation. Direct methods of assessing the microcirculation rely on highly sensitive video microscopes that use in vivo visualization of the microcirculation to allow for direct measurement of capillary density, perfusion, and flow dynamics. Until recently, video microscopic methods of assessing the microcirculation were really clinically inaccessible because of their large size, operator dependency, and the need for time-consuming offline analyses to generate data. Several handheld vital microscopes are now available on the market and allow for direct visualization of the microcirculation. The cytocam is pictured here. This is the third generation handheld vital microscope that uses incident dark field illumination as well as real-time automated analysis of digital images to visualize the microcirculation. These devices are typically used in the sublingual area because it's readily accessible, highly vascularized, and vessels are close to the skin. The sublingual microcirculation has also been shown to be closely correlated with organ dysfunction and mortality, making this a reasonable location for assessing the microcirculation. There have been some more recent studies that have evaluated whether the sublabial area may be preferred. And in instances when both the sublingual and sublabial areas are unavailable or inaccessible, for example, during non-invasive ventilation or with an uncooperative patient, then the conjunctival area could also be used. There are some limitations of handheld vital microscopes that should be noted. First, the evidence related to whether these are useful as diagnostic tools is still somewhat limited, and there's also a lack of data on what the normal values for these microcirculatory variables are. The effect of fluid on the microcirculation is variable based on the time point at which it's assessed as well as other patient-specific variables. But I'll give a kind of general overview of how fluids may impact the microcirculation. So giving intravenous fluids increases filling, which in turn increases flow in volume-responsive patients, and this results in increased pressure at capillaries, which in turn will increase microcirculatory perfusion. Giving fluids will also cause hemodilution, which results in decreased viscosity, which promotes flow. So this is desirable in the hemoconcentrated patient, but it also has the potential to decrease oxygen carriage in the microcirculation. Lastly, extravascular leakage of fluid increases tissue edema, which there in turn decreases vessel density, and this increased diffusion distance results in increased diffusion distance between red blood cells and the tissue, which can decrease the efficiency of oxygen delivery. The vast majority of studies assessing the impact of microcirculation or of using fluids to assess microcirculation are really observational, but I want to highlight one randomized controlled trial that was conducted in China and published in 2021. The study randomized 31 patients with septic shock to receive fluid resuscitation through point-of-care microcirculation, or the POM score, versus usual care. The POM score is a five-point ordinal scale of microcirculatory flow and heterogeneity that's derived from four video microscopy clips. A POM score of one indicates the worst microcirculatory dysfunction, whereas a score of five indicates the best function. In this study, a score of 3.5 was used as the resuscitation target because of previous literature indicating this was a good cutoff for sepsis prognosis. So in this study, patients that received POM score-based resuscitation received one liter less fluid on ICU days one and two. Macrovascular indices, including MAP, CBP, and cardiac output were essentially identical between both groups at 24, 48, and 72 hours. Organ function, on the other hand, was measured by Apache 2 score and SOFA score and was improved in patients that received the POM score-based resuscitation, particularly at 72 hours. This is a small study, and it has some limitations, but this is the first randomized controlled trial to show a benefit of microcirculation-directed fluid resuscitation on decreasing resuscitation volume while maintaining organ function without seeing any changes in macrovascular circulation. So I think this provides some really interesting evidence that perhaps microcirculation targets may be another important component of our resuscitation efforts. Tools to assess microcirculation at the bedside are definitely on the horizon. I think this should be a focused area of future research, but we're not quite ready for adopting these tools in all patients at the bedside for a number of reasons. First, interventions that consistently improve the microcirculation in most patients really are lacking, as a lot of the studies have shown great variability between patients. Also, target values for microcirculatory variables are not well-established and may be time-dependent, meaning that our goal at 24 hours may be different than our goal at 48 or 72 hours, and these just aren't well-established at this time. It's also unknown if our goal should be normalization versus improvement of the microcirculation. And while we do have new technologies that have allowed for bedside assessment, these aren't widely available in most practice sites at this time. So to conclude, microcirculation is the gatekeeper to tissue perfusion. It's known to be altered in sepsis and to be related to patient outcomes, and we also have some evidence that interventions we make can improve microcirculatory variables and also improve patient outcomes. There have been very significant technological advances in developing tools to enable us to assess microcirculation at the bedside, and I think there's great potential for this to become more common practice as we have more research defining our microcirculatory targets and also identifying interventions with a consistent benefit. So thank you all very much.

microcirculation

sepsis

assessment methods

organ function

patient outcomes