Hi, everyone. Thank you for being here. So, thank you for the introduction. My name is Brittany. The next speaker is going to talk about the clinical evidence surrounding beta blockade in sepsis. I, myself, am going to focus on the physiologic rationale and our mechanisms of action as a true pharmacist would. I do want to make a couple of disclaimers about my personal opinions and thoughts on this matter, the first of which, yesterday, I hope everyone has had the chance to listen to the updated Surviving Sepsis Campaign Research Priorities, or has been able to read that paper, if you have. You probably noticed that that has a lot of implications for our topic today. There's a lot of conversations around personalized medications or personalized precision medicine for specific patients. I think that really has a lot of interplay with our topic here, as well as some of the questions still surrounding hemodynamic management and et cetera. I also want to mention that I think this topic, like a lot of topics in critical care medicine, in some ways we've oversimplified. There are a lot of potential areas where beta blockade may come into play, but there are also a lot of considerations around beta blocker use. There are a lot of things that impact how a beta blocker may work, depending on the underlying patient. So, past medical history, underlying catecholamine exposure, whether endogenous or exogenous, other comorbidities or active medical issues at the time, renal function, hepatic function, things of that nature. What I'm going to focus on today is specifically, one, our mechanisms that we're targeting and how this varies on the basis of beta receptor. So predominantly focused on beta 1 and beta 2 receptors and what that looks like physiologically or what we think that it looks like physiologically. So personally, nothing to disclose financially or personally as it pertains to the topic. And again, my key objective is really just to work through the rationale in which beta blockade is potentially useful in patients presenting to our intensive care units with septic shock. So as a brief review, probably nothing novel to anyone in this room, the autonomic nervous system is composed of both our sympathetic and parasympathetic. However, we focus all of our attention on the sympathetic nervous system given its role in the fight or flight and the potential implications in septic shock. Our primary neurotransmitter of interest is norepinephrine. And while this has a lot of physiologic benefit for us and patients presenting in septic shock, there are potentials for dysfunction. And this is mediated through, yes, our adrenergic receptors, but also a number of other potential mechanisms as well. So we're going to focus in on our adrenergic receptors, and even more specifically, beta blocker or beta receptors and the potential for beta blockers and mediating this. However, there's a number of different factors at play here and a number of different therapeutic approaches. So looking at the sympathetic nervous system, I'm going to focus in on three key areas where the sympathetic nervous system may come into play or target areas of modulation. And so the first of which being metabolic dysfunction, also looking at thrombogenicity in patients presenting with septic shock, cardiomyopathy, which is probably our most well-known area of therapeutic modulation, at least in regards to this specific agent or agents of choice, and then immunosuppression, as kind of alluded to in Dr. Kahnen's presentation right before mine. So when talking about beta blockade pharmacology, again, just reminding ourselves of the basics, beta blockers work via competitive catecholamine inhibition. And most of our beta receptors focus predominantly as G-protein coupled receptors, which results in an increase in intracellular cyclic AMP. Now again, this is a bit of an oversimplification. Some of the beta receptors have slightly different mechanisms, but by and large, that's really our predominant mechanism of action when we talk about our beta receptors. There's three or four key beta receptors, depending on where you fall in that discussion. Both beta receptors being the most prevalent, so 75% of our beta receptors in the body within that cardiac tissue, as well as elsewhere. Beta-2 receptors we often think through or think of for our vascular and smooth or bronchial smooth muscle tone. And then beta-3 receptors that have a role in fatty acid metabolism, and definitely not the most prevalent beta receptor that we see. There is a beta-4 receptor. Some call it a subphenotype of beta-1 receptor. Definitely not worth discussion today, but nonetheless, three or four key beta receptors, and we're going to focus on both beta-1 and beta-2 for the rest of our discussion today. Looking left to right on the graph pictured here, I've honed in specifically on beta-1 versus beta-2 affinity and the selectivity of our beta blockers that we see in practice. This is not all exhaustive, but it is a few of our key beta blockers that we reach for at bedside, both inpatient and outpatient. So by and large, Landiolol is our most selective beta blocker for beta-1 action, followed, as you see here, as you move to the right, with more beta-2 activity. We tend to think of Landiolol, Nebivalol, Esmolol as more of our selective beta-1 agents. However, there is potential, as you move across this graph, to have more and more beta-2 activity as you continue to escalate your doses. Again, this is affected by a lot of other things. It's chronic exposure to noradrenaline or beta blockade and et cetera. But again, for today's purposes, we're going to focus in on just this. I think it's important to note there are many other mechanisms in some of these drugs that will influence hemodynamics or other considerations. For example, Nebivalol has potential to increase nitric oxide, which can actually cause basodilatory responses. But nonetheless, focusing in on beta-1 and beta-2 affinity, this is what we see. So I'm going to talk a little bit about catecholamine pathophysiology and potential adverse effects of catecholamines. And then we'll talk about where our beta blockers then fit in to circumvent or overcome this potential maladaptation or pathophysiologic effects. So again, as briefly introduced by Dr. Khanna just a few minutes ago, we do see a number of immunologic effects of catecholamines. We see a selective inhibition of our T helper-1 cells, so our cellular immunity response based on beta receptor location, which I'll talk about further here in a minute. We tend to generally see, just looking at face value, an upregulation of our anti-inflammatory cytokines and downregulation of pro-inflammatory cytokines and decreased natural killer cell cytotoxicity with some other alterations in immune cells as well. Now this wanes over time with catecholamines having a more intense effect early on. But with more long-term catecholamine exposure, you see less and less immunologic effects. Sepsis and myocardial dysfunction is fairly well-defined, so I'm not going to spend a ton of time on it. But as we all know, at least over 50% of our patients do have a decrease in left ventricular ejection fraction during the throes of sepsis. And this goes all the way down to the mitochondrial level, with evidence demonstrating mitochondrial dysfunction in cardiac tissue as well. Looking specifically at beta receptors and the interplay there, we do know that there is an attenuation of cardiac beta receptors based on the downregulation. One of these receptors, but also with beta receptor uncoupling that has been demonstrated in patients presenting with sepsis. Last but not least, both coagulopathy and metabolic disturbances that can occur in sepsis. These are probably the less evidenced considerations from a beta blocker standpoint, but I still think it's pertinent to call both of these out as we talk about discussion of these agents in this patient population. Of course, sepsis has a known catabolic response that we all, for the most part, find to be adaptive until you hit a certain threshold that becomes potentially maladaptive. We have an increase in arresting energy expenditure, a negative nitrogen balance, fat, protein catabolism, mixed hyperglycemia in a number of different ways. So a lot of metabolic changes that are seen in sepsis within the early throes, as well as late sepsis as well. Looking at coagulation, we know that these patients tend to be more pro-coagulopathic, and so they tend to be more pro-thrombotic, with the worst case scenario being our disseminated intravascular coagulation that we see in some of our severest patients that present. What we see from potentially the catecholamine side is an inhibition of fibrinolysis, as well as increase of our modifiers of coagulation and overall activation of coagulation. So I really liked this graph from Dr. Carr and colleagues, and this actually, if you are pulling up this paper, you'll see a number of different receptors. They even talk about the potential effects of specifically alpha receptors in the different locations and therapeutic modalities in which they impact. But honing in on the beta receptors, really, my takeaway point from this slide here is that you do see some similar effects across the beta receptors physiologically, but there's also potential differences in your immunologic, hemodynamic, and other therapeutic areas that differ on the basis of beta 1 versus beta 2 targeting. And so that's important to think about when we're talking about administering beta blockers in this patient population and how we're looking at these agents comparatively. So as I stated earlier, now to kind of go back to each one of these therapeutic areas and talk about where beta blockade may or may not be beneficial, starting with the immune system, any immunologist in the room will probably tell us that, again, we do oversimplify this in a lot of ways, and I think we have a lot of, really, research to be done as far as our immune response and sepsis and what this looks like on a personalized and precision medicine basis. But beta receptors are present on almost all of our lymphoid cells, and so there's the potential for modulation of our immune response on the basis of either beta 1 or beta 2 blockade. Now, while a lot of these cells contain beta receptors, the density varies, the responsiveness of these cells varies based on whichever cell you're discussing. So a lot of complexities, again, talk about three, probably talk about this for three or four hours, but we'll leave it simple for now. Monocyte differentiation and production and maturation is affected by your beta 2 receptors, and you also see apoptosis of immune cells that can be influenced by some of our beta receptors. Now, alpha receptors are also very important here, so when you start talking about our beta blockers and the administration of beta blockers in sepsis, there is the potential, especially since alpha receptors tend to be very pro-apoptotic, that administering beta blockade would then allow for unopposed alpha stimulation in certain populations. Hemodynamic rationale, there's been a lot of preclinical murine and other animal studies that have looked at the potential benefit in beta blockers, and I won't go through all of these different studies with you this time, but I will give a brief summary in that beta 1 blockade tends to show improvements in our diastolic function and that overall oxygen extraction and consumption. Beta 2 stimulation, alternatively, has shown to decrease myocardial apoptosis, so not necessarily seeing the same benefits with beta 2 blockade that you would see specifically with beta 1, as expected. Again, pulling back into our coagulopathies and metabolic disturbances, beta 2 signaling has shown to impact protein and lipid catabolism. Epinephrine, for example, has shown to increase insulin resistance, an effect not seen with norepinephrine, for example, so again, keeping in mind our other drug exposures when we're talking about implementation of beta blockers in specific patient populations, and again, varied responses when it comes to glucose production from a hepatic standpoint. Looking at coagulation, again, alpha receptors have a big role here, so not something we're necessarily discussing today, but the beta blockade or potential for beta blockade may allow for, again, unopposed alpha receptor triggering, which can increase platelet aggregability. Now, there's a number of other effects, potentially, of beta 1 and beta 2, both on immune signaling that comes from our coagulation cascade, as well as the actual coagulation factors themselves. So, to summarize it all, I know that's quite a lot, looking at the difference between beta 1 and beta 2 receptors, and what we kind of expect to see, if we hypothesize what an ideal world we're looking at, if we had the most clear-cut picture, beta 1 blockade is probably what we're thinking of to be most beneficial in our patients that are presenting with sepsis. It's a cardioprotective, metabolically neutral, and may actually help with coagulopathies that we see in these patients. Beta 2, of course, is really different or almost opposite in a lot of ways than we would see with beta 1. However, I have to say that, again, particularly with the immune system, there's a lot of considerations here, and I think this is probably much more personalized and patient-dependent than we know of at this time. In the preclinical data that we have, looking at beta 2, well, I should probably say non-selective beta blockers, such as propranolol, compared to what we tend to think of as more selective agents that are listed in the orange here, we do see what we kind of hypothesize for these different therapeutic modalities, we do see that tend to play out. Again, the one area where this, I think, tends to be a little less clear-cut is when we talk about immunomodulation, and what has been seen in our preclinical and early human studies, as far as what our cytokines and our phenotypes look like after the administration of blockade. Nonetheless, I'll focus down on the bottom half with our more selective beta 1 agents demonstrating improvements in myocardial function, oxygen consumption, and et cetera. So in conclusion, when thinking through all of this and thinking through our physiologic approach, hopefully everyone at least takes away, I think there's a lot of complexities here and we have a lot really still left to learn, even despite some new clinical evidence. Beta receptors are important in a lot of different organ homeostatic processes, but specifically hemodynamics as most of us are aware. Our preclinical models do demonstrate an impact on a number of different physiologic outcomes, but what these effects are varies a lot based on the patient, the drug, the underlying receptors, and a lot of other factors. So that's it for me. Thank you everyone for your time. Thank you.

beta blockers

sepsis treatment

adrenergic receptors

catecholamine pathophysiology

personalized medicine