Thank you, Steve, and good morning, everyone. Last day of Congress and we're still coming in and it's nearly full house, so I'm excited. I'm going to, I know this panel is about flipping the script and focused on beta blockers, but I'm going to start with what we normally do, catecholamines, and then that'll sort of set the stage for the rest of the speakers. Affiliations and relevant disclosures right here. So, a very basic slide. All of you know this surviving sepsis campaign. This is what we do. We give some fluids if we have hypotension. Then we start with our favorite drug, norepinephrine. Then we add vasopressin or more epinephrine. And then, you know, if we have a pump failure, we look at the butamine. And again, very simplistic way of saying the same thing. Fill the tank, still can't get to that MAP of 65. Decrease the capacity of the tank or increase the pump speed. Now, we all know hypotension is bad. That's why we're trying to fix shock with vasopressors traditionally. This is some of our published work, retrospective data in septic shock patients that did show that every one unit increase in time-weighted average MAP less than a MAP of 65 substantially increased the risk of both myocardial injury and acute kidney injury. This is not new news for you guys. We are trying to focus on hypotension and get to that elusive MAP of 65. When we try and defend a MAP in the ICU, it is broadly a very common sense approach. But if you look at the early phase of shock that I've highlighted on this slide, that is really where we're trying to identify, treat the cause of shock, give some fluids, and that's where norepinephrine monotherapy usually comes in. Now, norepinephrine monotherapy is all good, but we do know that there is counter-regulatory balance to how we maintain the vascular tone and or blood pressure in shock states. And ideally, we should have all three legs of this tool, the sympathetic nervous system, the arginine vasopressin, and the RAS system all activated to maintain blood pressure. The other issue is the issue around blood pressure versus vasopressor. So this is conceptual work that I'm still looking at. And the idea here is to look at the effect on mortality of average vasopressor rate and lowest MAP for at least two hours in a critically ill patient in the ICU. And what we've seen and what we all sort of know is that if you try to get to a higher MAP here on the x-axis and you have a vasopressor going along, you will see that we start going to a spot here where you're getting to a higher MAP with the same dose of vasopressor, but your co-exposure effects on mortality, the lighter shades are higher co-exposure effects on mortality, start increasing. Same with on the other panel here, if you're having to escalate vasopressors rapidly to get to the same MAP, then co-exposure effects on mortality are high. So try to get to a higher MAP, but do it with more vasopressors, your patients are more likely to die. More to follow, but we need to find that sweet spot for our patients. Going back to our favorite drugs we use to manage shock, the issue that my good friend Patrick Wierzefsky and I have highlighted in some of our reviews is that high dose catecholamine monotherapy is bad. As you get to about 0.5 to one microgram per kilo per minute, the overall death rate or association with poor outcomes increases. Most of these are retrospective large data sets, but the signal is very, very strong. And these are some sort of seminal papers, I'd say I quote this one a lot, this is Sam Brown's work 10 years ago now, published in Chest, where he did show that exposure to high dose vasopressors, upwards of about one microgram per kilo per minute, increased 30 day and 90 day all cause mortality substantially. And again, those patients who survived also probably had morbidity such as this. More recently, Siddharth Dugar, myself and others looked at the first 24 hours of ICU stay and exposure to maximum norepinephrine equivalents. And we saw the same signal here. If you get to more than 0.5 micrograms per kilo per minute of norepinephrine equivalents in hospital mortality is upwards of about 50%. So again, you'll say, oh, okay, all of this is, there's a lot of confounding here. Patients who need a lot of norepinephrine are the ones who are sicker and they're going to die in any case, but the signal seems pretty strong. And the other problem is this, the infamous stress induced cardiomyopathy. I learned recently that the name Takotsubu comes from a Japanese octopus trap and that's how the heart looks like. And that is what we're doing to our patients with catecholamine monotherapy. So the other two speakers are here to talk to you about why we should not use catecholamines or why we should probably use beta blockers. Well, one issue is that noradrenaline drives immunosuppression in sepsis. And I would refer you to this excellent work published in Intensive Care Medicine. It does decrease expression of HLA-DR and then TNF-alpha IL-10 ratios. And the issue that the authors highlight and offer as potential solutions is what we're going to now talk about should we look at alternative vasopressors and or should we look at beta blockers? So what about alternative vasopressors? Well, Patrick and I again published this review about two years ago and I say this and I say this generally when I'm rounding in the ICU, vasopressors work well together. It's a simple statement, vasopressors work well together. And this is the reason they do that because as all of you, you and I sit in the audience, we have ongoing counter-regulatory mechanisms where our bodies are secreting hormones that are maintaining our blood pressures and they work well together. Our patients get sick in the ICU, we just focus on the adrenal medulla, which is unfair and I'll show you why. So we have been advocating for a while now for a more early multimodal vasopressor approach and a synergistic approach. It is almost synonymous with early broad-spectrum antibiotics for patients with sepsis, although it seems very, very disruptive to our usual thought process of we'll do norepinephrine, more norepinephrine, then two days later we'll do vasopressin. So think about it, are we ready for it? One of my colleagues and collaborators used to say this and I stole this from him. We never give 80 grams of metoprolol as a single agent to treat hypertension. Then why do we give 100 micrograms per minute of norepinephrine to treat hypotension? Think about it and maybe this will help you modify your practice. So let's talk about alternative vasopressors real quick. Early vasopressin is really, really important. Gretchen Sasha and colleagues from the Cleveland Clinic published this really important paper in critical care medicine. They looked at the timing of initiation of vasopressin in patients with shock and looked at it in terms of predicted probability of in-hospital mortality. And here on the x-axis is different lactate levels and different times that vasopressin was initiated. And the earlier it was initiated, the better it was in terms of in-hospital mortality. Here is the more obvious and clear statement with this paper. Mortality increased about 20% for every 10 micrograms per minute of a delay in initiation of vasopressin. So 10 micrograms per minute of norepinephrine and for every 10 micrograms per minute, you delay initiation of vasopressin, mortality increased by 20%. It's retrospective and again, you'll say there's a lot of confounding. And as I told Gretchen, I was the infamous reviewer number two for this paper. But I think we're definitely showing that we should think about early multimodal vasopressors. Some years ago, we published this, the ATOS-3 trial, angiotensin II in high-output shock. You all know this. We showed hemodynamic benefit of ANGDU. We also showed catecholamine unloading. And that for me was a very strong outcome that isn't talked about too much with this trial. People focus on, oh yes, you got to a blood pressure. That's okay, that's no big deal. The real big deal was that ANGDU was able to unload catecholamine monotherapy or background vasopressors. The other big deal was we saw that patients who got angiotensin II had an appreciable drop in this thing called renin. Renin, a really important biomarker in the evolution of bad things in septic shock. And then in the days to follow, we did a post-hoc analysis where we did see, if you follow the bright red solid line here, in the ATOS-3 population, patients who had renin above population median and were given exogenous ANGDU, they had a survival benefit, a pretty significant survival benefit compared to those who did not. So how does all of this sort of fit into what I'm trying to say? Well, more recently, the famous VICTORS trial, you know, vitamin C, thiamine, and steroids, we again looked at a set of biomarkers there and we saw the same signal. We again saw that high renin within the VICTORS population of septic shock was associated with poor outcomes as you got to that renin level of about 182 picograms per ml or higher. There was near linear increase in the hazards of mortality. So alternative vasopressors combined with biomarkers might be the way to the future. Finally, again, I talked about early vasopressin, same deal with early angiotensin II. In patients within the ATOS-3 group, when we initiated ANGDU early, that's at less than 0.25 micrograms per kilo per minute of norepinephrine equivalent, we had a survival benefit compared to those where we initiated ANGDU late. So final few slides. What do the latest surviving sepsis campaign guidelines say? Well, we're finally getting to a point that we're starting to talk about earlier initiation of alternative vasopressors. So here the remark is that in our practice, vasopressin is usually initiated at about 0.25 micrograms per kilo per minute of norepinephrine. And then we're still trying to work on the early multimodal vasopressor strategy. We published this review. We found out that there's not many large randomized trials. In fact, most trials are small pilot trials of early multimodal vasopressor therapy. They have shown some benefit, but we definitely need to do a larger trial. And again, we published our suggestions with identified gaps around the surviving sepsis campaign guidelines. I'm leaving this up for you guys to read, and I'll be happy to answer questions around it afterwards. And then with the group in Italy, we're planning to follow this meta-analysis with an updated meta-analysis very soon, where we are looking at non-adrenergic vasopressors and their benefits in vasodilatory shock. This one did show very slight benefit. I won't really say that this is anything appreciable right here. Final comments, less is more. And the three things I'd like you to take away here is early multimodal vasopressor therapy works. So don't delay it till three days later when your patient has a lactate of 10 and a bicarb of five. More reliance and work around targeted biomarkers. So decide, choose a vasopressor based on a biomarker, and do not forget adjuncts. I didn't have time to talk about it. We'll now flip to beta blockers, but my final shameless plug is for what we released yesterday. Speaker to follow, Brittany Bissell, and others in this audience, Patrick Wieroszewski and the ESICM group. If you're thinking about norepinephrine, please do read our work. It'll help you understand why all of this is so important. Thank you for your time today. Thank you.

septic shock

vasopressors

catecholamines

multimodal therapy

biomarkers