Hello, everyone. It's a pleasure to be here. Great preceding talks. I am going to be focusing on the use of beta blockers specifically in shock states and really try to ask that question, do we have the clinical data? Do we have the information to inform us to use these drugs in patients who are critically ill? As far as disclosures go, I don't have any disclosures, but I do have to say that as a critical care cardiologist, I do have an inherent subconscious bias to want to prescribe the beta blockers. So I just have to fight myself not to do it. The objectives are very clear. We're going to go through the clinical trial data, which there's not that much, but there are recent studies that have actually gleaned a little bit more in terms of what we should be doing. Now Brittany did an amazing job actually running down through the physiological rationale. So we've actually established good biological plausibility. This is despite the fact that it's very counterintuitive to think about using beta blockers in patients who are critically ill. But if we try to understand that spectrum, Ashish talked about how the initial stages of resuscitation and when we use too much catecholamines along with the native host adrenergic response may lead to organ dysfunction. But we're actually talking at the other end of the spectrum. So when you're de-resuscitating the patient, when the patient's getting better, all that adrenergic response is actually leading to what? Untoward effects. So why are we focused and obsessed with beta blockers? Well, the answer is very simple. It's because it works in other pathological states. Now when it comes to the hemodynamic effects of beta blockers, it's very clear. It decreases cardiac work. If you decrease cardiac work, you allow for normal conformational and structural changes of the heart. And the function improves over time. And we've seen this in states such as acute coronary syndrome. The AHA, ACC guidelines always recommends the use of beta blockers in patients who've had ACS. And sometimes in patients who've had lower EF, you'll actually use these beta blockers indefinitely. Similarly, we see patients who have heart failure with reduced ejection fraction. Incredible morbidity and mortality benefits in using beta blockers. And lastly, when it comes to atrial dysrhythmias, we know that the appearance of atrial fibrillation in itself is an independent bad prognostic sign in our critically ill patients. And using beta blockers may actually attenuate that atrial dyssynchrony that we see. But there's a big caveat here. If you look at all the guidelines and you look at the way we use the beta blockers, we always institute it in those patients who we think are fluid resuscitated, stable, hemodynamically stable, and do not have a high risk of developing shock. This is why beta blockers are usually started after the patients are off norepinephrine or any kind of vasopressor who don't have high inotrope needs, et cetera. So before we move on with the clinical trial data, we really have to contextualize what exactly it takes to actually look at these studies and try to interpret them for our patients clinically. As stated before, there are different types of beta blockers. You have beta blockers that are short acting. You have those that are long acting. You have those that affect beta 1 versus beta 2 at different affinity levels. Most of these studies are done in a wide variety of different ICU settings. They're done in different patient populations, all comers, patients with sepsis, septic shock who may be on vasopressors, post-op patients, post-cardiac surgery patients, and then burn, as well as patients with neurological catastrophes, and recently COVID-19 as well. We also have to understand the timing. As stated before, if you started too early when the patient is still in that phase where they're trying to save themselves, that beta blocker may lead to more worsening effects. Very interestingly enough, patients who've had previous exposure to beta blockers also plays a very big role. There's been studies that have shown that there is improved outcomes in those who were previously exposed to beta blockers, regardless of their exposure during their critical illness. And it's also important to try and understand whether we should continue these beta blockers or not. And then there's the confounding bias, obviously, with these trials is that those patients who are less sick, the healthier patients, the less comorbidities are the ones who are going to less likely, actually more likely, tolerate the beta blocker. So we have a multitude of different studies. I put a question mark here because if you actually look at these studies, even though there's approximately 20 randomized controlled trials, all of them spanning between the 1980s to now, it's actually a really small number when you look at the number of patients, small, non-blinded, single-center studies. All of these studies used a different slew of beta blockers at different time periods, propranolol, esmolol, the ultra short-acting IV beta blocker, carvatalol, metoprolol, and most recently, landilol. And as I stated before, you have a multitude of different pathological states, burns, cardiac surgery, trauma, ACS, and septic shock as well. So the question comes of whether these results are actually generalizable to our patients or not. And then obviously, the outcome measures are varied as well. Some of these studies just looking for a brief hemodynamic response. Others looking at abating dysrhythmias. And as stated, there are coagulation effects of beta blockers in some studies in the perioperative period, just looking at whether or not there's increased bleeding in these patients. Length of stay, cost, functional outcomes, all of this has been looked at. But bang for buck, what's most important for us is what? Mortality. This is what we do. We try to save lives. So show me the money. Is there a mortality benefit in these patients? So this is a systematic review meta-analysis of 11 studies that was done, published in 2022. You can see that when it comes to mortality, and this is long-term mortality, that's over 14 days, there is a signal that indicates that there is some benefit in the use of beta blockers. However, if you look really carefully in these studies, the plot thickens. The mortality period varied tremendously. Some of these studies just looked at a short, brief 12-hour period after starting the beta blocker, or even 24, 48-hour periods. Only a few of the studies looked at 26 or 30-day mortality, and then again, even fewer actually looked at 60-day mortality. If you look at the meta-analysis, the later studies that were done after the 2013 Morelli study that used Esmolol, a lot of the mortality is heavily weighted on these later studies. And then you have to really start to think about ICU care has really changed since the 1980s into now. There's a lot of stuff that we do, adjuncts that we do, when it comes to sedation and trying to blunt or attenuate this sympathetic surge. These things we didn't do in the 80s, and we do more nowadays. Interestingly enough, this is something that's gained a lot of notoriety is the fact that that Morelli study in 2013 that used Esmolol in septic shock patients, if you look at the control, there was an 80.5% mortality in control patients. Obviously that is an extremely high number. Now also interestingly enough, in the study by Kakihana in 2020, one of the added benefits of using the beta blocker was the fact that we actually decreased what new onset dysrhythmias. And we know that atrial fibrillation is a independent bad prognostic sign in all patients who are critically ill. Another interesting thing is those studies that showed those mortality benefit actually use what's known as a targeted treatment effect. They gave the beta blocker, and they ensured that the beta blocker led to a decrease in the heart rate. And when your heart rate was less than 95 is when we started to see that benefit in decreasing new onset dysrhythmia, as well as an improved mortality as well. So we are still obsessed with beta blockers. And recently in 2021, beta blockers were repurposed for no other than COVID-19. And this study showed very clearly that it attenuated inflammatory markers. A BAL was done before and after, and it was clear that inflammation had decreased. The clinical relevant outcome was that it showed that there was decreased mechanical ventilation days, decreased PF ratios with patients who were given beta blockers. This brings us to the most recent study published in 2023. This is a STRESS-L randomized clinical trial. This is where they tested the efficacy and safety of Landolol. This is the one that has the greatest affinity to beta 1 receptors. In patients who had septic shock, the criteria was that they had to be on norepinephrine for at least more than 24 hours. They had to have a heart rate greater than 95. It was a multicenter study over 40 different ICUs in the United Kingdom. Unfortunately, it was prematurely stopped due to concern for harm. The mortality at day 28 for patients exposed to Landolol was 37% versus 25%. Mortality at day 90, which is well beyond that critical illness period, also was maintained for about 43% versus 28%. And we saw higher adverse events in the Landolol group. And this was specifically the hemodynamic effects that you would expect in using beta blockers in patients who are on norepinephrine, which is increased hypotension, greater lactate, greater SOFA scores, and more norepinephrine requirements. So the question is, why did it fail? There's a great accompanying editorial by Steven Hollenberg that really touches and illustrates the reasons possibly why this happened. And one of them is the early use of beta blockers. We know from our experience with patients who have cardiogenic shock, or ACS, who are developing cardiogenic shock, that early institution of beta blocker can lead to cardiogenic shock or worsening organ dysfunction. Secondly, there wasn't a very stringent algorithm to look at patients and their echocardiographic findings. So oftentimes, potentially, these patients who were started on the beta blocker had some undiagnosed septic cardiomyopathy or some form of pump failure. And as we know, starting a beta blocker in a patient with pump failure will probably lead to demise. Another point that was brought up is the fact that there wasn't as much cardiac monitoring, either with Swann-Gans catheters or ECHOs. And so the titration of these medications were actually done in terms of the heart rate and tolerability from a hemodynamic standpoint. And lastly, you chalk it up to the complex interplates, the multiple systems that the beta blocker actually affects. So do we have any guidelines about instituting beta blockers in critically ill patients? We have very little guidelines. There is a recent one, I think, published in 2023 from the Italian Society of Anesthesiology. They use a lot of logic and practical advice. Persistent tachycardia is something beta blockers should not be started until you rule out other causes, specifically things that cause a decrease in your stroke volume. You have to rule out things like anemia and hypovolemia, endocrinopathies, et cetera. One important thing is that if you have a patient who you think will tolerate the beta blocker and has a very good concomitant indication for the beta blocker, this may be a good reason to start it. It's also advised in critically ill patients. Use IV drugs that have a short duration of action. Go slow and monitor your patients very closely. So the question is then, what do we do? What do we do after we leave this place? Do we start the beta blocker on the patient? Who are the patients who will benefit from it? So I'm going to say this again. Not all patients are created alike. What we do know for sure is indiscriminate use of beta blockers in patients while they're still in shock is detrimental. The biggest issue is that these clinical trials to date do not sufficiently phenotype or create patient subsets that may benefit from beta blockade. And what do I mean by that? For number one, a lot of these patients who may not have responded to the beta blocker may have had inadequate fluid resuscitation. They may have had conditions which led to decreased stroke volume. And you know when you add a beta blocker in these patients, they will not do well. You have to rule out other secondary causes which may have not be addressed in a clinical trial that is just focused on a beta blocker versus a placebo. And then what I mentioned previously is that you always have to look at your patient's heart function. Is there signs of septic cardiomyopathy or pump failure that may preclude the use of the beta blocker? When phenotyping patients, it's also important to understand most of these beta blocker studies and large databases of septic shock never truly distinguish your patients. A patient who has severe diastolic dysfunction, for example, may not tolerate faster heart rates and can benefit from beta blockers. Not only that, they actually require the slower heart rates in order to increase diastolic filling time. And atrial dysrhythmias, especially like AFib, are not tolerated because you lose your atrial kick. These are stuff that are not accounted for during clinical trials. And these are stuff that we need to look at at the bedside. And we need to cater to the patient. Valvular heart disease, very similar. Patients with stenotic aortic valves also have LVH, also have some form of diastolic dysfunction, and may also benefit from slower heart rates. Left ventricular outflow tract obstruction is something, especially the dynamic variety, I think is criminally underdiagnosed in ICUs. In one study, about 5% to 10% incidence in an open ICU. These are MICU patients who do not have previous cardiac comorbidities. Again, very underdiagnosed. But not only that, a lot of patients who do not carry a diagnosis of hypertrophic cardiomyopathy or have septal hypertrophy, the first time they actually present is sometimes with a diagnosis of what? Of outflow tract obstruction. And so if you're not looking for it, you'll never find it. So conclusions, do beta blockers work in shock? So you guys need to be ready for my definitive statement here, perhaps, but for specific patients. It should never be used indiscriminately. Careful, thoughtful approach, that's what an intensivist needs to do, to pinpoint patients who would actually benefit. I think the jury is still out. And we still need larger randomized controlled trials for beta blockers in the critically ill. Specifically, we need to start phenotyping from a hemodynamic, immunological, and echocardiographic standpoint. We need more studies that will delineate timing, duration, of course, the choice of beta blocker, patient selection, as we mentioned, and finally, optimal hemodynamic targets. Thank you.

beta blockers

critically ill patients

shock states

STRESS-L trial

patient phenotyping