So thank you so much for the kind introduction, and thank you all for joining us this morning. So to disclose, I previously served as a consultant for La Jolla. This was terminated a couple years ago. Today's objectives are to discuss emerging concepts in multimodal vasopressor approaches and examine evidence of the role of angiotensin II as a clinical vasopressor. And so the Surviving Sepsis Campaign puts forth recommendations in contemporary clinical practice for the provision of vasopressors to correct hypotension and septic shock. And in their most recent edition in 2021, they put the highlights here. They recommend using norepinephrine as a first-line agent. This is a strong recommendation. And the following two recommendations are if patients receive norepinephrine with insufficient mean arterial pressure, they suggest adding vasopressin, and after that, suggest adding epinephrine. We'd like to note that these last two recommendations are weak recommendations, and the specific details regarding how and when to use other agents beyond these in relation to norepinephrine are vague and widely contested in the literature. And so how do clinicians decide? Well, this is a survey of nearly 1,000 clinicians from over 80 countries. And one of the questions that was asked to respondents was, when a patient does not respond to your current vasopressor strategy, what is your main reason for adding another vasopressor to the current therapy? And you can see here that the answers are mixed, and there's almost an equal distribution amongst all the possibilities, including wanting a synergistic effect between two mechanisms of action, maybe a predefined maximum dose was achieved, increases of previous doses were ineffective, or wanting an independent mechanism of action than the current one. And so conceptually, this leaves us in an environment that might look something like this, where we have a heterogeneous patient population of distributive shock, we administer a first-line vasopressor, a portion of these patients might respond to this vasopressor just fine, but a portion of these patients might not. And then at some arbitrary time point, we decide to give a secondary agent from which, again, there's responders, and then there might be non-responders, and then a third agent, and so on and so forth. But the problem is, during this entire time, vasopressor doses are being escalated because there's inability to achieve hemodynamic targets, and so you have a prolonged state, or incremental accumulation of time of hypotension and hypoperfusion. And as doses continue to increase, you begin to ensue adverse drug effects from vasopressors, you have decreased responsiveness, and progressive multiple organ failure. And such a stepwise approach might encourage the progression to refractory shock, and refractory shock is really the endpoint of treatment failure, and there's additional mechanisms at play here in refractory shock, such as compromised microcircuitry flow, membrane hyperpolarization, and dysregulated mitochondrial respiration. And all of this contributes to unresponsiveness to vasopressors, and ultimately a state where cardiovascular collapse is imminent. I'd like to take a step back and consider that the blood pressure regulation in non-pathologic normal conditions is multifactorial. We of course have the sympathetic nervous system with catecholamines, the pituitary vasopressin access, and also the renin-angiotensin access beyond these first two considered, in contemporary practice, first and second line agents. And although there are excellent examples of angiotensin II being used as a vasopressor dating back to the 1960s, it was really until the ATHOS Dose Finding Study pilot trial and the ATHOS III Phase III clinical trial that reestablished angiotensin as a vasopressor in contemporary practice. And the ATHOS III clinical trial shown here demonstrated that in patients with high output vasopressor refractory shock, angiotensin II more effectively restored hemodynamics than continued escalation of standard of care vasopressors. And following the approval of angiotensin II in the United States, several observational post-marketing studies sought to understand the clinical application of this vasopressor. This cohort study of 270 patients across five academic centers found that it was quite interesting that the application in which angiotensin was used in the real world setting was quite different than in Phase III. These patients were severely ill. They had a predicted baseline mortality of approximately 80 percent. They were already receiving two or three vasopressors at a vasopressor dose that was three times that of the enrollment criteria for the Phase III trial. But nonetheless, despite the severity of illness, about two-thirds of them had a positive hemodynamic response to angiotensin II. And in the multivariable model, you can see here that lower lactate concentrations and concomitant administration of vasopressin were predictive of a positive hemodynamic response. And these responders, again, the survival curve on the right-hand side is all recipients of angiotensin II. And so those that had a positive response were two-fold likely to survive at 30 days. Another similar study of similar severity of illness of 162 patients reported similar hemodynamic effects. And interestingly, they found that there was a greater vasopressor sparing effect when the baseline vasopressor dose was lower at the time angiotensin II was added. And this was true for patients that had less than 0.3 mics per kilo per minute of vasopressor, but it was more profound for patients that were even lower at 0.2 or less when angiotensin II was added. In the ATHOS clinical trial, 0.2 mics per kilo per minute was an enrollment criterion. And in a post-hoc analysis, there were about one-third of the patients in the study sample that had a dose of 0.25 or less at the time the study drug was given. And you can see on the left-hand side, these patients with lower vasopressor doses before they received angiotensin II had far better survival than those who had continued escalation of standard of care. And in those with higher vasopressor doses, perhaps more refractory shock, there was no difference in their survival. Now there might be a suggestion here that there's a subset of patients that have a profound response to angiotensin II. And in fact, there was about half the patients who received angiotensin II in the phase three trial were hyper-responsive. They required a reduction in their angiotensin II dose at just 30 minutes because of the profound response on hemodynamics. And these patients were not only more likely to achieve a satisfactory map and the primary hemodynamic endpoint, but they also had better survival than those who were not classified as hyper-responders. Some insight might be able to be gained from their endogenous physiologic disturbances. Patients with lower baseline angiotensin II concentrations, these are endogenous concentrations before study drug, were more likely to be map responders and achieve the primary hemodynamic endpoint if they were classified as this hyper-responsive subset. And interestingly, at the trial level, low angiotensin II concentrations at baseline were not uncommon. And in fact, the angiotensin I concentration was three times that of the angiotensin II concentration before any study drug in the entire study sample. And so this produces a ratio of imbalance between angiotensin I and II. And this is important because healthy volunteers have tenfold less imbalance than these patients with refractory shock. And this imbalance might be served as a prognosticator for survival. This is a plot of all the persons enrolled in the ATHOS-3 clinical trial data, regardless of what intervention they received. If they had an imbalance in angiotensin I to II at baseline that was greater than the study median, they had far less survival than those who did not have an imbalance. Again, these are all comers, regardless of the intervention that they received in the trial. And this imbalance might be able to be rationalized by the inability to convert angiotensin I to II by the angiotensin converting enzyme. And in fact, when the angiotensin I to II ratio increases or this imbalance gets more disturbed, the renin concentration increases. And specifically, with the study sample in ATHOS-3, those above the study median of renin of 173, you can see that the imbalance in this ratio is three times that of those with low renin. And these patients with low renin, they essentially have similar survival in the trial, regardless of their intervention. However, amongst the patients with high renin shock, these are, again, renin concentrations collected before any study drug was administered. This is a high output refractory shock. These patients that received angiotensin II that had high renin shock had better survival than those had continued escalation of norepinephrine or whatever other standard of care vasopressor they were receiving. And high renin shock is something that has been described by many. On the left-hand side is a really elegant analysis from the Victish trial investigators published recently. If you recall, the Victish trial was a randomized trial studying hydrocortisone, ascorbic acid, and thiamine. And patients with sepsis, the outcome was a null outcome and was terminated early. But the investigators were able to retrieve frozen specimens from their biorepository and assay various components of the renin-angiotensin system. And they found that as the baseline renin concentration increased in these patients, the hazard of death at 30 days also increased. And they found that the hazard of death, rather a hazard ratio of 2.8 for 30-day mortality in patients with baseline renin levels above the study median of 188 picograms per milliliter. And again, these are patients with sepsis of a completely unrelated intervention that present with high renin shock. Other studies, to put this into context, normal individuals have a baseline renin concentration around 3 to 20. Patients with a central hypertension, maybe 2 to 3 times this. However, patients with sepsis, septic shock, and critical illness, you can see on the three studies on the right-hand side, their baseline renin concentrations are 10 to hundreds-fold higher than normal individuals. Now another context where angiotensin II might be interesting and considerable to apply in the setting of critical illness is on its effects on oxygenation, particularly given the predominance of the angiotensin-converting enzyme in the pulmonary vascular endothelium. Shown here is a multicenter study of about 250 patients with vasopressor refractory shock. These patients were on approximately 0.6 micrograms per kilogram per minute of norepinephrine when they received the angiotensin II, and you can see in the plot, in the hours leading up to the time that angiotensin II was administered, the P to F ratio was declining. And following angiotensin II, the PF ratio increased. And some possible explanations here could be, from these high amounts of catecholamines, there might be sympathetic overactivation in the pulmonary vascular tree, promoting inflammation, pulmonary edema, and eventually a shunt. You could also have excessive catecholamines constricting well-oxygenated alveoli, leading to a VQ mismatch. Might also be impaired diastolic function from excessive amounts of vasopressors, leading to myocardial stunning and dysfunction. And angiotensin II might be able to spare these excessive vasopressor doses in these patients that have profound refractory shock, where these mechanisms might be at play. And similarly, a recent analysis of the ATHOS trial data found that there were 81 patients in the trial that met the Berlin criteria for the acute respiratory distress syndrome. And these patients at baseline, you can see here on the left-hand side, that they had a low P to F ratio, and there were a balance between the groups. Of course, it was a randomized trial. However, at 48 hours, you can see the patients that were randomized to angiotensin II had a much greater increase in their P to F ratio, an improvement in their oxygenation index. And in their multivariable model here on the right-hand side, you can see that angiotensin II treatment was associated with a greater increase in P to F ratio at 48 hours after adjusting for baseline PEEP, minute ventilation, and these other variables that you see here in the table. And so to close out, I'd like to take us back to the beginning into this context that blood pressure regulation occurs in a multifactorial fashion. It's an interplay between the vasopressin pituitary axis, the sympathetic nervous system, the adrenals with catecholamines, and of course, the renin and angiotensin aldosterone system. And so perhaps as we move into the future of critical care, we might be considering transition into a more precision-based approach to vasopressor management, where instead of a stepwise approach where we have these consequences of time against our side with organ failure, we might move towards predictive enrichment and biomarker-guided therapy to better optimize responsiveness to various vasopressors and ultimately achieve perfusion targets faster. And so in conclusion, angiotensin II appears to elicit favorable hemodynamic effects and a positive outcome in patients with high renin shock, and high renin shock appears to be quite frequent in critical illness, the acute respiratory stress syndrome with injury of the pulmonary vascular tree, and also those requiring lower vasopressor doses. And it might be reasonable to use a multimodal vasopressor approach to target the mechanisms responsible for blood pressure regulation to improve shock management, but this certainly requires much more investigation. And with that, I'd like to thank you.

vasopressors

angiotensin II

hypotension

septic shock

ATHOS-3 trial