Hello, and thank you for joining this session. My name is Patrick Wieroszewski, and I'm a pharmacist in the cardiothoracic surgery and ECMO program at Mayo Clinic, and it's my pleasure today to talk to you about a multimodal approach to vasopressors. My disclosures are listed here. I've previously served as a consultant for the Hoya Pharmaceutical Company, which was terminated a few years ago. The objectives of today's session are to evaluate patient-specific factors to determine selection and timing of additional vasopressors, design optimal titration parameters for dose escalation and de-escalation in patients requiring multimodal vasopressor treatment plans in accordance with the Joint Commission standards, and finally, to recognize the potential side effects of a multimodal vasopressor plan and consider patient-specific factors to minimize these side effects. Vasodilatory shock is the most common form of circulatory failure, and this condition can arise from a variety of etiologies. Most commonly, this is due to sepsis, but can also be as a result of postoperative vasoplegia, anaphylaxis, widespread inflammatory syndromes such as pancreatitis, as a result of general anesthesia, and also neurogenic shock in the case of spinal cord injury. In general, vasodilatory shock is a state of fluid-resistant arterial hypotension. This is problematic because there's decreased perfusing pressures to drive appropriate oxygen delivery into tissues, and therefore, there's inadequate cellular oxygen utilization, and eventually, the conversion to anaerobic metabolism and progressive multiple organ failure. In contemporary clinical practice, the Surviving Sepsis Campaign puts forth recommendations for the provision of vasopressors for correcting hypotension and septic shock, and I've highlighted some of their recommendations here. They recommend using norepinephrine as a first-line agent, however, you can see here in the subsequent two recommendations, they suggest adding vasopressin instead of escalating the dose of norepinephrine when the MAP levels are insufficient, and then they also suggest adding epinephrine when these two agents are also insufficiently increasing the mean arterial pressure. But you'll note here that these are weak recommendations. And so how do clinicians decide between which vasopressor to select? This is a survey of nearly 1,000 clinicians from over 80 countries a few years ago, and the respondents were asked, when the patient does not respond to your current vasopressor therapy, what is your main reason for adding another vasopressor agent to the current program? And you'll see that the responses are mixed. Clinicians will say anything from a predefined dose, max dose was already achieved with the current vasopressor, maybe increases in doses of that vasopressor were not effective, maybe they want to reduce or limit the side effects of that first vasopressor, or they're seeking an alternative or synergistic mechanism between the vasopressors. And so conceptually, this leaves us with an environment that looks something like this. You have a heterogeneous distributive shock population that presents. We apply a first-line vasopressor. A portion of these patients will have a satisfactory response to this vasopressor, but a portion of these patients will not have a satisfactory response. And at some arbitrary time point, which is quite vague, we might add a second vasopressor. Again, some will respond to the second vasopressor and some will not, at which point we'll reach for a third-line vasopressor and so on and so forth. And the problem that this poses is that during this entire continuum, the vasopressor doses are constantly being increased because of the inability to achieve hemodynamic targets. And this results in prolonged states of hypotension and hypoperfusion. And as the doses continue to rise, there's adverse drug effects that ensue, the responsiveness to vasopressors declines, and there's progressive multiple organ failure. And this traditional stepwise approach to vasopressor escalation may encourage the progression to refractory shock. Refractory shock is truly the endpoint of treatment failure. And although various definitions have been proposed, in general, refractory shock is characterized by persistent hyperperfusion despite increasing doses of vasopressors. Additional mechanisms are present in refractory shock, such as compromised microcircuitry flow, membrane hyperpolarization, and dysregulated mitochondrial respiration. And all of these things lead to impaired responsiveness to vasopressors and create a situation where complete cardiovascular collapse may be imminent. Now, if we take a step back and consider that blood pressure regulation during normal non-pathologic conditions is a multifactorial process, and there's three major systems that contribute to blood pressure homeostasis, and these are the sympathetic nervous system with catecholamines and their derivatives, the vasopressin posterior pituitary axis, and also the renin-angiotensin system. Now, when we consider vasopressors, what we expect is to achieve a near-linear dose-response relationship, and that's largely based on data like these. These are data from conscious rats without shock, and you can see the various vasopressors that were administered and the log dose across the x-axis and the mean arterial pressure on the y-axis. And with all of these vasopressors, there's nearly a positive linear dose-response relationship between dose and mean arterial pressure. And a similar relationship is seen in acute critical illness. These are data of an animal study with dogs that were induced with sepsis. In the left-hand panel, you can see during normal physiology, with incremental increases in norepinephrine infusion, there's an increase in the mean arterial pressure. However, after sepsis is induced, this response is dampened, however, you can see that the incremental increase in the mean arterial pressure still remains with increasing doses of norepinephrine. However, when we translate these fundamental concepts from laboratory settings with controlled experiments, they appear to behave differently in critically ill humans. This is a really nice study of nearly 3,000 septic shock patients that were identified in the MIMIC dataset out of Boston, Massachusetts. And you can see that at low norepinephrine doses, there's a constant increase in mean arterial pressure. However, as the norepinephrine doses begin to exceed approximately 0.2 or 0.3 micrograms per kilogram per minute, there's a dampening in the mean arterial pressure change with those incremental increases in doses. And so how do we address this concept of a single vasopressor agent that progressively reduces responsiveness as doses are increased? Well, vasopressin has been considered, and in states of shock, vasopressin is modestly elevated in early shock states from release from the posterior pituitary in response to hypotension. However, these tend to deplete over time, and this has been called the relative vasopressin deficiency in sepsis. However, what's important to note, and you can see on the right-hand side, is that in septic shock, vasopressin concentrations appear to be inappropriately low compared to other hypotensive syndromes, in this case, compared to cardiogenic shock, which appears to have a normal posterior pituitary response. These are data from Gretchen Sachs and Seth Bowers' group at the Cleveland Clinic of nearly 1,000 patients with septic shock, and what they sought was to understand the hemodynamic responsiveness to vasopressin. Hemodynamic response was defined as achieving a mean arterial pressure of at least 65 by 6 hours after vasopressin was initiated, and they found that only 45% of the patients that received vasopressin met this hemodynamic response criteria. And you can see that in patients who responded to vasopressin, their catecholamine doses reduced rapidly in the first 6 hours following vasopressin initiation and continued to decline in the 72-hour follow-up period. However, those that did not have this positive hemodynamic response had continued escalation of norepinephrine, and these were greater over time. Additionally, lactate concentrations were higher in patients who did not respond to vasopressin, and they continued to rise in the first 24 hours after vasopressin initiation, where those that had a positive response had stabilization in their lactate concentrations. And importantly, the patients who did not respond to vasopressin had longer lengths of stay and nearly 50% greater mortality than those who had a positive hemodynamic response. Another very important study from the same group, now using a slightly larger dataset of around 1,600 patients, suggests that earlier initiation of vasopressin in terms of the norepinephrine dose can be beneficial, and they found that the probability of in-hospital death increased by 20% for every 10 microgram per minute increase in norepinephrine that was delayed until vasopressin was initiated, and this held true in a linear fashion to approximately a norepinephrine dose of 60 micrograms per minute. And similarly, the lower the lactate concentration was at the time of vasopressin initiation, the lower the in-hospital mortality was. So taken all together, we can see here that lower norepinephrine doses and lower lactate concentrations appear to be a better environment to apply vasopressin in. The same group phenotyped vasopressin responsiveness to better understand their clinical trajectory when vasopressin was added in norepinephrine refractory shock. And the phenotypes that they defined were early death, which was within 14 days, chronic critical illness, which was greater than 14 days spent in the intensive care unit with persistent organ dysfunction, or rapid recovery. And you can see on the left-hand side that patients who are classified as vasopressin responders were more likely to recover quickly, whereas those who were non-responders were more likely to die early. And on the right-hand side, you can see their adjusted survival curves, and responders were more likely to survive at 30 days than non-responders. And a natural question might be, well, if vasopressin concentrations are inappropriately low in sepsis, can we use them to guide selection of vasopressin and understand if these patients will respond better? This is a study of 18 patients with septic shock that had vasopressin concentrations collected, and unfortunately, they did not find that vasopressin concentrations predicted hemodynamic responsiveness in this small sample. So to summarize vasopressin, vasopressin concentrations appear to be inappropriately low during septic shock. Half of patients who receive vasopressin for in septic shock might not respond to it hemodynamically. However, adding vasopressin at lower norepinephrine doses and lower lactate concentrations improves hemodynamic responsiveness, and likely most importantly these patients who have improved hemodynamic responsiveness to vasopressin have better outcomes. Now going beyond vasopressin, there's been a considerable interest in the renin angiotensin system ever since the first descriptions of high blood pressure as a disease in the 1800s. Now angiotensin 2 was first identified in the late 1930s by a group in Argentina, and back then it was referred to as hypertensin, and it was known as a hormone that caused intractable hypertension, and of course as you know over the next 80 years or so what would ensue would be a tremendous amount of research focusing on suppressing this powerful hormone. And so if you recall, the juxtaglomerular cells of the kidneys sense low perfusing pressures and produce renin. The liver produces angiotensinogen, which is then converted by renin to angiotensin 1. The angiotensin converting enzyme catalyzes angiotensin 1 to angiotensin 2, and then of course angiotensin 2 goes on to act on the vasopressin systems, on aldosterone to increase water and sodium reabsorption, and of course angiotensin 2 is also a direct vasoconstrictor by engaging with G-coupled protein angiotensin type 1 receptors in the arterial and venous systemic vasculature. All of these then stimulate the kidneys to stop producing renin. Although there's many descriptions of angiotensin 2 being used as a clinical vasopressor dating back to the 1960s, it wasn't until this group from George Washington approximately 10 years ago did the ATHOS pilot study to really bring back angiotensin 2 into contemporary critical care practice. Now the ATHOS pilot study was a dose-finding study. They randomized 20 patients with norepinephrine refractory shock to receive six hours of either angiotensin 2 or placebo, and during the six hours you can see that the patients who received angiotensin 2 had a rapid decline in their norepinephrine dose, and then at at the six-hour mark when the study drug was discontinued, you can see that the norepinephrine doses returned to baseline, whereas those who received placebo had continued high doses of norepinephrine throughout the study period. This dose-finding study then led the foundation for the ATHOS 3 phase 3 clinical trial, which was a registration trial with the FDA. Now the ATHOS 3 trial was designed to demonstrate that angiotensin 2 behaved as a vasopressor and indeed had the mechanism, and because of this, the primary endpoint was defined as a mean arterial pressure of at least 75 or a change in mean arterial pressure by 10 millimeters of mercury at three hours after study drug initiation. In the ATHOS 3 trial, patients were eligible if they had norepinephrine refractory shock. This was defined as a norepinephrine dose of at least 0.2 micrograms per kilogram per minute. The patients needed to have high or normal cardiac output and demonstrate that they were not hypovolemic, so essentially high output vasodilatory shock. The patients had a baseline predicted mortality of approximately 50% based on their Apache 2 and SOFA scores. In this study, over two-thirds of patients who received angiotensin 2 achieved the primary hemodynamic endpoint, whereas less than one-fourth of the patients who had received placebo, which was continued escalation of catecholamine vasopressors, achieved the primary endpoint. And you can see in the first three hours, the mean arterial pressure significantly increased in angiotensin 2 recipients, whereas this was only a steady increase in those who received placebo. And more importantly from the study, there was a quite profound norepinephrine sparing effect in the patients who received angiotensin 2. Following the approval of a synthetic version of angiotensin 2 based on the ATHOS 3 clinical trial, post-marketing studies sought to understand the clinical application of this vasopressor in practice. Our group was very interested in this, so we did a cohort study of 270 patients from five academic centers in the United States that received angiotensin 2. Interestingly, we were surprised by the conditions in which angiotensin 2 was applied in practice, as these were quite different from the conditions of the phase 3 clinical trial. The patients that received angiotensin 2 in this multi-center study were severely ill, and they had a baseline predicted mortality of approximately 80% based on their Apache 2 and SOFA scores, and they were already receiving two or three vasopressor doses at a dose that was nearly three times higher than the ATHOS 3 enrollment criteria at the time that they received angiotensin 2. And despite this profound severity of illness, we found that over two-thirds of patients had a positive hemodynamic response when receiving angiotensin 2. In the multivariable model, the lactate concentration, a lower lactate concentration predicted positive hemodynamic response, and patients who were already receiving vasopressin also were more likely to have a hemodynamic response to angiotensin 2. And most importantly for findings, we found that patients who responded in the multivariable adjusted Cox regression model, these patients that had a positive hemodynamic response were twice as likely to survive at 30 days than those who were non-responders. Another cohort study at the University of Georgia that followed approximately 160 patients receiving angiotensin 2. These patients had a similar high severity of illness that was disproportionate with the ATHOS 3 clinical trial. However, these investigators found that angiotensin 2 had a greater vasopressor sparing effect when there was a lower background vasopressor dose at the time angiotensin 2 was started. And you can see here, this was true at a cutoff of 0.3 micrograms per kilogram per minute, so when the dose of norepinephrine was less than 0.3 micrograms per kilogram per minute, there was a greater vasopressor sparing effect when angiotensin 2 was added. And this vasopressor sparing effect was even greater when the baseline norepinephrine dose was less than 0.2 micrograms per kilogram per minute. Now, we wanted to investigate these signals of lower vasopressor doses. If you recall, a similar signal that was identified in observational studies of vasopressin. And so in the ATHOS 3 clinical trial, if you recall, a vasopressor dose of at least 0.2 micrograms per kilogram per minute was an enrollment criterion for the trial. And so we did a post-hoc analysis of the trial data and found that approximately one-third of patients that were enrolled in the study had a vasopressor dose of 0.25 micrograms per kilogram per minute or less at the time the study drug was initiated. And what we found was when the vasopressor dose was high or greater than this cutoff of 0.25, the survival curves between those who received angiotensin 2 and placebo were similar. However, when the study drug was initiated when the dose was low or less than 0.25 micrograms per kilogram per minute, the patients that were randomized to angiotensin 2 had nearly twice the survival as those who were randomized to placebo, which again was an escalation of standard care vasopressors at 28 days. Now, an interesting finding was after the initial ATHOS pilot study, once the results were analyzed and published, the investigators were able to unblind the data and what they found was that there was two patients out of the ten that were randomized to angiotensin 2 that had a robust hemodynamic response to angiotensin 2. These two patients were completely separated from 0.3 micrograms per kilogram per minute of norepinephrine rapidly after angiotensin 2 was initiated, and they remained hypertensive despite norepinephrine being completely discontinued. And at the end of the six-hour study period, there was rebound hypotension when angiotensin 2 was stopped and required resumption of high-dose norepinephrine. Now, these findings suggested that there might be a subset of patients that are particularly responsive to angiotensin 2, and we might be able to use this to optimize how we apply this vasopressor in patients with shock. And in the ATHOS 3 trial, there were approximately half of the patients who received angiotensin 2 appeared to be these hyper responders. These hyper responders were defined by requiring a dose reduction in angiotensin 2 just 30 minutes after it was started because of the profound increase in mean arterial pressure. And you can see here that the patients who were hyper responders, again requiring this dose reduction on the right hand bar, the green bars, they had a greater odds of achieving the primary hemodynamic endpoint than the patients who were not hyper responders. And what was striking is that these patients who were hyper responders to angiotensin 2, again, they required a dose reduction just 30 minutes after starting angiotensin 2 because of a profound increase in mean arterial pressure. These hyper responders were more likely to survive in the 28-day follow-up period than the patients who were not hyper responders. In the ATHOS 3 trial, the specimens were available at the time of randomization before they received study drug, and so they were able to assay various angiotensin metabolites. And what you can see here is that patients with lower endogenous baseline angiotensin 2 concentrations were more likely to have a positive hemodynamic mean arterial pressure response and achieve the primary endpoint of the study if they were classified as angiotensin 2 hyper responders. And when the patients were evaluated at the trial level, you can see the distribution of their angiotensin 1 and angiotensin 2 concentrations at the time that they were randomized. Again, this is before they received study drug. And you can see that the angiotensin 1 concentrations were high and the angiotensin 2 concentrations were low. And this produced an angiotensin 1 to 2 ratio of approximately 3. And this is an important finding because if you compare this to healthy individuals, again, patients who do not have refractory shock, healthy individuals have an angiotensin 1 to 2 ratio that is approximately tenfold lower than these patients with refractory shock. And so how do we rationalize what might be going on here? And so if you recall, the juxtaglomerular cells in the kidneys release renin in response to low perfusing pressures. And so what we have is an accumulation of angiotensin I and a reduction in angiotensin II concentrations. Now this might indicate that there's a deficiency in the ability of the angiotensin converting enzyme to catalyze the conversion of angiotensin I to II. And what this might result in is angiotensin II not being able to stimulate its hemodynamic targets and increase blood pressure, which then promotes the kidneys to produce more renin. And of course, we have accumulation of renin concentrations. And so a natural question is, well, why can't we just measure angiotensin I and II concentrations to identify these patients? And this is problematic because angiotensin I or II are very large peptides, and they require special handling for collection, they have to be processed in special laboratories, and they could take a couple weeks to result values. And so this is simply just not practical in critical care practice. However, if this imbalance exists, there's accumulation of renin, and so renin concentrations might be able to serve as a surrogate in this context. Now this is a nice biomarker study from Jean-Louis Vincent's group in Brussels. And what they did is they took a mixed ICU population with varying shock states, approximately 30 of these patients did not have any shock, and they assessed renin concentrations and compared them to lactate as prognosticators for survival. And what they found was that renin was inversely correlated with MAP, so as the renin concentration increased, the mean arterial pressure was lower. And they found that renin was not affected by diurnal variation, continuous renal replacement therapy, or medications that you would expect to impact the renin-angiotensin system. And what they found was patients with higher renin concentrations at every time point assessed in the study were more likely to die than those with lower renin concentrations. And on the right-hand side, you can see their ROC curves, and renin was a better predictor at predicting survival than lactate concentration was. A similar study was done by John Chow's group when he was back up in Maryland, and they looked at the change in renin concentration over time. They had patients with hypotension that required vasopressors for at least six hours. They included patients that had hypotension from different etiologies. And what they found, that as the slope of the change in renin was highly predictive of mortality, while the change in lactate was not. And you can see here that the proportion of patients with renin concentrations that were above normal or above 40 picograms per milliliter, they were more likely to die at every time point assessed in the study. And indeed, if we look at the angiotensin one to two concentrations, they correlate with renin. And what you can see here on the right-hand side is that as the angiotensin one to two ratio increases, the renin concentration also increases. And in the ATHOS-3 trial, when these patients are subgrouped based off of their baseline renin concentration as a cutoff of the study median of 173, you can see that the patients with high renin concentrations have this imbalance in angiotensin one to two, and they have a ratio of approximately three, whereas those with a low renin concentration do not have this imbalance in angiotensin one to two. And when these patients are plotted on their survival curves, you can see on the top panel when the renin concentration is low or these patients have low renin shock, the survival curves between the two randomization arms are nearly similar. However, in patients with high renin shock, again, these are patients that had renin at baseline before randomization of study drug, if this renin concentration was high and they were randomized to angiotensin two, they were more likely to survive at 28 days than those who received placebo. And you can see that the placebo arm, nearly 50% of them were deceased at just one week after randomization in the high renin shock subgroup. And so how do we rationalize what is going on here? And so if you recall, the situation we have is high angiotensin one and low angiotensin two concentrations, and this leads to an accumulation of renin from the inability of the angiotensin converting enzyme to produce its actions. And this is problematic because now there is increased angiotensin one substrate and this promotes metabolism through alternative angiotensin degradation pathways. And so angiotensin one can be metabolized into angiotensin one nine and angiotensin one seven. These two substances go on to act on the mass receptor and angiotensin type two receptor to produce vasodilation. And of course, the angiotensin converting enzyme is also critical in the degradation of bradykinin. And so if this is inhibited, we have accumulation of bradykinin, which can also lead to vasodilation by stimulation of nitric oxide pathways through the B2 receptor. And so all of this vasodilation then stimulates the kidneys to produce more renin and you produce this vicious cycle of production of vasodilatory substances. And so can we take a look into the angiotensin converting enzyme and better understand how we might be able to identify who these patients are? And so, of course, the angiotensin converting enzyme is a capillary bound endothelial ectoenzyme and it primarily lives in the pulmonary vascular tree. And conditions that affect pulmonary function and the pulmonary vascular endothelial integrity appear to affect the production and activity of angiotensin converting enzyme. This is a study of patients with acute respiratory distress syndrome. They're mainly due to trauma, but some of them had sepsis and pneumonia. And you can see that as the lung injury score increases, the angiotensin converting enzyme activity declines. And so a natural question is, well, who has high renin shock? Well, it's likely individuals who have any dysfunction of their endothelium. This could be from sepsis, trauma, toxins, inflammation, leading to endothelial dysfunction, and of course the impairment of the angiotensin converting enzyme production and its function to do its abilities in the renin-angiotensin axis. And for context, patients who have no shock, who are normal with no hypertensive or vascular conditions, their renin concentrations are approximately three to 20. Those with chronic hypertension have renin concentrations that are approximately two to three times higher than normal. And then patients with shock and critical illness have renin concentrations that are ten to hundreds-fold higher than normal. And you can see here the BRUSSELL study with renin concentrations in the hundreds to thousands and the ATHOS-3 trial with concentrations that were approaching 10,000. These are patients with vasopressor refractory shock have very high renin concentrations. And so to summarize, angiotensin-2 high renin shock is associated with poor outcomes and does appear to predict angiotensin-2 responsiveness. Approximately one-third of patients with shock may not respond to angiotensin-2. Again, a similar signal that we saw with vasopressin. Adding angiotensin-2 when the vasopressor doses are lower might improve responsiveness. And positive hemodynamic response to angiotensin-2 is associated with better outcomes and survival. And again, a lot of these summary points are very similar to what we saw with vasopressin, suggesting that these vasopressors might work well together. And again, if we take a step back and consider normal blood pressure homeostasis in non-pathologic conditions, this is mechanistically maintained with three foundational systems, the sympathetic nervous system with catecholamines, the vasopressin posterior pituitary axis, and the renin-angiotensin system. And so perhaps the future of vasopressor management, instead of this stepwise approach that we discussed at the beginning of the talk, we might move toward a more precision-based vasopressor management approach. And this could either be through predictive enrichment or biomarker-guided therapy, where, again, you have a heterogeneous distributive shock population that presents, and instead of stepwise adding vasopressors and waiting for a vasopressor to fail, instead we could provide multiple vasopressors up front to maximize the responsiveness in a quicker fashion. And this, of course, would be the goal to increase the chances of achieving hemodynamic responsiveness, to reduce hyperperfusion states, to reduce excessive drug events from high doses of vasopressors, to increase the responsiveness of vasopressors, and, of course, to minimize the progression to multiple organ failure. And so beyond the evidence that we have discussed today suggesting that vasopressors of varying mechanisms appear to play well together, particularly when they're used in combination at lower doses, there might be reasons why it may be beneficial to go beyond just adrenergic stimulation in shock treatment. And excessive catecholamization in septic shock can be detrimental to cardiac performance. Shown here on the left-hand side is a study of about 250 patients who received norepinephrine for septic shock and assessing the impact on new onset arrhythmia development. You can see the various arrhythmias that developed after norepinephrine was started, and approximately one-third of patients developed an arrhythmia after norepinephrine was started for septic shock. And the patients who had an arrhythmia were twice as likely to die. And in the multivariable model, it was found that as the dose and duration of norepinephrine increased, the odds of having an arrhythmia also increased. And strikingly, for just every five micrograms per minute of norepinephrine increase, the odds of having an arrhythmia increased by 6%. And on the right-hand side is a really nice study of about 20 patients without coronary artery disease who were receiving norepinephrine for shock and had an echocardiogram performed. And during the echocardiogram, they measured myocardial blood flow and found an inverse relationship with the norepinephrine dose. And you can see that as the norepinephrine dose increased, the myocardial blood flow declined. And importantly, this myocardial blood flow was not affected by the mean arterial pressure. Norepinephrine is also detrimental to survival outcomes. Here's a study where you can see the in-hospital mortality rate increases as the norepinephrine dose increases. Whereas the norepinephrine dose was approaching 100 micrograms per minute, the in-hospital mortality rate was nearly 100%. And these findings have been replicated by many studies of high-dose norepinephrine in vasodilatory shock. You can see here as doses are in the range of 0.9 or 1 microgram per kilogram per minute, around 90 to 100 micrograms per minute, the death rates are in excess of 60 to 90%. However, on the other hand, decatecholaminization appears to reduce the toxic effects of high doses of norepinephrine. This is a meta-analysis of 23 randomized controlled trials of vasopressin use in shock. And the authors wanted to compare the effect of receiving vasopressin with catecholaminization the effect of receiving vasopressin with catecholamines or catecholamines alone on arrhythmias in patients with various shock states. And you can see here that amongst all the studies and those with low risk of bias, there was a reduction in the relative risk of having an arrhythmia in the group that received vasopressin with the catecholamines. Now coming back to this early multimodal vasopressor concept this has been tried and tested by this group recently where they looked at approximately 1,500 patients from the MIMIC data set out of Beth Israel in Boston and they included patients who had septic shock that were receiving at least two vasopressors and they compared whether the second vasopressor was added at a low norepinephrine dose less than 0.25 micrograms per kilogram per minute or at a higher dose and you can see here that the patients who received early multimodal therapy that this was any agent that the survival was higher in these patients and on the right hand side you can see that the hazard of death at 28 days increased as the norepinephrine dose increased when the second vasopressor was added and so some of the things that we need to consider with the multimodal vasopressor strategy in a practical sense in our patients in the unit are the predictors of responsiveness and how do we identify these patients who would be responsive to various agents, what are the lowest effective doses that we can use to achieve a satisfactory response, is there a plan to interchange agents if side effects develop from any particular agents and of course patient safety is it should be of utmost importance when considering this strategy. Now regarding patient safety the joint commission puts for standards for titratable medication orders and this is a standard that was recently released in recent years standard mm.04.01.01 and in the standard they talk about titratable orders requiring a starting dose a range for dose titrations a frequency for changing the infusion rate and they allow a range for this as well for example every two to three minutes double range orders are are allowed so you can have a dose range and a frequency range there must be a maximum dose specified and there must be a clinical goal for the titration for example mean arterial pressure for a vasoactive agent and they specify that this goal must be consistent when multiple agents are used for the same purpose and importantly they do specify that the clinical goal for titration does not actually need to live within the medication order and we'll come back to this in a few minutes. Now there an interesting observational study implemented these recommendations and assessed the impact on patients with shock before and after this implementation and so these investigators assessed before and after titration instructions were added to norepinephrine from the joint commission standard and they found that after the titration instructions were implemented the time to hemodynamic stability was longer and so this suggests that implementing these stringent standards might actually compromise our ability to provide clinical care and achieve the hemodynamic targets that we're trying to achieve and you can see their multi-variable model here they found that after addition of titration instructions the achievement of hemodynamic stability took 24 minutes longer after adjustment for all of these other variables that are listed here. Now it's important to remember that this is a retrospective study that was over time a pre-post study so there could be a time bias here there might also be unmeasured variables that affect the care delivery in the post-implementation group and also the post-implementation group was sicker at baseline than the pre-implementation group but nonetheless these data stress the importance that we must consider how the care delivery process is implemented when we're considering complex interventions. Now coming back to the joint commission standards I did want to point out some specifics that they describe for titratable medications and importantly using multiple agents that seek to achieve safe physiologic targets is permissible although the joint commission specifies certain criteria must be met for these conditions. So they do permit this in critical care settings for titratable vasoactive medications and they state that nurses may select between the ordered agents based on a patient's condition and unique physiological response as long as an order exists for the medication that is written in accordance with institutional policy and that it's not prohibited by local laws and that it's allowed by hospital policy or the medication order and there's competency that's defined by the institution and that the nurse has to stay within the defined parameters of those orders. So there's a lot here but we'll talk about some strategies of how to keep this a safe practice. To increase the safety of titratable vasopressors the Institute of Safe Medication Practices, the ISMP, provides recommendations. Included in this are to include pharmacists and ask pharmacists about safe ranges that are relevant to your specific practice area, require assessment of orders at a minimum of every 48 hours to see if the titration limits should be revised, that inclusion of maximum dose limits is important to assess the effectiveness of vasopressors and also the safety of them frequently during the practice, and that these medications should be administered through smart pumps that can provide alarms at the specified dose limits. Now one way to do this in the context of an electronic medical record is to build titratable vasopressor orders with standard options that are relevant to your practice. This is one example where you can see all of the concepts of the Joint Commission standard being reflected in this order. There's a dose titration range, there's a maximum dose for each of the titratable options, there's an initiation dose, a titration dose, a frequency of titration, and how the vasopressor should be discontinued, as well as the hemodynamic goal that is seeking. So as a provider you can go through here and select the options that you choose and this would be compliant with the Joint Commission standard. Now an interesting concept that comes back to early multimodal vasopressors that we discussed over this talk and with the Joint Commission standards, allowing for two vasopressors that achieve the same physiologic goal to be used at the same time. One way to achieve this could be through integrating goals for your vasopressor agents. And so this is an example of what we have done locally with sedative agents that we're looking to apply for vasoactives here very soon. But what we've done is we've built an order that specifies the sedative goal that lives outside of medication orders. And again, this was specified as permissible by the Joint Commission. And so when in a patient's chart, anyone involved in their care can see what the target sedation goal is for that patient. And so the idea here for multiple vasopressor agents is to define the mean arterial pressure goal to live outside vasopressor orders. And that way each vasopressor can be titrated safely to a consistent mean arterial pressure goal. And so in summary, we've proposed this multiple vasopressor strategy, but there needs to be many considerations to make this successful in critical care practice. Really, we talked about stepwise and multimodal vasopressor application and shock resuscitation. And I would argue that there should be a greater focus on rapid restoration of organ perfusion. And again, using a stepwise vasopressor approach where escalation of vasopressors to achieve hemodynamic targets and waiting for them to fail before adding another vasopressor increases the probability of organ dysfunction. We also need to classify biologic endotypes to better understand who these patients are that are responding. There's very clear responders and non-responders for every vasopressor. Norepinephrine, vasopressin, angiotensin 2, all of these vasopressors have a subset of patients who respond and a subset that don't. And we need to understand this on a biologic level. Point-of-care biomarker assays will be important, particularly those that can be used to guide these specific endotypic responders. We need a safe implementation and we should focus on patient safety when designing electronic medical record builds that promote the use of multimodal vasopressor therapy. And ultimately, all of this leads to personalized vasopressor approaches. And hopefully you would appreciate that all of this variable responsiveness to vasopressors provides an argument that not one size fits all in terms of vasopressor application and shock. And so with that, I'd like to thank you for attending this session as part of the 2024 SCCM Advanced Pharmacology Board Review Course.

vasopressors

vasodilatory shock

sepsis

norepinephrine

vasopressin

epinephrine

organ perfusion

personalized care

smart pumps