SCCM Resource Library-Under Pressure: Use of Vasoactive Therapies Beyond the Guidelines

Video Transcription

Well good morning. Thank you for attending this next to last session. My name is John Whitcomb. I am a professor and director of the undergrad nursing program at Clemson University,  and I have the honor of moderating this session as well as giving a talk. We are going to start off with Gretchen, followed by myself, and then Larry will bring us in the end,  and then we'll save some time at the end for questions. Thank you.  Thank you for the introduction. So we are going to be starting this first session by talking about titrating and discontinuing vasopressors. And to get right into it,  I do not have anything to disclose regarding this presentation or the content therein.  And by the end of the presentation, you should be able to identify the current evidence surrounding  effective titration and discontinuation of vasopressors. And then we're going to talk about specifically utilizing the literature to develop a discontinuation approach for patients  receiving both norepinephrine and vasopressin. Now to begin with a brief refresher that I know  none of us in this room actually need, but listed for you on the slide are the various or some of  the various vasoactive agents that are currently available in the US. We have catecholamine and non-catecholamine-derived agents, all with different and varying receptor activities  that result in an increase in afterload as well as cardiac output and ultimately augmentation of  blood pressure. These agents are utilized for a variety of shock states. And because of their  quick half-lives, all less than 10 minutes, they can be rapidly titrated to achieve the goal blood  pressure or MAP. Now this leaves the question, though, of how do we effectively and most optimally titrate these agents once we have someone initiated on them? And unfortunately,  there really is not a lot of literature looking into this clinical question. And in fact,  in practice, there's a lot of variability in who's actually doing the titration of these drugs at the  bedside. Primarily, physicians give nurses the liberty to titrate these agents to a pre-specified  goal blood pressure that they have designated. But that's not exclusively done, and many  institutions still have providers or physicians doing the titration themselves. One review actually  lamented that to date there are no guidelines or guidance documents assisting nurses or physicians,  for that matter, in the titration of these agents. What this ends up looking like is experience-based  or titration by experience, with more experienced nurses and providers feeling more comfortable more  rapidly titrating these agents. We can look to our landmark studies like SOAP2, CATS, VAST,  ATHOS3, and look at their protocols that they used for titrating these agents. But even those  are not as nuanced as you might like them to be, as they don't all go into how quickly they titrated these agents or by what dose they titrated these agents. So they can be really  used more as a starting point. And knowing that, really, we have the pharmacokinetics of these drugs  to rely on in helping us know how quickly to titrate these drugs. One approach that has been  taken is the addition of titration instructions to the medication orders. And this has come about  in response to one of the Joint Commission medication management standards that dictates  all medication orders be clear and accurate. And a lot of institutions have actually been cited  because of not having these transparent instructions for the nurses within their titratable  medication orders. So an example of titration instructions are listed for you on the slide.  One institution actually evaluated the addition of these instructions and found that after adding  them, this was associated with a 24-minute increase in the time to achieve hemodynamic stability. Now it's not known what drove this result as the norepinephrine starting dose,  the maximum dose, the max amplitude of change between doses, as well as the time to achieve maximum doses, was same before and after these instructions were added. It could be that  patients are, or it could be that nurses had the liberty and the independence of more quickly  titrating before they were added. And it could also be that patients with shock are just so  dynamic that they need more leniency in the titration of these medications. But regardless,  this is one approach that has been taken. But what we really need are more tools and approaches that  really truly help us know how to titrate these drugs. And one of the approaches that has been  studied is dynamic arterial elastance. This uses pulse pressure variation to stroke volume  variation, the ratio of the two, as a functional index of arterial tone. It is said to be able to  predict arterial pressure response to fluid expansion even in spontaneously breathing  patients. It's also said to be able to predict a fall in blood pressure upon norepinephrine weaning.  One evaluation described the utilization of this approach and found a 22-hour reduction  in norepinephrine duration when they use dynamic arterial elastance to either wean norepinephrine  or to provide fluids if the MAP was less than 70, but the dynamic arterial elastance was greater  than 0.94. Now, unfortunately, this isn't heavily done at a lot of institutions. I think it's not  very commonly known. And also, it requires a femoral artery catheter with a pulse pressure  waveform analysis device. And because of this, it's likely not feasible to implement at most institutions. Another way of the future, one that actually gets me really excited,  is the concept of closed-loop titration. This uses high-tech algorithmic processes that can convert data, such as the patient's blood pressure and norepinephrine or vasoactive dose,  and convert it into what they call fuzzy data sets that can automatically calculate the required  change in vasoactive dose based on the patient's fluctuating MAP requirements. And you can see  that it has been studied. In patients with septic shock, they found that the shock duration was  reduced by about half when utilizing closed-loop titration. It's also been studied in the  operating room in one site in Belgium in which they utilized a similar technology in an attempt  to maintain the MAP within 5 millimeters of mercury of the goal. And they were able to successfully do so for more than 91% of the intraoperative time. And patients only experienced  hypotension for less than 3% of the intraoperative period. And then finally, one evaluation actually  described creating a model out of a lot of common medical record data that was able to actually  predict what the MAP would be out to 20 minutes in advance or in the future after the fluctuating  norepinephrine doses. So they could predict what the MAP would be. All of these advancements,  I hope, are going to be our way of the future one day. But unfortunately, until that time,  we're left with our current practice, which is very variable and doesn't have much guidance in how to titrate these high-risk medication agents. Where we do have more data, though,  is in the discontinuation approach. Now, if we're talking about norepinephrine monotherapy or a  patient on one catecholamine, the approach becomes pretty similar to what I described with titration.  Variable, no guidance. Maybe we might have some help in the future, especially with closed-loop  titration. But what gets more complex is when we talk about patients on multiple agents,  particularly if they're on a catecholamine agent like norepinephrine as well as a non-catecholamine  agent like vasopressin, the combination of which has the most data around the discontinuation order.  Now, if we look at a patient's typical course of shock, you can see the norepinephrine dose in blue,  the corresponding MAP values in orange. Patients typically present on increasing norepinephrine  doses. And then at some point, if they survive, they actually start to be able to wean norepinephrine  as their MAP becomes more consistent. If we overlay this with the different phases of shock that a  patient can experience. And I'm going to simplify this for the purpose of the presentation.  But particularly in septic shock, patients present often are diagnosed in that early phase where  they have that massive hypoperfusion, uncoupling at the micro and macrovascular level.  If they survive that phase to the maintenance phase where they have more restoration of perfusion at  that micro and macrovascular level. And then if they, again, survive that phase to the recovery  phase where they have endogenous restoration of vascular tone as well as cardiac function.  If we look at patients and actually overlay on top of this a patient initiated on vasopressin  in the early phase at about hour six, the question then becomes once they start to recover and enter  the maintenance and recovery phase, at what point can we start discontinuing our vasoactive agents?  And more importantly, which agent should we discontinue first? Now, believe it or not, there's actually a lot of data or I would say a lot of data regarding this clinical question.  And I'm not going to go into all of the nuances of each of these studies. There's two things I want  to point out. First, the 2018 GIAN study. It's the only randomized control trial that we have  looking at this clinical question. The remaining five studies are retrospective in nature.  And the second thing is the primary outcome that each of the studies looked at was hypotension  occurrence. And this was a composite outcome that did vary a little bit between the studies,  but the base of the definition was about the same. And it was having a low MAP, typically less than  60 or 65, depending on the study, with the addition of an intervention because of that hypotension occurrence. Now, when all of these studies were combined in a meta-analysis that  was published in 2019, they did find a significant association with discontinuation order and the  development of hypotension in that discontinuing vasopressin first was significantly associated  with an increased odds of developing hypotension. But because this is a composite outcome, we should ask what drove those results. And when we break down the definition,  you can see this is, again, meta-analysis, all of the patients that have been evaluated  for this question, 60% of those that had vasopressin discontinued first developed hypotension.  And of those, 40% of them met that definition because the norepinephrine dose that they still  had on needed to be increased to compensate for the loss of vasopressin. Now, to me, that's not  surprising based on the way we titrate these drugs in septic shock with norepinephrine being more  commonly titrated and vasopressin being more commonly administered at a fixed dose. But the  next question that should be asked is whether or not this is actually impacting outcomes for our  patients. And the answer is no. When the meta-analysis evaluated the outcome of short-term mortality,  they found no association with discontinuation order on short-term mortality. And I would be  remiss to stand up here and talk about vasopressin in any context without addressing its cost.  We all know that in 2014, the vasopressin was rebranded. And at that time, its cost has  exponentially increased from around $4 per 20-unit vial up to the current wholesale acquisition cost,  which is around $180 per 20-unit vial. Now, the reason I bring this up is because it does have  some place, a role in the discussion today. It was found that when vasopressin is discontinued first, this is associated with a reduction in vasopressin duration by about .8 days,  which is not surprising, which equates to 19.2 hours. Now, that might not sound like a lot,  but if we look at a standard concentration of vasopressin, 20 units in 100 ml, if you run that  bag at .03 units per minute, it will last you 11 hours. If you run it at .04 units per minute,  it will last eight hours. So, by discontinuing vasopressin first, it's estimated that you can  save at least one to three bags of vasopressin per patient. And if you practice at an institution  that utilizes a lot of vasopressin, that can result in significant cost avoidance over time.  And it's because of all of these factors, the fact that there's really no difference in outcomes,  knowing that, yes, I might have to increase my norepinephrine dose when I stop vasopressin first,  but particularly this cost piece, as I am a pharmacist, this is why I recommend in my practice to discontinue vasopressin before norepinephrine. So, let's go back to our patient  and their shock course. Say I was able to convince you to discontinue vasopressin first. The question  then becomes, at what point or does it even matter when I should discontinue vasopressin?  And as I have said a lot of times throughout this whole talk, we don't have a lot of data,  but we can glean some insight into this question if we look at the norepinephrine dose at the time  vasopressin was discontinued or weaned, as in the case of the RCT, and use that as a surrogate  marker for where the patient was in their course of shock. You can see the GIAN study actually  tapered vasopressin over three hours when the norepinephrine dose was at 0.3 mics per kilo per minute. Now, if you don't practice at an institution where they do weight-based  norepinephrine like me, that's around 20 to 30 mics per minute, depending on the patient's weight.  They actually found worse outcomes with this approach. And to me, it's likely that they discontinued vasopressin too early, as they only had to be on 0.3 mics per kilo per minute of  norepinephrine for just two hours before it was weaned off. And now, compare this to our five retrospective studies or prospective study, retrospective studies. You can see that all  of them discontinued vasopressin when the norepinephrine dose was around or even less than 10 mics per minute. So it's likely these patients were definitely in the maintenance,  likely in the recovery phase of septic shock when it was discontinued, and they found no difference in outcomes with this approach. And this also makes sense when we talk about  vasopressin levels. So looking at what I consider one of the famous graphs of vasopressin levels  from the VAST study, you could see the blue line is patients who received vasopressin. Not surprisingly, they had a dramatic increase in vasopressin levels after it was initiated,  compared to the orange line is patients who received norepinephrine alone. But what's interesting is you can see there was a subpopulation of patients who had vasopressin  discontinued between hour 6 and hour 24, and they had a rapid reduction in their plasma vasopressin levels. So what I'm thinking about all of this is that it's likely that if you  discontinue vasopressin before the patient has had time to adequately restore their vasopressinergic  system, it's not surprising that maybe worse outcomes might occur. But as long as you feel  that the patient is truly on the road to recovery and in the recovery phase of septic shock, the discontinuation approach likely doesn't matter, and you can feel safe that you can  discontinue vasopressin first. So the final clinical question or piece of this puzzle is whether or not vasopressin should be just stopped or tapered off when it's discontinued.  Now these are the results of a retrospective study that looked at about 1,000 patients and compared their discontinuation approach. This was presented in abstract form earlier  this week at Congress. And you can see that based on the discontinuation approach, there was no difference in ICU length of stay, ICU mortality, hospital mortality,  or the development of hypotension. But not surprisingly, stopping vasopressin abruptly rather than tapering was associated with a reduction in vasopressin duration. So this  says to me, we can feel comfortable that we don't need to taper vasopressin off, we can just abruptly discontinue it. So to conclude, when we're talking about titration,  there's very variable practice in how this is done. And we, at this point, don't really have enough guidance on how we should optimize and most efficiently titrate these agents.  But when it comes to discontinuation in patients with septic shock who are on both vasopressin  and norepinephrine, it's likely that you can discontinue vasopressin before norepinephrine  as long as the patient is in the recovery phase and as long as you know or educate your nurses  and providers that you might have to increase your norepinephrine dose to compensate for the loss of vasopressin. And that is all I have for my section. So I'm going to pass it off  to my co-speakers. Okay, so I'm going to take a little different slant on this, and hopefully you'll ride with  me as I go along. As it's been pointed out, there's not a whole lot of research, if any,  out there on this. And so I want to try to bring to light the complexity of what we're talking  about today. I have no disclosures or conflicts. And I want to talk about recognizing the utility  of evidence-based and protocolized vasopressor use in the intensive care unit. So we know that  there's many, many, many options and issues that we deal with the patient, with the sepsis, with  cardiac failure, hypovolemia, and all the pieces that we go in to try to correct this. And we got  to go to the basics. When we're talking about inotropes and vasopressors, you know, you got to  look at the patient's clinical presentation. Is it shock? We got to look at the pathophysiology,  cardiac output, stroke volume. We got to look at monitoring, something like SVR, looking at the  preload, the afterload, the drugs that affect all this. And the fundamentals of this is it's  multifaceted. We've got the volume status, one drug, many receptors, dose response curve, direct  and reflex actions. There's many, many things that are involved here. So when we talk about shock,  we know we have hypotension, we got low SVR, we got low cardiac output. And within that state,  we have multiple things going on depending on where the patient is. And you've got that in the  center, the synergy of that fluid resuscitation with possibly myocardial dysfunction. And so  depending on what's going on, it's going to, we reach into our toolkit, if you will, to look at  what are some of those common drugs that we would use. Because what we're trying to do is strategize  what we need to do in order to improve the overall cardiac output, whether that's vasoconstriction,  vasodilation, but we're looking at that peripheral vascular. And if you look at it on a sliding chart  here in terms of the adrenergic receptors and what these agents do, they have multiple uses  in places where they can be placed. So I blinded this chart here for you to kind of take a moment  to think about in these boxes, these four boxes, what drugs you might commonly use.  I'll give you just a little bit, just think what you would put in those boxes.  So hopefully that's pretty close to what you thought might go into these boxes. And again, this is what I alluded to, that it is a very complicated process. I mean, we know  specifically ones that we want to use, but the amounts that we're going to use and how we're  going to titrate those is what comes into play. And here's another representation, maybe a little  bit different in terms of what we're trying to achieve, vasoconstriction, vasodilation,  or positive inotropy, and where these medications fall out. And here's another one where we look at,  where we got zero agonist activity all the way up to very potent. And so there's varying ranges on all these medications and how we're going to implement them and how we're going to  use them. So really, how do you make the choice? You've got a lot of options in what your patient  is presenting. And this was the study that Gretchen just mentioned about the effects of titration instructions on time to hemodynamic stability. Now, this was 1,300 patients. And  when you compared those who had the titration instructions versus those that did not,  you saw an increase of 24 minutes before hemodynamic stability occurred. A lot can happen in 24 minutes with the patient. And so again, with the mention that there's not a lot  of data out there, I know for myself when I was, I worked my first ICU in 1984, and there were no  instructions with titrating drips. Somebody took you to the bedside, and this is what you did,  and they walked you through it. And over time, you use that critical thinking to make those  decisions and know when to go up on the drip, when to go down, and that sort of thing. So when we  talk about the rationale of choice, we're looking for what effect do we want and what agents are  going to be able to do that. Here was one, here was a systematic review done in October of 2019,  Australia study, that talks about looking at all the research that's out there from 1965 to 2019.  And out of all that, there were 13 articles that were found and with varying uses of research  methods to do that. And what they found was, again, it is so varied, there's nothing there that says this is the way to do it. And I think also comes into question the fact that  when nurses are given that latitude, and we've had that latitude, that we've got a starting dose,  we've got a max dose, we've got an end goal, and we use our critical thinking to get in there to make those decisions and make those adjustments. Is it bringing the question,  are nurses practicing medicine when they do that? But that is critical care nursing, that's critical thinking, and you have to be able to have that autonomy in order to react  to what is in front of you. So one of our rationale choices, we want to restore adequate BP.  So typically we look to that vasopressor, but BP doesn't always equate to blood flow, adequate blood flow. We might want to increase the cardiac output, so we might reach for the  inotrope. To determine whether cardiac output is adequate in patients with shock is a very difficult  and multifaceted problem. With the hypotension, you get reduced perfusion pressure, you get abnormal  shedding of blood within the organs, you get cellular alterations, and then you get the down  regulation of adrenergic receptors. So what we're trying to do with this, with the fluids  and the pressors, is to restore effective tissue perfusion and normalize cellular metabolism. But  in order to do that, we've got to look at the volume status, we've got to be able to monitor  what the patient's doing, what they're presenting to us, and then look at what vasopressors we may  need to add or inotropes. So then that comes in the critical thinking, the decision, which one  works, what sequence should we do this, the mechanism of action, the goals of the therapy,  what are we trying to achieve, and what's the best available clinical evidence. And as Gretchen  presented earlier, there is some research out there that shows here's some meds that may be  used, but again, you're not really seeing how do I titrate that. And I think that's the crux  of our issue right now is that how do we titrate. So in a case of cardiogenic shock with a  complicating acute MI, you have the ventricular arrhythmias, you may have the infarct expansion,  you've got further reduction in CPP, increased myocardial O2 requirement. So again, it's a critical hypotension that you've got to manage these drips of vasopressors and inotropes.  So if you use the two charts that I put up earlier, depending on which one kind of fancies  your suit, you can kind of see where you might select on this continuum of which drug you might  go to. And in this case, maybe dibutamine. So one of our parameters is that systolic blood  pressure, right, 70 to 100. If you've got no signs of shock, maybe dibutamine is your choice.  Well, if you've got signs of shock, maybe we need to add dopamine. But we know that moderate  doses of these agents maximizes inotropia and avoids excessive alpha-1 adrenergic stimulation  that can result in organ ischemia, which is really our end point. We want to preserve that.  So when you have systolic BP less than 70, and you've got inadequate response to medium-dose dopamine or dopamine and dibutamine, you might consider norepinephrine, but it has that  antithrombotic effects. And the high-dose epinephrine, if that is a drug of choice, really, you've got to use it with caution because it promotes thrombosis in the coronary vascular  and may exacerbate the lactic acidosis. Now, norepinephrine in resistant vasodilatory shock improves the MAP, reduces norepinephrine dose, and improves coronary blood flow.  Another one that we're faced with is sepsis. So typically, vasopressor therapy, initially, target is that MAP of 65. So we're going with the vasoconstriction in terms of what we're  trying to improve, systemic blood pressure, looking at equivalent efficiency and increasing mean arterial pressure, oxygen consumption, and oxygen delivery for that end organ.  And if we add epinephrine, it can be added and potentially substantiate,  be substituted for NE, which is when an additional agent is needed to maintain adequate MAP.  Dopamine can be an alternative agent to NE only in highly selective patients, though. And it's really not recommended in terms of, in this case, where, say,  cardiac output is known to be high and BP persistently low. So again, it's about looking at the patient. What are they presenting to you? How are they responding? Because  not every patient is the same. We've got a general idea of what they're going to show us,  but until they show their cards to you and you know how to react to that, we're really kind of trying to find that sweet spot with the meds.  Gretchen talked a little bit about vasopressin. It can be added to NE with the intent of either  raising the MAP or decreasing the NE dosage. And then the VP doses higher than listed here should be reserved as a salvage med. She mentioned the VAST study, and you can see  out of 778 patients, this is on a 28-day and 90-day morbidity, the similar incidents of serious side effects were the same. And in this study here where we had  epinephrine and norepinephrine plus dibutamine, again, titrated to a MAP of 70, the primary  outcomes at 28-day mortality was the same, and then out at mortality at three months.  And then the last one I'll talk about is anaphylactic shock. Again, pretty simple. We can identify it. We know we've got to maintain the blood pressure.  It's obviously potentially life-threatening. We know the hypotension and anaphylaxis is due to dramatic shift in intervascular volume, so vasopressors may be needed to support the  blood pressure. We can do IV epinephrine, can be administered, especially when the  response to the intermuscular is poor. And then dopamine infusion can possibly be used, as well as glucagon that can reverse the bronchospasm.  So I think this is the picture that we're seeing in folks in ICUs that are trying to stay within the mandated joint commission guidelines for titration of these drips.  And I think it's causing some distress in individuals because if they don't follow that, they get in trouble. If they fall outside of it, they get in trouble.  If they follow it and it's a bad outcome, they get in trouble.  So it's really a no win for trying to do this. So I think the group out of the nursing research section, the titration task force is really on to something.  And I think they are the tip of the spear in terms of bringing this to the forefront so it can really be addressed.  And whether that's through simulation studies, we need to have data that we can present  to the joint commission that says, here's the standard, here's the protocol,  and see where we go from there.  So again, thank you. It is kind of like a shopping cart when you're looking at all the meds and things you can do and all the options that you have.  And I think there's going to be much more to come out of this.  I look forward to participating in it if possible, because I think, again,  I think it's putting nurses and providers all around. Because now you're putting more, I don't know whether you call it duty  or what the nurse is calling the physicians constantly, it just, it's overloading the system and it doesn't need to be that way.  And there's my email. Thank you.  Thanks, everyone. I'm Larry Bussey, and I'm from Emory University. I'm a left-hander.  Pardon my congestion. I would recommend for future meetings, go to Disney World after the Congress.  So I'm going to be talking a little bit about some of the emerging evidence regarding vasopressors,  in particular angiotensin-2 and the RAS system. This is work that I've been doing now for a few years, and I'm excited to share some of the data with you.  So angiotensin-2 is a new vasopressor, having only recently been approved in the last couple of years  for vasodilatory shock, but this is an old molecule. We've known about this for decades. This is ubiquitous in mammals. It's involved in a complex, highly evolved homeostatic system  of blood pressure regulation, which it does in conjunction with the sympathetic nervous system, or catecholamines, as well as arginine vasopressin.  And angiotensin-2 is also active in the microvasculature, particularly in the kidney, where it can affect GFR through manipulation of the afferent and efferent arterioles.  And it's active on a number of receptors, but the one we care about really for the purposes of this talk  is the AT1 receptor. And the picture on the right there is a cartoon of the RAS, and you can see angiotensin-2 starts out as angiotensinogen, synthesized in the liver,  and then gets cleaved by renin in the kidneys to angiotensin-1. Ang-1 then further gets cleaved by angiotensin-converting enzyme, or ACE, in the pulmonary circulature to ang-2.  And as I mentioned, ang-2 has been approved for shock based on the shoulders of a couple of studies,  including this one. This is the pilot study we did in 2014, 20 patients randomized to placebo or angiotensin-2, and we showed a nice effect on the catecholamine background dose,  which really led to this paper, the ATHOS-3 study we published in the New England in 2017. And this was a positive study. Our primary endpoint of a blood pressure effect  was reached with a high degree of statistical significance, but we did not show  a large degree, any degree really, of patient-centered outcomes. You can see the Kaplan-Meier curve there,  while showing a trend in benefit mortality was statistically non-significant.  And this has led to a lot of consternation among clinicians as to what the true role of angiotensin-2 is.  There's really been a paucity of prospective clinical research looking at this, and we're really trying to answer a number of fairly important questions.  Is there, in fact, a benefit to reducing catecholamine doses, and can we improve mortality or organ function,  or are really we just buying time while the body recovers during its shock state? The question that I really want to get to the bottom of, and I know a number of us do,  is do different agents impact different patients unequally?  And the answer to this is yes. There are certain studies that look at patient populations where we've seen a mortality benefit, including this study. This is the Jim Tunland paper  looking at a post hoc analysis of the athos-3 population, in which patients who had kidney injury at the start of the study, and who received angiotensin-2,  had a fairly profound mortality benefit compared to placebo patients. And these patients also were able to be weaned from renal replacement therapy more so than their comparators.  As well as this study, this is a study looking at low doses of angiotensin-2 and mortality.  And we found that in patients who received a small dose of angiotensin-2, 5 nanograms per kilogram  per minute or less, actually had a mortality benefit compared to those that received higher doses. And this was controlled for organ dysfunction and severity of illness.  And it was found that this is an independent predictor of mortality with a relative risk of around 0.5.  And so this got us thinking. I think what we were seeing here was a phenotype of angiotensin-2 insufficiency or deficiency versus something else such as an angiotensin-2 resistance.  And so when we looked at these two post hoc studies, the question became, what do these two patient populations have in common? And I think the answer is RAS failure.  And so I think this is nicely described by this flowchart.  We published this cartoon in a case, actually, of a patient that was rescued from an ACE inhibitor overdose by angiotensin-2. And I think it illustrates the pathophysiology nicely.  As you can see, as you recall, angiotensin-2 starts as angiotensinogen in the liver. And then through the effect of renin gets converted to angiotensin-1.  And then a normal person would be converted by ACE to angiotensin-2.  But in the setting of ACE inhibitor therapy, ANG-1 gets rerouted to an alternate pathway, a non-ACE pathway, to angiotensin-1-7.  Incidentally, ACE inhibitors also prevent the breakdown of bradykinin into its inactive metabolites. And so there's an increase in angiotensin-1-7 and in bradykinin.  Both of these are vasodilatory. And so with the increase of these molecules and the relative decrease of angiotensin-2, this leads to hypotension.  And in the setting of appropriate ACE inhibitor therapy, this is a good thing. But in the case of an overdose, obviously, this is very bad.  And this ACE inhibition, we think, is similar to ACE dysfunction that we see in sepsis. ACE activity is reduced in sepsis.  And this has been well-described, particularly in cases of endotoxemia and acute lung injury. This has been known for decades.  This is a graph of a study from 2000 showing both the decrease in ACE levels as well as ACE activity in folks with acute lung injury or ARDS compared to their comparators without lung injury.  And this ACE activity is also correlated with mortality. This is a study of 58 patients with septic shock.  The investigators looked at ANG-2 levels, lactic acid levels, Apache, SOFA, and ACE levels.  And they found that all of these were associated independently with mortality and regression. And look at the sensitivity and specificity of ACE levels.  Pretty high for predicting mortality. And incidentally, ACE outperformed both Apache and SOFA in the ability to predict mortality.  So given our knowledge of the RAS pathway and that there is a well-known ACE defect in sepsis and that RAS failure causes a reduction in ANG-2, the question then becomes,  will giving angiotensin-2 improve the outcomes in patients with RAS failure? And we looked at this.  This is another post hoc analysis, a pre-specified analysis of the athos-3 population in which we looked at ACE function and the reduction of ACE function.  And we did this by looking at the relative levels of ANG-1 and ANG-2. And in healthy patients, angiotensin-2 levels are higher than angiotensin-1 levels.  So if you look at these levels as a ratio, your ANG-1 to 2 ratio would be less than 1. And in septic patients, the opposite is true. ANG-2 levels are lower than ANG-1 levels.  So this ratio, ANG-1 to 2, becomes greater than 1. And this is, in fact, what we saw as part of the athos-3 population with the median 1 to 2 ratio of 1.63.  And when we dichotomized these patients by this median, half above the 1.63 and half below the 1.63,  we found that those patients with a ratio on the high side or greater than the study median actually had increased mortality with a hazard ratio that was almost 2.  But where this gets really exciting is the treatment effect of angiotensin-2. When we gave angiotensin-2 to these two groups, and again, this was part of the athos-3 study,  we found that in patients who were in the high ratio group, ANG-1 to 2 above 1.63, when those patients received angiotensin-2,  there was a mortality benefit compared to those patients who received placebo. In the opposite group, we did not see this mortality effect.  And so when you ask the question, are there specific populations that can benefit from ANG-2,  I think we need to include those with ACE dysfunction and those with high 1 to 2 ratios. And so look what happens here with the ANG-1 to 2 ratio during treatment.  You can see in the red, the ANG-1 level is fairly steady in the placebo group, and the ANG-2 level also fairly steady. And in the blue, that's the group that got the ANG-2.  You can see ANG-2 levels predictably went up after receiving exogenous ANG-2. But look what happens to the ANG-1 level in that group of patients. It falls precipitously.  And the question is, why does that happen? And the answer simply is renin. In the setting of septic shock, when you have ACE dysfunction or ACE absence,  you have a reduction of angiotensin-2 and aldosterone. And through a feedback mechanism, renin is upregulated, and accordingly, angiotensin-1 gets produced.  And when you treat shock with angiotensin-2, you increase your angiotensin-2 levels. You short-circuit this feedback mechanism. Renin drops, and angiotensin-1 drops.  Hyperreninemia is very common in critically ill patients, and it is associated with some important sequelae. In this study of 105 septic shock patients,  plasma renin activity was associated significantly with mortality. And in regression, it was an independent predictor of mortality,  and compared fairly similarly to Apache and SOFA in predicting mortality, as you can see by these superimposed areas under the curve.  And so we looked at this as part of the ATHOS-3 study. And this is a manuscript that's submitted.  But because you're all my closest friends, I'm going to share with you some of the data here.  And we looked at serum samples from about 80% of the patients who were part of the ATHOS-3 study and looked at renin at 0 and 3 hours.  And you can see predictably the serum renin levels in our patients were very high, a median level of 172. And look at how this compares to patients, normal patients,  and then patients with these other diseases that are commonly associated with high renin, cirrhosis, salt depletion, SBP, or unilateral renal artery stenosis.  Where this gets really exciting is when we looked at survival according to renin levels. So we did a similar analysis to the 1 to 2 ratio,  where we dichotomized our patients with those with a high renin and those with a low renin at the study median.  And predictably, those with high serum renin who received angiotensin II had a mortality benefit when they received angiotensin II.  And those who had a serum renin below the median, we did not see that benefit. And so I think we can add to this list of those that would benefit from angiotensin II,  patients with a high serum renin. So the question is, can we operationalize this? Can we check ACE levels? Can we check the 1 to 2 ratio? And the simple answer is no.  As I mentioned, ACE is primarily in the pulmonary endothelium. This is very hard to measure. It takes a specialized lab. And likewise with ANG1 and ANG2 levels.  These are not routine levels. They're send-out levels. And only a few labs around the country will actually do this. But we can operationalize serum plasma renin.  This is a widely available test. It's inexpensive. It has established performance. This is available probably in all of your hospitals right now.  And so where I think we're going with the future of vasopressor therapy is the potential use of renin as a biomarker, where an undifferentiated patient with shock shows up.  We do our diagnosis. We give them a little bit of fluid. We get our nonspecific biomarkers, lactate, blood cell count. We get a blood culture, which comes back in four days.  And we get a serum renin. And with that, we're able to decide and shape our therapy accordingly. High serum renin, maybe these patients would benefit from angiotensin 2.  And as I'm about to show you, we can also do a responder analysis and look at the response to this therapy. Serum renin already has been looked at in this vein.  And this is the recent study by Gleason looking at plasma renin levels from patients with various types of shock and without shock.  And they found that the rate of change of renin was correlated with survival. And so we looked at the change in renin as well in our analysis.  And you can see here, as I mentioned, those with high renin who got angiotensin 2 already had a mortality benefit.  But you can see here that at three hours, the serum renin level falls in the folks that got ang 2 compared to basically no fall in those who received placebo.  And so renin might be a very nice biomarker, especially because angiotensin 2 has not shown patient-centered benefit in those patients with undifferentiated shock.  As I mentioned, populations with ACE deficiencies do benefit from ang 2. And renin can identify those patients who have an ACE deficiency.  And this is an easy-to-measure available test, which will correlate with disease. And so I'll end there and tell you this is an exciting time.  I think that we're going to start checking serum renin in our patient populations. I would urge you to do the same, if for nothing else, just to see what happens.  And perhaps as a cumulative body, we'll be able to understand this phenomenon a little bit better and become a little bit smarter about treating our septal shock patients.  And with that, I thank you.  left for any questions for any of the speakers? Hey, how are you doing? This is Bruno from Dallas. I was wondering if you guys saw any difference between people  that were, that had received AIDS or an ARB and the response to angiotensin-2. There wasn't a robust analysis of that in the athos-3 population. We did see a few patients with that.  That wasn't something we looked at robustly because we just didn't have the numbers there. But there are case reports describing a nice blood pressure effect in both drugs.  My anecdotal observations are that in folks who receive, who have ACE inhibitors, they have a more robust response than those with ARBs only because you're  dealing with an absence of ANG-2 versus out-competing a receptor for ANG-2. But in fact, there was a poster that was presented in this meeting describing  a recovery of an ARB overdose in a patient with ANG-2. And obviously, you saw our manuscript of ACE inhibitor overdose. So I think it works probably in both cases. Hello.  This is Juan from the University of Wisconsin-Madison. Great presentation to you guys. Very educational. I have a question, Dr. Booth, regarding  the use of renin in patients with sepsis when they come. It was really interesting to hear that it can be used as a biomarker. But the first thing that comes to my mind  is we have several patients that are in the ED and they already receive fluids, other vasopressors. And we know that both of those several interventions  are going to alter their levels of renin, basically. Aside from that, is it still might be a reliable biomarker? It's hard to know because we haven't looked at that yet.  One of the problems with serum renin is that it's not a point-of-care test. It's not a one-hour test. It's a 24-hour test. I know that there are a number of folks looking  at trying to shorten that into an ISTAT type of test where you can get it and direct your therapy right then and there. So whatever serum renin we're getting,  we're looking at it retrospectively, if you will, after a day's worth of therapy. Renin will absolutely be affected by just volume resuscitation.  And in fact, will be affected probably by the non-RAS pressors. So that's a good question. I don't know the answer. What also excites me is, what about those patients  with low serum renin who show up with shock? What is that phenotype? So I have more questions than answers.  All right. Any other questions?  Got one? Yes.  I'll ask you one quick question. My name is Zach from Idaho. With some of the regular concerns around titrating pressors and adding multiple pressors in which you're titrating both,  the survival data that you showed with angiotensin responders at 5 nanograms, does it make sense to add angiotensin 2 at a set rate of 5 nanograms  to see if that would benefit patients? I've often thought about, so I'm a big believer in multimodal therapy early on in the course of disease.  I think that, as I think Gretchen was alluding to, using multiple therapies with different mechanisms of action make perfect sense. While there's not a robust library of outcomes  with that strategy, I think we are seeing some signals that decatecholaminization is helpful, that vasopressin has a role, that angiotensin 2 has a role.  The other side of the conversation is it's complicated to titrate angiotensin 2. All of a sudden, you're bringing in another titratable drug  and the nurses at the bedside, given the new JACO requirements, will have that extra complexity. Maybe there is a role for just a fixed angiotensin 2 dose at 5 nanograms.  I've often thought about doing it. I haven't done it yet. We have a protocol at Emory that I wrote that actually calls for titration.  But I think it's absolutely something worth looking at and maybe someone smarter or with more resources in the room may look at that here.  Hi, nice presentation. I'm Juan from Oregon. What is your take in the dose of vasopressin of 0.06?  So I think that's a good question. There is some data, of course, regarding the comparison of 0.03 to 0.06667, however they did it in that study.  And I will say, at least in my population, it's not something that we have adopted heavily. But I do believe that there are some patients who  are refractory to every agent that we put them on. And in those patients, those are at the extremes of our severity of illness. I have actually utilized higher doses of vasopressin.  I would say, again, it's very rare. And I have seen some benefit in those patients that I do it with. Again, it's more so from a hemodynamic standpoint.  I can't say overall that that is impacting their outcomes. But I do think that there are some patients that can benefit from that therapy.  But again, it's not a practice that I generally incorporate for every patient. I assess their response to vasopressin if they're having a good response to it.  I keep them on the dose that we started on, which is at my institution, 0.03. And then maybe if I saw a positive response, and then maybe further decompensation  later down the road, I think it's at least something that can be discussed. But I do think we need more data in the comparison.  Hi. My name is Ying. I'm from Chicago. I just have a quick question for you. At Emory, what is your practice now regarding angiotensin-2, like when you started?  We start vasopressin at 0.1 mikes per kg per minute of catecholamines. I think that's in keeping with the data that Gretchen showed on the down titration, but  I think the same holds true for the up titration. So we start vaso at 0.1 and then start ang-2 at 0.2. So we're fairly early in the disease process, and we're using all three.  Our down titration is similar and driven by background norepinephrine equivalent doses. And I'm happy to share the protocol with anyone if you'd like. I'm happy to email it to you.  We've got time for one more. Pervin Shaw from Florida. I missed the first couple of minutes, so Gretchen may have covered this, but if you're on two  or three vasopressors, should you maximize those before adding another agent? That's a great question.  I actually did not cover that specifically because we really don't have a lot of data. I feel like I said that throughout my whole presentation.  But I do think, and I agree with Larry, too, that there is some more data, again, not hugely robust, but that might give a signal towards multimodal therapy more earlier up front.  So I don't think that we know what the right approach is, but I do at least, I am a believer in the decatecholaminization.  And I try to not necessarily maximize my doses before I add other ones. You might be at an institution where you have varying levels of where your cutoffs  are for max, but I, too, do tend to agree that maybe we should be adding some of these other agents first before we maximize.  But like we've all talked about, that makes it difficult, at least at the bedside on titration for our nurses on how do they titrate it.  I personally have a very detailed conversation with my nurses when patients are on more than  one agent, unless it's vasopressing because it's a set rate, and saying this is the agent you should target first.  Once you get here, then maybe you can start weaning back this agent, et cetera, if that helps answer the question.  And we actually don't allow the use of ANG2 once our catecholamines are above a certain level, really for, because the evidence, at least at our institution, has shown that once  your catecholamines are 0.5, 0.6, 0.7, those patients don't live. And so we use it early, and we prevent its use late in the disease only because you're  basically, I hate to boil it down to this discussion, but you're throwing good money after bad.  You're using a valuable resource, an expensive drug, in a patient who, if catecholamines have already outrun you, they tend not to live.  And we have 250 patients that we've looked at with early versus late use, and in those patients who have catecholamine doses that are 0.5, 0.6, 0.7, none of them live.  Last question. Hi. I'm Bobby Rezai from St. Bourne, New Jersey. Question for Larry.  Did they look at the renin levels in patients with AKI or CKD on presentation to see if there's a fluctuation? As part of athos? Yeah.  I mean, because of the renin, with the high renin levels in septic shock, will AKI or CKD have any effect on those levels that we measure? I am not sure. But I think they would.  The real question is, in which direction would it go? I mean, the conventional wisdom was that, in folks with CKD or AKI, you'd have renin dysfunction and low renin.  But I actually don't think that that's the case. But I think that's something we'll have to take a look at.  And this is something that is an ongoing discussion, and we can look at this going forward in all of our patients. I think it's worth doing. Thank you. All right. All right.  I want to thank you all. And if you could help me thank the speakers again. All right. This ends this session. And safe travels.

Video Summary

In this session, the speakers discuss the titration and discontinuation of vasopressors in the treatment of shock. They start by discussing the various vasoactive agents that are currently available and their different receptor activities. They then highlight the lack of guidelines and variability in practice when it comes to titrating these agents. One approach that has been taken is the addition of titration instructions to medication orders to assist nurses in their administration. However, the effectiveness of this approach is still unclear. The speakers also discuss the discontinuation approach for patients receiving both norepinephrine and vasopressin. They note that there is some evidence suggesting that discontinuing vasopressin first may be associated with an increased risk of hypotension, but it does not impact short-term mortality. They also mention the high cost of vasopressin and the potential for cost savings by discontinuing it earlier. Finally, they discuss the emerging use of angiotensin II as a vasopressor, particularly for patients with angiotensin II deficiency or resistance. They highlight the potential use of renin as a biomarker for identifying these patients. Overall, the speakers emphasize the need for more research and guidelines to improve the titration and discontinuation of vasopressors in the treatment of shock.

Asset Subtitle

Pharmacology, Shock Non Sepsis, 2020

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2020 Critical Care Congress held February 16-19, 2020, in Orlando, Florida, USA.

Learning Objectives

Review the current evidence surrounding effective titration and discontinuation of vasopressors
Recognize the utility of evidence-based and protocolized vasopressor use in the intensive care unit
Discuss novel vasopressor agents in catecholamine-resistant hypotension

In the Details: Titrating and Discontinuing Vasopressors

Gretchen L. Sacha

Protocolized Vasopressor Utilization: Regulatory Considerations

John J. Whitcomb

Emerging Evidence: Where Do New Vasoactive Treatments Fit?

Laurence W. Busse

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Shock Non Sepsis

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Vasoactive Agents

Tag Guidelines

Tag Shock

Year 2020

Keywords

titration

discontinuation

vasopressors

shock

vasoactive agents

guidelines

variability

norepinephrine

angiotensin II

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