Hello. My name is Ashish Khanna, and this presentation is titled Ready, Set, Squeeze, Optimal Timing for Vasopressor Initiation. These are some of my relevant disclosures, and these are some of my affiliations. I will start with a very basic schematic of the types of circulatory shock. The most common type of circulatory shock is distributive shock, which accounts for about two-thirds of all circulatory shock. If unspecified, distributary shock is mostly septic shock, although non-septic variants of distributive shock are also present. The other types of circulatory shock include cardiogenic, hypovolemic, and obstructive shock. The bottom line with most forms and manifestations of shock being hypotension, that is low mean arterial pressure or MAP, and vasopressors are then applied to increase blood pressure in most cases of shock. If you look at the initial assessment of shock states, this is a really nice review by John Levenson and Daniel DeBacker, published in the New England Journal of Medicine almost 10 years ago, that divides up shock into clinical categories based on manifestations, including clinical signs, lab values, and echocardiographic findings. I highly recommend this as sort of a basic start for all listeners of this as they try and understand and assess shock states. So the guidelines for management of hypotension in sepsis and septic shock, also known as the surviving sepsis guidelines, also focus on hypotension and vasopressors. The basic essence of these guidelines is if there is low blood pressure in the setting of sepsis, which would constitute to be septic shock, then the initial therapy is crystalloids to at least 30 cc's per kilo, and or colloids, and if the blood pressure is still low, then the first vasopressor of choice is norepinephrine, followed by epinephrine or vasopressin, and then dobutamine in cases of pump failure. And various iterations and revisions of the guidelines have, by and large, sort of maintained the same stance on fluids and vasopressor therapy in septic shock. So like I just said, the overall philosophy is fill the tank, and if the patient still doesn't maintain a pressure of an adequate blood pressure, then decrease the capacity of the tank or increase the pump speed or both. Now hypotension is important, you know, in critically ill patients. It does lead to organ system failure. This is a study we did in 10,000 patients with septic shock across various US ICUs, and we saw that for every one unit increase in a time-weighted average mean arterial pressure less than 65, the odds of in-hospital mortality increased by about 11%, and the odds of acute kidney injury increased by about 7%. So both organ system failure and mortality substantially go up as more time is spent at lower blood pressures in patients with septic shock. When we look at how to best defend a mean arterial pressure in patients with septic shock, it's important to look at things in the perspective of early and severe and refractory shock, and early shock is when most interventions are time-sensitive and important, so underlying and treating a cause and fixing the source of the problem, appropriate fluid resuscitation and physiological measures. And then norepinephrine monotherapy is, like I just said, the underlying foundation of early vasopressor use in patients with septic shock, and as the shock worsens, then, you know, correction of metabolic derangements like acidosis, continuous correction of volume status, and then applying other vasopressors like vasopressin, epinephrine, and angiotensin to along with adjunctive therapy like corticosteroids also becomes really, really important. Now I will say that keeping all of this in perspective, you see that the only vasopressor here mentioned in early shock is norepinephrine, although as I'm going to show in the slides to follow, more and more evidence suggests that both vasopressin and angiotensin too might have a role in early septic shock as well. So I just talked about three different kinds of vasopressors. You can basically link them to the three stools of a three-legged stool of counter-regulatory systems for blood pressure. That's the sympathetic nervous system, the arginine vasopressin system, and the renin angiotensin system, and that really constitutes early multimodal vasopressors. Now in the same breath, less exposure to vasopressors might also be better, as suggested by this, the results of the 65 trial where patients more than 65 years of age were randomized to usual care, which was a map between 60 and 65, sorry, usual care, which was a map at least 65 or more, and permissive hypotension, which was a map between 60 or 65, and no difference was found in the two groups in terms of mortality as an outcome. So it might totally be that squeezing patients too hard may also be an issue, and we've got to be careful as we decide and titrate and understand how we are using vasopressors in these types of patients. And importantly, the vasopressor blood pressure sweet spot is critical. On the left side here, we see on the x-axis, lowest map for at least two hours, and on the y-axis, average vasopressor rate in micrograms per kilo per minute in norepinephrine equivalents, and the co-exposure effects on mortality. In both the panels, the lighter shades indicate a greater co-exposure effect on mortality, and a darker blue indicates a less co-exposure effect on mortality. On the left side, for a constant vasopressor dose, for example, at about 0.2 micrograms per kilo per minute, there is a sweet spot somewhere between a map of 55 to 65, where there is minimal co-exposure effects on mortality. But as the map actually goes up at the same vasopressor dose, there might be, once the map gets to about 85 or 90, there might be a slightly increased effect on mortality. On the other hand, if we look at the lowest map and trace it up vertically, and say we look at a map of 60 and trace it up vertically on the left side panel, we will see that the overall threshold for vasopressor dosage and co-exposure effects on mortality tilts a little bit towards the left side, which means that as vasopressor use increases, the optimal sweet spot for blood pressure might be slightly lower. You can understand that in a rather simplified manner with the figure on the right side. So it's really how compliant the system is in terms of a vasopressor response. If we look at the three arrows here, the most compliant arrow where there is maximal blood pressure response to very little increase in vasopressors is the arrow that is at about 30 degrees. That really shows very little co-exposure effects on mortality. But as you need more vasopressor to get to the same blood pressure, then the co-exposure effects on mortality are higher. So the bottom line here being that it's important to understand where that sweet spot is for every critically ill patient. Now what about vasopressors and inotropes? We know that basic vasopressors include catecholamines and catecholamine derivatives like norepinephrine, epinephrine, dopamine, phenylephrine, and then vasopressin. And then I talked briefly about angiotensin too. They all have different receptors that they act on and different effects on inotropy and chronotropy and afterload increase. I won't go into the details. I will leave the slide up here for everyone to digest. The important other part on this slide is the concept of norepinephrine equivalents and important to understand that everything equated to norepinephrine, dopamine is a very weak vasopressor. Vasopressin is a very potent vasopressor compared to norepinephrine and phenylephrine is similarly a weak vasopressor compared to norepinephrine. If we look at norepinephrine, we go back to the 1950s where norepinephrine first started being used in the treatment of shock and was almost revolutionized how shock was being managed. Fast forward to 2022, catecholamine monotherapy, which is still very prevalent. We've now understood that once we get to really high doses, that's about 0.8, 0.9 to 1 microgram per kilo per minute or 100 micrograms per minute if looked at otherwise, that that does lead to a substantial increase in organ system failure and mortality. The issue there is that even though this is retrospective data, the signal is very, very strong and that's why we need to think beyond just catecholamines when it comes to management of shock states in the ICU. The other problem is refractory vasodilatory shock, although we don't really know how to define in terms of a dose relationship clearly a certain very specific threshold dose. We do know that, again, higher doses of norepinephrine and norepinephrine equivalents, somewhere around 1 microgram per kilo per minute, increase all-cause mortality to about 50% to 80% and this is irrespective of the primary source of the shock being treated or not. For patients who don't have mortality, they often have lots of morbidity with ischemic changes as shown here in the slide. High-dose vasopressors also portend poor survival. This is a study we did with a certain subset of patients in the medical ICU where we saw that exposure to high dose of norepinephrine equivalents in the first 24 hours of ICU stay increased in-hospital mortality, the green dots here being survival, red dots being death, as you got to about maximum norepinephrine equivalent dose of about 0.5 microgram per kilo per minute in-hospital mortality went up to 50% or more. And then this is the infamous Takotsubo cardiomyopathy, also named after Takotsubo, a Japanese octopus trap, and really sympathetic nervous systems affect on the heart, increasing myocardial injury, troponin leak, and ballooning of the LV apex. So why are we talking about all of this? Well, it's important to understand that vasopressors work well together. It's a very simple statement that myself, Patrick Wierzewski, Mark Leone, and others have talked about in the last five years or so, knowing that there is a very well-orchestrated counter-regulatory system for blood pressure in the human body, both from the pituitary vasopressin secretion to the adrenals, secreting the adrenal hormones, norepinephrine, epinephrine, with the beta and alpha receptors on blood vessels on the heart, the vasopressin receptors on the blood vessels, and then the renin release from the kidney as well, and turning angiotensin I to angiotensin II, the downstream cascade, which really shows that we should be using vasopressors together and synergistically, because that's how the human body functions at baseline. And that's what we've been talking about, a synergistic model for management of blood pressure that includes not just the adrenals, but also the posterior pituitary and the renin-angiotensin system in the liver and the kidneys. So what's the big deal? People say, okay, well, why do we really need to do multimodal and early vasopressors? Any vasopressor can increase blood pressure. Well, if you say something like that, it's almost like saying, why don't we give 18 milligrams of metoprolol as a single agent in hypertension? And we don't do that. We don't give 80 grams of metoprolol as a single agent in hypertension, because that would fix the hypertension, but kill the patient. And we try and do a multimodal balanced approach to fix hypertension. Similarly, we need to do a multimodal balanced approach to fix hypotension. So what can we do? Well, the first issue is early vasopressin. And let's see the data with that. This is an important study that comes from Gretchen Saucha. She looked at patients who received vasopressin and looked at predicted probability of in-hospital mortality and looked at the timing of vasopressin initiation. The different colors here denote the different times of vasopressin initiation. And you can plot them down to lactate levels and vasopressin initiation. And as there is increasing delay with vasopressin initiation, which is a more darker colored curve here, the in-hospital mortality increases and increases at similar levels of lactate compared to earlier times of vasopressin initiation, time here being time after diagnosis of shock. And to make it simpler, if you look at, yes, norepinephrine was initiated in these patients, and then you look at time or dose of norepinephrine at which vasopressin was initiated, mortality increased by 20% for every 10 micrograms per minute of norepinephrine equivalents at vasopressin initiation. So for every increase of 10 for norepinephrine equivalents, there's a 20% jump in mortality. And there's almost a straight line here on the graph that you see with the mortality going from 40% to about 70% as norepinephrine equivalent dose went from 0 to 60 micrograms per minute. So are we really ready for early multimodal vasopressors? We have to ask ourselves the question after looking at this, again, retrospective data, are we really willing to start vasopressin that early in our management paradigm for septic shock? Well, before we go into that, let's also talk about angiotensin 2. We are all familiar with our results of the ATOS 3 trial, the angiotensin 2 for treatment of vasodilatory shock. We published this in the New England Journal in 2017. And remember for ATOS 3, angiotensin 2 or placebo was initiated at a norepinephrine equivalent dose of 0.2 micrograms per kilo per minute. That is the point of randomization and enrollment into the trial. And yes, we know the results have a hemodynamic benefit and also catecholamine sparing with patients who received angiotensin 2. That is the blue graph here on the right side compared to the red-orange placebo line. So who responds to angiotensin 2 and vasopressin? This is a post-market study at the Mayo Clinic where they saw that in patients who responded to angiotensin 2, that is in the pink-red line here, they had an increase in blood pressure. They had a lower background vasopressor dose. And for these responders who were also on vasopressin and had normalized lactates, there was a survival benefit. So if there was balanced resuscitation, angiotensin 2 led to an improved survival. More recently, we've looked at data in cardiothoracic surgery. And this is what we do at our institution with cardiothoracic surgery. We start angiotensin 2 in the setting of optimized cardiac function and ruling out hemorrhage. We start angiotensin 2 at about 20 nanograms per kilo per minute. But the threshold background vasopressor dose is pretty low. We start at about 0.15 micrograms per kilo per minute of norepinephrine equivalents. And then we titrate those background vasopressors down and angiotensin 2 up to achieve that balanced state and keep the map above 65. So we have a rescue mechanism if angiotensin 2 does not work at all. But let me look at the early angiotensin data, like the early vasopressin data that I just showed you. And similarly, if you look at ATOS 3, I just told you that we randomized at 0.2 micrograms per kilo per minute of norepinephrine equivalents. Patients who were randomized at less than 0.25 micrograms per kilo per minute was half as likely to die at 28 days compared to placebo. The difference was statistically significant. And the Kaplan-Meier curves for survival are shown here in the slide. So again, both vasopressin and angiotensin 2, when initiated early, make a difference in survival. So what does surviving sepsis say? The latest iteration of the guidelines does provide some guidance to when to start and switch vasopressors. And in a remark here, they have said that in our practice, vasopressin is usually started when the dose of norepinephrine is in the range of 0.25 to 0.5 micrograms per kilo per minute. And then they also suggest when to add epinephrine and vasopressin and provide quality of evidence for each of the interventions along each of the vasopressors. So what about early multimodal strategies? Well, they sound really attractive, and we do believe that there's physiological reason to do early multimodal vasopressors. But if you read our review that we just published with Sheila Maitra, Patrick Marcleoni, and several others, the quality of evidence and RCT-based evidence around early multimodal vasopressors is very thin. So we definitely need to do a bigger RCT and plan something where we can test this theory of early multimodal vasopressors. More recently, our group looked at the timing of vasopressors or vasoactive agents and corticosteroids and septic shock and sort of the shortcomings of the surviving sepsis guidelines. And based on published data, we indicated when it would be most appropriate to initiate different types of vasopressors. And I would encourage you all to read this review in detail, and I'd be open to questions afterwards. And if you look at the whole spectrum of vasopressors, there's definitely an emphasis on non-adrenergic vasopressors. So the methylene blue and hydroxycobalamin and so on, and including vasopressin, angiotensin 2. This is a systematic review and meta-analysis of randomized trials where there's a very slight benefit in favor of non-adrenergic vasopressors. But this was done before angiotensin 2 came along, and we are now planning a bigger one with all of the angiotensin 2 data in it. And that'll be interesting to look at those results. So as I come to the end of this talk, the bottom line is less is more, and catecholamines sparing strategies and septic shock are really important. And three things I would like you all to go away with today is early multimodal vasopressor therapy is really important. Do not wait for failure of one vasopressor before initiating the next one. I did not talk about this today, but biomarker-based resuscitative vasopressor therapy is really important. And do not, do not forget adjuncts, adjunctive therapy. Again, I didn't talk about it today. Both steroids, vitamin C, and several other adjuncts are really important in the management of sepsis and septic shock. Thank you for your patient listening. Please reach out with questions, and good luck. Thank you.

circulatory shock types

vasopressor initiation

hypotension management

norepinephrine guidelines

multimodal vasopressors

septic shock management