Hi, my name is Shibashi Chatterjee. I'm a cardiovascular surgeon and intensivist at the Baylor College of Medicine in Houston, Texas, and it's a privilege to present at this year's Society of Critical Care Medicine annual meeting. My assignment is to discuss the pathophysiology of vasoplegic syndrome, and I look forward to this session. These are my disclosures. So today what we'll do is we'll begin with discussing what is vasoplegic syndrome, why does vasoplegic shock occur, the role of vasopressors, and what does our clinical experience teach us about our understanding of the pathophysiology. First, what is vasoplegic shock? This is typically characterized hemodynamically as a mean arterial pressure in the 60 to 65 range, a high cardiac output, a low systemic vascular resistance, the need for, quote, high dose vasopressors, and what hinders us really academically is a lack of a consensus definition to which to be able to compare different series and different interventions. Now, refractory vasodilatory shock is associated with a very high early mortality. Things like limb ischemia plague these, our patients with this, and clearly we can see here that the higher the norepinephrine equivalent dose and need for vasopressors, the higher the mortality. Now, when does vasoplegic shock occur? Most commonly it's in the setting of septic shock. It's also common after post cardiopulmonary bypass, and it can be seen in burns and ARDS and pancreatitis. And what does it do? It results in a capillary leak that results in hypovolemia, systemic vasodilation, and it's associated with tissue hyperperfusion and increased serum lactate levels. When does vasoplegic shock occur? So the physiologic adaptive state is such that the resistance vessels defend the blood pressure so that depending on the clinical condition, they constrict or dilate as necessary to support the blood pressure. In the maladaptive pathological state, the loss of vasomotor tone in the resistance vessels results in systemic hypotension. Now, endothelial and smooth muscle mediated vascular dysfunction has a host of factors. There are a number of intrinsic factors that are responsible for the systemic vasodilation, as well as extrinsic factors that influence this as well. And here you can see the interrelated model of refractory vasodilatory shock. Sometimes, I think as researchers, we target one single intervention as a silver bullet. I think this sort of suggests that it may be necessary to target multiple areas of this cascade with different therapeutic strategies. Now, the physiologic response to vasodilatory shock really requires three systems. As a counter-regulatory system, how nature has evolved us to be able to defend the blood pressure. Here, you can see the sympathetic system, the renin-angiotensin-aldosterone system, and the arginine-vasopressin system all interact in different ways to be able to support the blood pressure. Now, unfortunately, in septic shock, each of these areas demonstrate hormonal deficiencies, and each of them are functioning at a less efficient state. Now, the role of vasopressors and how do we come to our understanding. So, it's important to recognize that when comparing different vasopressors, it's also important to be able to understand that we compare comparable doses. So, the concept of norepinephrine equivalent doses is very helpful to be able to do that and to translate different pressure requirements. The Society of Critical Care Guidelines, the Surviving Sepsis Guidelines, gives us some small insight into this, but really, aside from norepinephrine as our first-line agent and a MAP of 65, everything else is sort of at a low evidence base. Now, how have we come here? How do we know that this is where we're at? Well, a lot of this starts with the SOAP-2 trial. So, this was a study of nearly 1,700 patients that compared norepinephrine to dopamine, found that the mortality was about 50% in both groups. They did notice a difference in a much higher incidence of arrhythmias in the dopamine cohort. What was interested is that in the cardiogenic shock group, there was a clear survival advantage with norepinephrine, which was less present in the other forms of shock. The VAST trial looked at almost 800 patients. Everybody was on low-dose norepinephrine. If they needed to escalate, they either got randomized to the addition of vasopressin, or they went on to higher-dose norepinephrine. You can see here that, overall, there was no real mortality difference. Both groups had about a 35% to 40% mortality. What is interesting is that in the less severe shock state, there was a benefit demonstrated with the addition of vasopressin. So, this has guided many of us in our strategy for early initiation of vasopressin. Now, the VANISH trial looked at a little over 400 patients. They looked at norepinephrine plus or minus hydrocortisone against vasopressin plus or minus hydrocortisone. So, really four comparator groups here with a primary outcome of kidney failure-free days. What they found was that results were similar with respect to kidney failure-free days and survival, but there does appear to be less need for renal replacement therapy in the vasopressin group. Now, the VANKS trial in cardiac surgery looked, it was a Brazilian trial of 300 patients that compared monotherapy vasopressin versus monotherapy norepinephrine, about half cabbage, half valve, with a primary composite endpoint of mortality plus severe complications. You'll see here that the Euro score was 5, which translates to about an STS-predicted risk of mortality of about 2%. So, this is a very low-risk cohort of patients. Here, the results indicate that the vasopressin group clearly had a better event-free survival results compared to the norepinephrine group. Now, it is important to look at the specifics of this to see what drove that outcome. You'll see here that survival was not that different, about 15% in both cohorts, indicating there was really not a survival difference, but it also illustrates how severe vasoplegia can be, since you would expect a 2% to 3% mortality in this group, clearly a five-fold higher increase in mortality. What we did see was that there was a higher incidence of acute renal failure in the norepinephrine group, with a number needed to treat of about four in the vasopressin group. To prevent this, and then clearly similarly in secondary endpoint of atrial fibrillation, much higher in the norepinephrine group, with a number needed to treat of six, favoring the vasopressin group. So, a systematic review by McIntyre of nearly 3,000 patients, of which seven of them were randomized trials that had over 1,100 patients. You can see here that this was basically comparing norepinephrine versus combination norepi plus vaso. You'll see with respect to early mortality, there was about an 11% relative risk reduction, favoring combination therapy, with a number needed to treat of about 25. Atrial fibrillation, similarly about a 25% relative risk reduction, and a number needed to treat of 12, favoring combination norepi and vaso. No real difference in renal replacement therapy, a really small difference in limb ischemia, favoring norepinephrine, but you'll see here a number needed to harm of over 40. Now, limb ischemia I think is important to understand in the setting of severe sepsis. This is a review of eight studies, over 1,500 patients. You'll see here that about a third of the patients were already in DIC. So, what they found was that it's hard to really tease out what to blame for limb ischemia, but for most patients it was a combination of being in DIC, liver shock, as well as the use of vasopressors. Now, where vasopressin I think has a unique advantage is in the setting of right ventricular dysfunction. In this setting here, you can see patients loaded with milrinone after cabbage, the effects on pulmonary vascular resistance over SVR ratio. You can see here that in the norepinephrine group, there really was not a significant change in the PVR to SVR ratio, but in the upper right, you'll see the vasopressin group did show a beneficial reduction in PVR and SVR, and that's illustrated most dramatically in the lower panel. So, I agree with Josephino and Yanni Agostini's that vasopressin really is the perioperative gift that keeps on giving. So, clinically, when do I use vasopressin over norepinephrine in monotherapy alone? I like it in the setting of atrial tachyarrhythmias and in the setting of RV dysfunction. Now, not everybody responds to vasopressin. This is an analysis from Sasha and the Cleveland Clinic group. What they see here is you can see that almost a little over 900 patients here, about half the patients were responders to vasopressin and about half were not. You'll see here that, as you'd expect, the responder group had a better survival outcome than the non-responders, clearly associated with the lower the lactate, the more likely they were to be a responder. You can see throughout that the non-responders needed more additional catecholamines and the responders had better mean arterial pressure results accordingly. Now, does timing matter with regard to vasopressin? This is an analysis from the same authors three years later, looked at over 1600 patients, a high-risk group of patients with a SOFA score of 14 and nearly a 60% overall mortality. What they found was that the mortality increased by 20% by every 10 micrograms per minute of norepinephrine equivalent dose that was needed before initiation of vasopressin therapy. So, the earlier the better. Here this shows that the later the initiation of vasopressin, the higher the mortality. You see here the higher the lactate at the start of vasopressin, the higher the mortality. So, if you're going to start vasopressin, better to do it earlier. Now, moving on to the renin-angiotensin-aldosterone pathway. Well known, the liver makes the angiotensinogen, the lung makes angiotensin-converting enzyme. This is converted to angiotensin-2 that acts systemically to support the blood pressure. In the case of shock where there's a disruption in ACE, you see high levels of plasma renin in angiotensin-1 and low levels of angiotensin-2 and aldosterone. So, in order to intervene, our moderator, Dr. Khanna and his group led the angiotensin-2 for the treatment of vasodilatory shock or the ATHOS-3 trial. Now, angiotensin-2 is not a new drug. It's been around for nearly 60 years and was used often in the 1960s. But the ATHOS-3 investigators led over 300 patients, 80% who had septic shock with a primary endpoint of increasing the mean arterial pressure by 10 millimeters or sustaining a MAP of 75 for at least three hours. And you can see here that the angiotensin-2 group successfully had a higher mean arterial pressure and they were able to come off of vasopressors more quickly than the placebo group. You can see here also a suggestion of a survival benefit, probably just a type 2 error, but clearly a suggestion of a survival benefit. Now, this is something that I've looked into as well in post-cardiac surgery. We looked into the ATHOS-3 in a subgroup, clearly a benefit with angiotensin-2 after cardiac surgery. And we looked at it in some other settings, including after thoracodominal aortic surgery, where you need to run a MAP of 85 or higher to reduce the risk of spinal cord ischemia. Now, just like vasopressin, who responds to angiotensin-2? So, this is the Mayo Clinic group, 270 patients, five centers. They found that about two-thirds of patients responded to angiotensin-2, about one third didn't. Those who responded tended to have lower lactates and already have vasopressin on board as a responsor, again, arguing for earlier initiation of vasopressin. And you can see the responders had a higher mean arterial pressure. They were able to come off vasopressors more quickly, and they clearly had a lower mortality in responders, cutting the risk of mortality by about one half compared to the non-responders. Now, who are the responders? What do we know about that? Well, interestingly, again, another subgroup analysis off the ATHOS-3 showed that those patients who had low renin were not really had less likelihood of being responders and less of a survival benefit. Those patients who had high renin at the start of treatment were more likely to be responders and more likely to have a successful outcome. This shows the same thing very similarly. Again, the patients who did the worst were the people who were placebo patients with high renins. And interesting, you'll see here in the blue, the angiotensin 2 group, basically, whether you were low or high renin, it basically normalized it for a survival benefit. Now, I think the renin kinetics are really interesting. Multiple studies in the literature do suggest that renin and comparing a little bit to lactate, clearly associated with worse outcomes with vasoplegic shock. In fact, some studies actually demonstrate that renin might be a better predictor than lactate of clinical outcomes. And our moderator even provocatively titled an editorial saying that is renin the new lactate and something we might be looking at more clinically. Now, what does our own clinical experience teach us about our understanding? So this makes sense. So we know how the renin-angiotensin cascade works. And clearly, we know that if diminished ACE leads to high renin, so clearly ACE inhibitors and IRBs, by blocking the ACE and creating a high renin, is much more likely to have a bad outcome. So stopping ACE inhibitors seems like a great idea to be able to prevent vasoplegic shock. Well, this interestingly was studied. A Canadian group led by Sean Van Deepen, they looked at almost 200 patients. And what they found was they stopped ACEs and IRBs 48 hours before surgery. And they found no difference, however, in the development of vasoplegia or the need for vasopressors. So there's still more to understand about the relationship between renin-angiotensin and what can affect this. So in conclusion, I'm going to discuss, this is our whole algorithm. And I'm looking forward to the next talks about this. We used to first start with norepinephrine, then we tried vasopressin. We tried multiple different systemic adjuncts. And finally, we just surrender in this setting. Now what we do, we start with norepinephrine. We go very quickly to add vasopressin. If that doesn't get us our pressure that we want, we go right to angiotensin 2. Once we get the blood pressure that we want, we try all sorts of different adjuncts and target it to what we think might help the patient most. And where we go next is working with earlier decision-making tools to perhaps be able to warn us sooner for those patients who are developing or worsening vasoplegic shock to intervene earlier. So in summary, I think earlier use of vasopressin and angiotensin 2 may be reasonable. An individualized approach is often necessary, and newer diagnostic and therapeutic strategies hold promise. I'd like to thank Dr. Khanna for the use of a few slides along the way. And with that, I look forward to the panel discussion and the opportunity to answer any questions. Thank you.

vasoplegic syndrome

pathophysiology

vasopressors

vasopressin

angiotensin 2