Hi there, thank you for this opportunity. My name is Ashish Khanna and I am going to talk to you all today about renin versus lactate for tissue perfusion and prognosis in the critically ill patient. These are some of my disclosures. When we talk about the physiological response to vasodilatory shock, renin angiotensin does combine with the sympathetic nervous system and arginine vasopressin as a three-legged stool for the counter-regulation of blood pressure in these patients. As far back as 1961, angiotensin II was first reported in the treatment of shock with good effect. And slightly more recently, this is a paper from the early 90s, where a patient with enalapril overdose was treated with angiotensin infusion and did show good response in terms of urine output and blood pressure. The earliest work with angiotensin II was the pilot study done on 20 patients by the group at George Washington, led by Dr. Lakhmir Chawla, where they did show a norepinephrine sparing effect and an overall improvement in the need for requirement of multiple vasopressors along with hemodynamic stability in patients with septic shock. This led to our more recent work in the form of the ATOS III trial done across 84 ICU centers all over the world and enrolling about 330 patients with distributive shock. We did find, first of all, a hemodynamic response to angiotensin II that was in the form of a blood pressure map of 75 or 10 more than baseline that was an odds ratio of nearly 8 in the angiotensin II arm compared to the placebo arm. This was our primary outcome. And then the mean arterial pressure separated out very early in the course of angiotensin II being started on these patients. And the separation was maintained for mostly all of 48 hours of angiotensin II infusion in the blue hair compared to placebo in the dark red. The Kaplan-Meier survival curves did not show a statistically significant difference in angiotensin II and placebo. This was survival at date 28, depicted right here. Importantly, the trial was not powered for a survival difference. So what have we really learned so far? We've learned that a synergistic model is the way to go when management of shock states in the ICU is concerned. And instead of relying just on the adrenal medulla and its hormones, there should be a more synergistic, early multiple vasopressors approach that involves the posterior pituitary and vasopressin receptors along with the renin-angiotensin cascade in the liver and the kidney through angiotensin II. This really sets up what I'm going to talk to you all today about, which is hormonal deficiencies in septic shock. The sympathetic nervous system is impaired in septic shock. The arginine-vasopressin pathway, we do know that plasma vasopressin is inappropriately low in these patients. And renin-angiotensin, where angiotensin receptors are downregulated in septic shock. All of this now takes me to the ACE enzyme, which is primarily located in the pulmonary capillary endothelium. Here is the ACE enzyme. It is the main regulatory enzyme that's going to convert angiotensin I to angiotensin II. And this is important because common situations like acute lung injury in critically ill patients do mean that ACE substrate is low in the injured lung along with ACE activity. Here is a neat experiment that was done and results published in Circulation about 20 years ago. Compared to right here, the top graphic where there is a difference between no ALI versus ALI ARDS and the bottom graphic where the same difference here is shown in terms of lung injury score. It is obvious that as lung injury increases, the A to KM ratio of the ACE enzyme decreases, thereby implying that injured lungs cannot produce ACE as efficiently as normal lungs. Now how does that translate into the RAS pathway? The pathway that you see right here is a normal pathway, angiotensinogen, renin, angiotensin I, ACE enzyme, angiotensin II, and aldosterone, and all the downstream effects coming from angiotensin II and aldosterone. The pathway that you see now is severe shock and endothelial injury. Here the conversion of angiotensin I to angiotensin II in the broken up arrow is through ACE. And as I just said, ACE is impaired in the setting of endothelial injury, which is commonly associated with severe shock. So as ACE is impaired, renin increases and angiotensinogen increases. And another way of looking at the same cascade is as a fairly simple feedback loop mechanism where here is angiotensinogen, angiotensin I, endothelial injury impairing ACE, less conversion to angiotensin II, and less downstream effects, thereby meaning that renin is increased as a biofeedback loop mechanism in an attempt to increase angiotensin I as a substrate production for ACE to act. Now what happens in the setting of us giving exogenous angiotensin II is that when we provide exogenous angiotensin II, this feedback loop mechanism where the back products as in renin and angiotensinogen are increased, this resets all of that and also means that there is enough angiotensin II to act on the ATR type I receptor to increase ADH secretion and aldosterone secretion and then renin itself is decreased because the entire loop is now reset. So when we talk about angiotensin II or angiotensin metabolism, here is the classical pathway, angiotensinogen, renin, angiotensin I, ACE, angiotensin II. Here is the non-classical pathway. The non-classical pathway is the pathway that is engaged when the ACE enzyme is impaired and there is also other byproducts of the ACE II pathway, that is kininogen, bradykinin, and so on. So it's important to realize that an impairment of primary ACE results in all of these secondary products, angiotensinogen, angiotensin I, renin, angiotensin II to dyne, and 1 to 7 being produced in excess along with calicrin and bradykinin. All of these lead to increased refractory vasodilatation and are possibly more important than just the deficiency of endogenous angiotensin II. So we finally come to why renin fits into this equation. Renin has been shown in experiments to be a better marker of tissue perfusion and prognosis in critically ill patients. This is an experiment done by John Louie's group in Belgium, where they looked at 112 arterial samples drawn from 20 patients with all kinds of shock in their ICU. They showed that in this heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. In fact, renin itself served as a marker of tissue perfusion and outperformed lactate as a predictor of ICU mortality. I wrote an editorial for this titled, Is Renin the New Lactate? And indeed, renin is very close to being the new lactate, just that there is no point-of-care assay for renin to guide resuscitation as yet. And this experiment was nearly repeated in another setting. This was the University of Maryland, where they used adult patients on vasopressors for greater than six hours to maintain a mean pressure greater than or equal to 65. Here they showed that compared to a change in lactate concentration, a change in renin concentration over 72 hours was significantly associated with in-hospital mortality. Specifically, if we look at these graphics here with the bar charts, as the renin concentration hit more than 40 picograms per cc, compared to a lactate more than 2 millimoles per liter, there was a significantly increased proportion of patients dying in the renin group with high renin levels compared to the lactate group with high lactate levels. Actually, these are the same patients that are compared with high renin versus high lactate. So the story seems to be clearer and clearer. And the back story here is obviously a disturbance in the angiotensin I to angiotensin II ratio that we have shown in various post-hoc analyses of ATHOS-3. There is one such analysis where we did show that patients with low angiotensin II had a significantly increased mortality when they were not given exogenous angiotensin II to reset this balance. We have also known hyperreninemia for a long, long time. Here are some of the causes of hyperreninemia. Essential hypertension, malignant hypertension, hemorrhage, cirrhosis, renovascular hypertension, renin-producing renal tumors. Here is what we saw in ATHOS-3 compared to the other conditions listed. And as is very obvious, the ATHOS-3 population had way higher overall renin levels compared to all of these other listed conditions, thereby meaning that this is a population of high renin shock which should be very responsive to exogenous angiotensin II. And here you see the difference. So another important post-hoc analysis here was the work that we did with Reynaldo Belomo where we looked at, in the solid red line, patients with renin above median who did not receive exogenous angiotensin II versus the solid blue line, which is patients with renin above median in ATHOS-3 that did receive exogenous angiotensin II. There was a clear survival benefit when exogenous angiotensin II was provided and renin, angiotensin, and the entire cascade could be reset compared to patients that did not receive exogenous angiotensin II where, you know, by day seven, looks like about half of them were surviving and half were not. Similarly, renin correlates with angiotensin I to angiotensin II ratios. There is a scatter that shows that as baseline renin increases, baseline angiotensin I to angiotensin II also increases. This was part of the same post-hoc analysis. And here is a tabulated version of the studies done so far. On the far right is the post-hoc analysis we did with Reynaldo Belomo. That's part of ATHOS-3. Then the middle is Gleason's group, Jean-Louis Vincent, and others in Belgium. And then in the far left is GeoRaju and the University of Maryland group. All of these three analyses showing that renin kinetics and vasodilatory shock appear to be strongly associated with mortality. And this association is stronger than a change in lactate by itself as a predictor of outcomes in this patient population. In the post-cardiac surgery environment as well, here is a recent analysis that comes out of Australia and Europe where there is an interesting observation that angiotensin patients that were given angiotensin II, their renin levels tended to drop after cardiopulmonary bypass, both at 4 hours and 12 hours, whereas patients who received standard of care, their renin levels stayed high at 4 hours and 12 hours after cardiopulmonary bypass. Here is another look at the same analysis. They also showed that in patients who did receive angiotensin II, there was a significantly less need for norepinephrine to maintain hemodynamics compared to standard of care. And further in a septic shock population, this is work from the Mayo Clinic with Patrick Wieruszewski leading this important work. They did see that in a prospective analysis, patients who received angiotensin II, they were able to maintain mean arterial pressure. Their overall total vasopressor needs were significantly less. And those that received vasopressin and had appropriate lactates, they did achieve a survival benefit with angiotensin II as well. Here is an interesting observation that comes from one of my patients at my center. This was a patient with COVID-19 on VVECMO that we decannulated and had floated septic shock. I struggled with four pressors on this patient, then finally started angiotensin II and had a significant stabilization of hemodynamics. Importantly, I sent off a serum renin. I told you it's not a point of care assay, but serum renin came back at 41 nanograms per cc per hour, which was about 10 times the normal value, and again, making the point for high output and high renin shock. So what is the entire cascade? The cascade itself is an inflammatory insert, significant endothelial injury, loss of face activity, angiotensin II insufficiency, and catecholamine resistance and acute kidney injury. Furthermore, we want to really, really come back down on the use of catecholamines and want to try and develop strategies for catecholamine sparing. We have tried to do the same in our cardiac surgery patient environment where we are doing RAS mapping and lactate checks and cardiac output and filling pressures and also checking cerebral hemodynamics. With that, I come to the end. I hope that this was useful, and I'm open for questions afterwards.

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