SCCM Resource Library-The New ABCs of Refractory Shock: Angiotensin II, Vitamin B12, Methylene Blue, and Vitamin C

Video Transcription

Hi there. It's an honor and a pleasure to be amongst you all today, even though virtually. And thank you again for this opportunity. We're going to talk about angiotensin 2 and  refractory shock and discuss the evidence and talk about what is new specifically with respect to the renin-angiotensin cascade and the molecular behavior of angiotensin  2 as a part of a complex biofeedback mechanism in these patients. These are some of my disclosures.  So very simplistically, angiotensin 2, and most of us know this so I'm not going to spend  a whole lot of time on this slide, is a naturally occurring hormone, the renin-angiotensin cascade.  So basically starting from renin release via the kidneys right here, going on to angiotensin  converting enzyme coming from the pulmonary capillary endothelium acting on angiotensinogen first, renin acts on it to make angiotensin 1, and then ACE acts on the ang-1 to ang-2  conversion, and then angiotensin 2 essentially has downstream actions, increases aldosterone,  sodium water retention, and also has some synergistic mechanistic action with vasopressin.  So bottom line, angiotensin 2 is an afterload increasing agent, also increases sodium water retention, so increases volume as well. What more do we know about angiotensin 2?  Well, from our perspective, the next really important thing is that it's part of a three-legged stool, and I call it a three-legged stool, simplistically speaking, because we've for  years focused on the sympathetic nervous system and arginine vasopressin, and the RAS cascade has been long forgotten, and based on some recent evidence, we now have the third leg  of this three-legged stool. It really establishes the counter-regulatory mechanisms for blood  pressure regulation in the human body. Angiotensin 2 is not new. It goes all the way back to the 50s and 60s. This is one of the early reports with angiotensin 2. Lots of patients  who had all kinds of shock were treated with angiotensin 2 and had favorable outcomes.  And then moving on further over the years from the 60s, the 70s, 80s, 90s, there was lots of case reports like these. This one published in the Lancet in 1993 in a patient  with enalapril overdose treated with angiotensin 2, had reversal of hemodynamic failure and increased urinary output after initiation of angiotensin infusion. It was not until  very recently where Lakmir Chawla, Larry Bussey, and their group at George Washington really got angiotensin 2 back into the mainstream in the ICU. They published the results of  a pilot study in 20 patients where they used angiotensin 2 and saw a hemodynamic response and a catecholamines-pairing response. And then our group led the large angiotensin 2  in high-output shock trial across three continents and nearly 80 ICU sites where we established very conclusively and published this about two years, three years ago now, four years  ago actually, in the New England Journal where we saw a hemodynamic response in a large majority  of our patients, nearly 70 patients who got angiotensin 2 compared to 23% of our placebo  population. And then we also saw a potency and efficacy of the drug in terms of the blood pressure response to a map of 75 or 10 more than baseline and a catecholamines-pairing  effect of angiotensin 2 compared to the placebo arm, which was actually standard of care, standard of care that could be a combination of catecholamines and vasopressin. The trial  did not show a survival benefit. It was a relatively small trial. It was a pre-FDA approval phase 3 trial, 330-odd patients, not powered to show a difference in mortality,  although the Kaplan-Meier curves did look fairly favorable for angiotensin 2. So really what's happened, and I wanted to just start with what we already know about angiotensin  2 is that, you know, we've sort of gone from the reliance on catecholamines and more catecholamines  and some vasopressin to a more synergistic model. And I really want you all to think about the synergistic model, which would be a combination of alpha beta receptors through the  adrenal medulla and vasopressin. And some people will also argue for cellopressin via the posterior  pituitary and now the advent of angiotensin 2. So really getting the renin-angiotensin cascade  to act through the AT1 receptor and increase volume and afterload. It's also important because hormonal deficiencies exist in septic shock. So we know the sympathetic system is  impaired in septic shock and catecholamines replace that. We know that arginine vasopressin is inappropriately low in septic shock. And we also now know that angiotensin receptors  are downgraded in septic shock. So all the more reason that when we look at our septic  vasodilatory shock that we counteract it with not just a sympathetic response via catecholamines,  but also with vasopressin and angiotensin 2 appropriately balanced and used early in a  synergistic fashion. Now what else is important about angiotensin 2 is where the S enzyme lives.  So the S enzyme lives in your lungs. It lives in the pulmonary capillary endothelial as an ectoenzyme in that space. And it's interesting and common knowledge that as the acute lung  injury spectrum increases so does the dysfunctionality of pulmonary capillary endothelium  bound angiotensin converting enzyme. And this has already been seen in animal models and some human studies that as ALI ARDS increases, as lung injury scores increase, so does the  dysfunctionality of ACE. And the dysfunctionality of ACE becomes more and more important because  if you look at the entire RAS pathway, this is the normal pathway, angiotensinogen, ANG1, ANG2, aldosterone, renin, and ACE. And this is what happens in endothelial injury,  which is a common consequence of severe shock and septic shock is this. ACE goes away and then renin and angiotensinogen, because the biofeedback is removed, start increasing.  And there's another way of showing exactly what I just said. Same pathway going on normally,  but then, you know, when the biofeedback is decreased because of endothelial injury, renin production goes up and renin production is critically important because if you restore  this biofeedback by giving exogenous angiotensin 2 right here, then you can effectively balance  all of these and decrease renin production once more and also have effective effectiveness of angiotensin 2 as a downstream hormone. So complex biofeedback mechanism, but  relatively simple in terms of an intervention that is now available to us. And then  there is the classical pathway of angiotensin 2 and the non-classical pathway. So when I talk  about biofeedback again, renin and ACE take it from angiotensinogen, ANG1 to ANG2. Not only is  this biofeedback mechanism impaired when angiotensin 2 is decreased and ACE is dysfunctional  leading to high renin and angiotensin 1. In addition, what happens in these circumstances  is that there is a diversion of this pathway to ACE2 and ACE2 leads to formation of angiotensin 2 to 9 and 1 to 7, which are in fact strongly vasodilatory and not vasoconstrictory  as traditional angiotensin 2. In addition, bradykinin and all of these also increase which,  which all of these hydrolysis products also add to a very bad cocktail that leads to intense vasodilatation. So septic shock is a complex insult, but as you can obviously see here,  the RAS pathway takes a brunt of that insult and not, not only is angiotensin 2 production impaired,  this increase in angiotensin 2 metabolites takes the pathway towards vasodilatation, which obviously is very bad for our patient that is already hypotensive.  So what's going to happen and what's going to happen is that we need to go and look back at,  at renin and angiotensin 1 and see whether the increase of renin is good or bad for our patients.  And Jean-Louis Vincent's group in Brazil or in Belgium, I'm sorry, published this work in critical care medicine in 2019, where they examined several patients with all kinds of  shock in the ICU and saw that in that kind of an ICU population, serum renin was a marker of tissue  perfusion and outperformed lactate as a predictor of ICU mortality. Not only that, renin measurement  was not affected by diurnal variation, CRRT, or commonly used drugs that affect the ACE and RAS  system. So a high serum renin as a counter mechanism of low endogenous angiotensin 2 or  a dysfunctional ACE is really bad for our patients. And in fact, as I suggested in this editorial, if we get a point of care renin test, renin might be the new lactate.  And renin angiotensin regulation becomes really important. As we see here, this is a post hoc  analysis of pathos 3 where patients with low endogenous angiotensin 2 in this right hand side panel, when they were given exogenous angiotensin 2, they actually had a survival  benefit. Furthermore, hyperreninemia is not unknown to us. It's part of a lot of common  conditions. However, the interesting part is that compared to other conditions that cause hyperreninemia  like, you know, a reninoma right here and some renovascular hypertension right here, pathos 3 had really high levels of serum renin in our patient population going all the way up  to nearly 6,000, but serum renin was way higher than say, for example, renovascular hypertension.  Only other thing that beat pathos 3 was a reninoma, which was not in our patient population in pathos 3. So clearly the renin part is important. And we've also recently established  that survival is dependent on baseline renin. And this really endorses the work done by John  Lewis group in Belgium that I just talked about. Here, we see four kinds of responders or four  kinds of patient population in a post hoc analysis from pathos 3. The dashed lines are patients with  renin that was below median. So renin was appropriately suppressed. They had adequate endogenous angiotensin 2. Their survival was great. However, the solid lines are patients  with renin way above median. And in these solid lines follow the blue line. These are, these are the patients that receive exogenous angiotensin 2 with renins above median.  They had a survival benefit compared to this bright red line where patients had renin way above median in the pathos 3 population, but received placebo. Half of these patients were  dead at a week out and nearly 80% or were dead at four weeks out from their initial insert.  So clearly serum renin predicts outcomes and angiotensin 2 when used to correct serum renin  also improves outcomes and improves survival. And as part of the same analysis, angiotensin 1  and 2 concentrations went up linearly as renin increased. So did the ang 1, ang 2 ratios.  So really shows that it was all part of a organized biofeedback mechanism. And more recently,  just published in the blue journal, a change in serum renin does affect acute kidney injury,  post cardiothoracic surgery, both as a change from baseline and also a change from a change  in the renin and listerone ratio. Furthermore, there is other analyses that have shown that  exogenous angiotensin 2 used in a prospective cohort of septic shock patients increases mean  arterial pressure, decreases total vasopressor dose, and in an adjusted analysis also increases  survival. Also note that there is way more responders than non-responders, almost twice  as many responders as non-responders, the patients who received angiotensin 2 with septic shock.  Furthermore, renin is important and we've seen this again and again. This is high renin vasodilatory  shock in a patient, we've just published this, who had COVID-19 and was on VB-ECMO. We just decanalated this patient and suffered with a repeat insult with septic shock,  started angiotensin 2 right about here, achieved immediate stabilization of blood pressures,  improvement blood pressures, and actually we're able, I'm not able to show it on the slide, but we were able to come off background catecholamines very, very, very quickly.  I did a serum renin analysis right here and I got the result two days later. It was about,  you know, 10 times more than normal, again showing the whole biofeedback loop and mechanism that was  obvious in this patient. So what's going to happen overall? Inflammatory insults, endothelial injury, loss of base activity, angiotensin 2 insufficiency, and catecholamine  resistance, poor outcomes, including acute kidney injury that I just talked about. So less is more.  Let's focus on alternative therapies for septic shock that includes catecholamine sparing therapies for our patients. And let's also look at post-cardiopulmonary bypass vasoplegia.  That's also another important avenue where there's lung injury, ACE dysfunction, low endogenous angiotensin 2, and where we've now seen in the ATOS3 population in this post-hoc  analysis about, you know, a few patients, about 17 odd patients where we saw that there was  catecholamine sparing. And even though 28-day mortality was the same, the results were pretty  encouraging in our post-hoc analysis. We've used angiotensin 2 prospectively at my institution  in post-cardiopulmonary bypass vasoplegia. Again, the rationale being dysfunctional ACE, low endogenous angiotensin 2 as the duration of cardiopulmonary bypass increases.  And all of our cases reported, we've seen robust hemodynamic response, catecholamine sparing, and no problems in terms of side effects or other issues of that nature.  This is our current protocol for the use of angiotensin 2 in post-cardiopulmonary bypass  vasoplegia. We are doing serial renin-angiotensin cascade mapping. We're comparing it to serum  lactate. We're doing granular cardiac output and filling pressure measurements. We're also doing  transcranial dopplers on these patients to see cerebral hemodynamics. And we're hoping to  accurately pinpoint the architecture of the RAS cascade when patients are given synthetic angiotensin 2 in these situations. So I'll end with this slide. It's all a  combination. Even though my talk was focused on angiotensin 2, I want you to take away from this  talk that it's not just angiotensin 2. It's a combination of agents. And never forget your  adjuncts like steroids, vitamin C, and other adjuncts that are going to help you achieve that  adequate balance and get better outcomes for your patient with septic shock. I'm open for  questions afterwards. Thank you for your patient listening. And thank you for this opportunity once  more. Thanks for having me today. I'm excited to be here to talk about a subject that has been near  and dear to my heart ever since starting as a clinical pharmacist in the cardiovascular ICU,  and that's the use of B12 and methylene blue for refractory shock. I have no conflicts of  interest to disclose. Today I will very briefly describe the pathophysiology of vasoplegic shock.  I will discuss the evolving role of vitamin B12 and methylene blue in vasoplegic shock, and I will help you select appropriate use of these drugs based on patient-specific factors.  What exactly is vasoplegic shock? Well, it's not well defined. In general, it is considered to be a shock state with a low systemic vascular resistance and mean arterial pressure  with adequate cardiac index and is refractory to high-dose vasopressors. It is present in 5 to 25  percent of major cardiovascular procedures using cardiopulmonary bypass. It is described in other  vasodilatory shock states. However, it is most consistently described in the cardiothoracic  surgery population, and that will be the content of this talk. Vasoplegic shock is associated with  an increased ICU length of stay, renal failure, and increased risk of mortality. There are several preoperative risk factors, including preoperative medication use, such as ACE  inhibitors, beta blockers, and calcium channel blockers, increasing age, male sex, increasing number of comorbid conditions, surgery for left ventricular assist device implantation,  and overall duration of cardiopulmonary bypass. The pathophysiology of vasoplegic shock is complex  and not well understood. However, there are three main processes that are thought to contribute to  the vasodilation. The first one is the depletion of catecholamines, vasopressin, and angiotensin 2.  This is thought to be related to persistent baroreceptor stimulation in the setting of a  stressful event such as cardiopulmonary bypass. This, in turn, stimulates release of inflammatory  cytokines such as interleukin 1, interleukin 6, and tumor necrosis factors, and that also  stimulates the release of nitric oxide, nitric oxide synthase, cyclic GMP, hydrogen sulfide,  and atrial natriuretic peptide. And this is actually going to be the focus of our talk today  as this is one of our medicated. Our treatment options consist of normal treatments such as transfusion and fluid resuscitation, vasopressor therapies, catecholamines, vasopressin,  and a potential role for prevention, so holding preoperative ACE inhibitors and calcium channel  blockers. And as we'll discuss in some of the coming slides, potentially there's a role for  methylene blue. Additionally, there are non-vasopressor rescue therapies such as vitamin C, methylene blue, and hydroxychlorobalamin or vitamin B12.  When reviewing the data that I'll be presenting today, I thought that there would be four main  questions that's in ourselves. When are these drugs indicated? What effects can be expected  from their use? How does this improve clinical outcomes? And if indicated, how quickly should  we use these drugs? So the first one I'll be talking about is methylene blue. It works by inhibiting guanylate, cyclase, and endothelial nitric oxide synthase in addition to direct  binding of nitric oxide. So not only does it bind the vasodilatory substances, but it's circle formation. Dosing is variable in the literature. However, the most recommended dose  is one and a half grams per kilogram over 20 to 30 minutes, followed by the option of an infusion  of 0.5 to 2 milligrams per hour for a varying duration. The half-life is around six hours, but maybe all the way up to in the case of probate blue. Adverse events are mild generally  considered a blue-green chromaturge can in turn cause interference of pulse oximetry monitoring  causing a falsely low oxygen saturation. There are also two patient populations that we need to be  particularly careful when using methylene blue, and that's PD patients in which it can cause a hemolytic anemia, and then patients on serotonergic drugs because it can cause SIRT.  There are several dose-dependent side effects that have also been noted in the literature  in various cases. As mentioned, methylene blue has been investigated as a preventative  surgery at high risk for vasopagic syndrome. So Azal and colleagues took 100 patients who were on ACE inhibitors, Ketorheparin, and randomized them to either methylene blue,  two milligrams per kilogram, one hour prior to surgery, and low care.  And what they found was that there was no cases of ACE in the aplesia group compared to just over  a quarter of the patients in the control group, and this was statistically significant.  This translated into an overall decreased volume of crystalloid resuscitation  and also translated into decreased both idle lengths of stay.  The authors concluded that methylene blue may prevent or limit the severity when administered  before or at the onset of cardiopulmonary bypass. So I think the next question we have to ask ourselves is if we're using in a rescue setting, what can we expect for the hemodynamic  effects? And colleagues asked that very question with this study in which they retrospectively reviewed 54 patients at their institution who received methylene blue  for their specified criteria for vasoplegia. Following the methylene blue infusion, they also assessed invasive hemodynamics at various time points.  And what they found was across all time points, there were statistically significant increases in the systemic vascular resistance and mean arterial pressure  concomitant with statistically significant decreases in norepinephrine doses across all of the time points.  The authors concluded that methylene blue improves systemic vascular resistance, mean arterial pressure, and decreases the need for vasopressors.  I think the next question then to ask ourselves is, do these impacts on hemodynamics actually translate into improved clinical outcomes?  Well, Levin and colleagues also asked that question. And so they randomized consecutive cardiac cases that met their institutional criteria for vasoplegia to either methylene blue,  one and a half milligrams per kilogram, or to placebo.  And what they found was that the patients in the methylene blue group had resolution of vasoplegia much more rapidly than patients in the control group  at two to three hours compared to durations lasting beyond 48 hours in the control group.  This actually translated into improved outcomes across the board for the methylene blue group, including decreased mortality, decreased incidence of renal failure,  decreased supraventricular arrhythmias, and decreased multiple organ dysfunction.  So what the authors concluded was that methylene blue may also improve morbidity and mortality in vasoplegic patients.  So now that we've established that it does improve outcomes, I think the next question is, well, when do we actually decide to administer one of these medications?  Well, Mahaffey and colleagues asked that same question in which they retrospectively reviewed all patients who were within 72 hours of bypass were hypotensive  and had an adequate cardiac index. At their institution, methylene blue, two milligrams per kilogram, followed by an infusion of 0.5 milligrams per kilogram  per hour for 12 hours was their standard of care. And they compared it to the usual care group. Their main outcomes of focus were major adverse events.  When comparing the groups, methylene blue across the board had an increased risk of major adverse events, including stroke, renal failure, deep sternal wound infection,  reapparation, prolonged ventilation, and increased risk of mortality. However, when they took those methylene blue patients and stratified based on early administration,  which was administration in the operating room, or late administration, which was administration in the intensive care unit, they found that despite no difference  in risk of adverse events, the early administration led to decreases in the incidence of renal failure and fatality. And this was confirmed  by a multiple logistic regression analysis in which the odds ratio was decreased for early administration.  So what the authors concluded was that methylene blue may be associated with poor outcomes if given late in the vasoplegia progression.  So now that we've established how methylene blue can potentially be used, let's move on to hydroxychlorobalamin. So hydroxychlorobalamin, or B12,  works as a potent inhibitor of nitric oxide, nitric oxide synthase, and it directly modulates hydrogen sulfide. The dosing per insert for cyanide toxicity  is five grams over 15 minutes. Its half-life is prolonged at up over a day.  Adverse events are also, for the most part, mild, including achromaturia, which can cause a false alarm on continuous renal replacement therapies,  and also interfere with laboratory monitoring for a period of time afterward. There are a few other more concerning side effects that have been documented in the literature,  such as renal failure, cobalt toxicity, with repeated administration of hydroxychlorobalamin.  So what data exists? Well, it's limited to multiple successful case reports and case series. However, there's significant heterogeneity in response to hydroxychlorobalamin.  This is a table that's been adopted from Chapman et al's which reviewed hydroxychlorobalamin, and there are some things that I wanted to point out  in these case series and case reports.  Dosing here, as you can see, it's significantly different between the different groups, ranging from a single five to multiple five gram doses,  or a five gram dose split up into bolus doses and a continuous syntheme. So this is really unclear exactly how we should be dosing it  after reviewing these case reports and case series. Furthermore, most of these patients actually wound up receiving methylene blue as well.  So they have asterisks by them. So there were Greek et al, Clem et al, and Warner et al cases.  Most patients didn't receive methylene blue, and then most of the other patients in these case series and case reports actually did receive methylene blue,  unclear exactly what the effect of that combination therapy is.  The only study that has really compared the two is by Furnish and colleagues, in which they looked at all patients who received either methylene blue or hydrolamin  in a perioperative setting for suspected vasoplasia. They identified 16 methylene blue patients of 1.6 milligrams per kilogram, and 19 hydroxycobalamin patients,  all of which received five grams. Their primary outcome was time-weighted change in norepinephrine over the first hour. Secondary outcomes in hemodynamics  at various time points over the first six hours.  Although there was no difference in the primary outcome of time-weighted norepinephrine equivalents between the two groups, you can see here that methylene blue  did its vasopressor requirements across any of the different time points. Whereas in the hydroxycobalamin group,  there are different time points in which there are statistically significant decreases in vasopressor doses.  Whereas when you look at the ability to increase MAP, both drugs across the board wound up increasing  at different time points except for six hours in the hydroxycobalamin group.  And so what the authors concluding was that there's no difference in efficacy between hydroxycobalamin and methylene blue, and that both met medication, vascular resistance,  and increased mean arterial pressure.  Which then this brings us to our study in which we get further that combination therapy compared to monotherapy. So we looked at all patients who received either methylene blue  in combination or monotherapy.  For all patients that met vasoplasia, we identified 14 patients in the methylene blue group and six patients who received combination therapy.  Our primary outcome was maintaining a MAP goal greater than 60 millimeters of mercury at the first hour. Secondary outcomes included assessing MAP  and vasopressor rates at the various time points.  What we found was that there's no difference in ability to maintain MAP goal between the two groups across any of the different time points.  Whereas when we looked at the difference in median absolute doses of norepinephrine, we found that both methylene blue and combination therapy decreased vasopressor requirements  across all time points with combination therapy having a slight edge.  When you look at this graphic here, it also demonstrates that in both groups our vasopressor requirements decreased across all the different time points,  again, leading to maybe a slight edge to the combination therapy.  And so what we concluded was that there was no difference in efficacy between monotherapy and combination therapy, but combination therapy may allow  for lower doses of drugs to be utilized. And this is because the methylene blue group had 1.2 milligrams per kilogram, whereas in the combination therapy group,  they only had a half milligram per kilogram.  In terms of future directions, there's a few studies that may help add to the body of literature that's out there. However, the bottom one there,  which I thought would be the most impactful, actually was withdrawn due to lack of funding. And so for the time being, we'll have to rely on our retrospective cohort studies.  So in conclusion, overall, there's a lack of robust data to support either methylene blue or hydroxycobalm doses in all of the studies. However, I would advocate for  bolus dosing plus continuous infusion, as I believe that those will bind whatever nitric oxide is present, and the infusion will prevent further nitric oxide from being formed.  There are variable definitions across all the studies, and in addition, there are small randomized trials and case series and case reports,  so it's difficult to extrapolate that to our own patients. However, if you are going to use one of these agents, I would take that into consideration  as it may be associated with improved outcomes. Drug selection should also be based on patient-specific factors, avoiding methylene blue and G6PD in concomitants or synergic drugs.  Combination therapy may allow specific effects, but more data is needed before that can be widely recommended. With that, I want to thank you for your time  to answer whatever questions that you have. Hi, this is John Sobranski from Emory University, and I'd like to thank the organizers and the moderator  for allowing me to talk about vitamin C in septic shock.  You can see both my financial and intellectual disclosures,  grant support, and a stipend to my institution for my work as Associate Editor for Critical Care Medicine.  So there's a fair amount of biologic plausibility for using vitamin C in shock,  and it centers around two specific topics. One of them is that vitamin C is an enzyme cofactor for the production of catecholamines, of endogenous catecholamines,  and it also has some anti-inflammatory properties.  So it therefore makes sense that people have thought to use vitamin C either alone or in conjunction with thiamine and corticosteroids for patients with sepsis.  And some of the rationale for that includes the fact that vitamin C and thiamine levels are both low in sepsis,  and there are some preclinical and early clinical data suggesting some efficacy in terms of specific targeted endpoints, such as lactate levels  when you give septic patients with thiamine, and some early studies that suggest that there might be clinical benefits for other important endpoints.  I should also note that vitamin C and thiamine and steroids are relatively cheap. They're low cost, and it's reasonable, therefore, to see whether or not they might help patients  with sepsis and septic shock. And I'd like to briefly review a couple of studies that have been done to look at the potential benefits of vitamin C in sepsis.  The first study was the Citrus ALI study that was published in JAMA in 2019. And for this and the subsequent studies, I'm going to use the PICO rubric to look at the patients,  the intervention, the comparator, and the outcomes, because all of these items will help, I think, highlight the differences between the trials.  So the Citrus ALI study enrolled 167 patients who had both sepsis and ARDS for less than a day. And the intervention here was vitamin C alone  at somewhat higher doses than earlier studies, including those that Paul Merrick used in his single-center study.  The comparator was placebo, and the primary outcome measure was the change in a modified SOFA score. They also looked at inflammatory markers, including CRP and thrombomodulin.  Of note, when you gave vitamin C intravenously to sepsis patients, their vitamin C levels went up, as you might expect. But it did not change levels of thrombomodulin,  and it did not change the modified SOFA score.  I should note that they looked at 46 different secondary outcome measures and did not correct for multiple comparisons. One of the secondary outcome measures was mortality,  which was difference between the groups, in which the interventional group had a lower mortality than the placebo-treated patients.  One of the things that I think is helpful in thinking about secondary outcome measures is that, in some ways, it's a little like the game of billiards,  where you have to call your shot. And by calling your shot, you have to pick which outcome measure is important to you. And if you don't call your shot  or you don't call your primary outcome measure, it looks nice, but it may not be true. It may not be right.  It may not be true. It may not be real. And in billiards, it doesn't count.  The second study that looked at the potential use of vitamin C in patients with sepsis was the Vitamins Trial, and they enrolled 216 patients with septic shock.  And their intervention was a combination of vitamin C at the same doses that Paul Merrick used in his study, thiamine, and hydrocortisone, given every six hours for 96 hours.  The comparator here, however, was hydrocortisone because the investigators believed that hydrocortisone was useful for patients with sepsis.  And the primary outcome measure was a combined outcome measure of being alive and free of vasopressors in the first seven days of the study.  There was no difference between the groups in the primary outcome measure. And, in fact, there was no difference in mortality. And in nine of the 10 secondary outcome measures,  there was no difference between the groups in between the intervention and the comparator group. Again, as a reminder, the comparator group received hydrocortisone.  The third trial that was completed and published was the ACT Trial. And here they enrolled 200 patients with septic shock. And the intervention here was IV vitamin C, thiamine,  and hydrocortisone every six hours for 96 hours.  Here the comparator group was placebo. And, in fact, if you were on steroids, that was one of the exclusion criteria for enrolling in the trial.  The primary outcome measure was the change in SOFA score between zero and 72 hours. And in this trial, too, there was no difference between the treatment  and the comparator group in the primary outcome measure or in mortality. There were, however, more shock-free days in the intervention group,  with one more shock-free days in the first seven days. Again, the treatment group received three therapies, vitamin C, thiamine, and hydrocortisone.  And it's not clear which of these therapies was most important in leading to this secondary outcome measure.  I'd like to end with the VICTIS trial, which has been completed with 500 patients. It was originally designed to enroll up to 2,000 patients,  but the funder declined to provide additional funding after the first 500 patients. And this enrolled patients with confirmed or suspected infection  and evidence of either respiratory or cardiovascular failure, i.e. the requirement for vasopressors. The intervention included the triple therapy of vitamin C,  thiamine, and hydrocortisone every six hours for four days or until ICU discharge. And the comparator was placebo unless the clinical team desired to give steroids,  in which case the comparator was the use of steroids. And the primary outcome measure was vasopressor and ventilator three days with an important secondary outcome measure  of 30-day mortality. Again, the inclusion criteria required either respiratory or cardiovascular dysfunction and anticipated ICU admission.  And it was an adaptive design that would only stop early if mortality was shown. But after 500 patients, and we did not get to this part, there was the possibility,  even if we showed the primary outcome measure, to potentially continue the study to see whether or not it would also show mortality. As noted, the clinical team was allowed  to give corticosteroids if they thought they were indicated. And if corticosteroids were given at a dose of greater than equal to 200 milligrams  of hydrocortisone a day, study drug three, which would either be steroids or placebo, would then be stopped. Here is the analytic approach that was published in trials.  And 501 patients were enrolled out of a little over 3,000 screened, and there was also an intent-to-treat analysis for patients who received at least four doses of the vitamin C.  And these results were presented at ESICM in late 2020. In both the primary analysis and the protocol analysis, patients were similar between the groups,  both in physiologic and source of infection. There was no difference between the groups in the number of vasopressor or ventilator-free days.  And you'll see that there was a large portion of patients who had no vasopressor or ventilator-free days because they either died in the ICU  or they remained on full support throughout the study. There was also no difference in 30-day or 180-day mortality between the groups.  I mentioned that one of the differences between the groups in the different studies between Victus, ACT, Citrus ALI, and the vitamin study was whether or not the comparator group  included corticosteroids. And there have been a number of studies looking at the use of corticosteroids in sepsis. Here's a meta-analysis that was led by Graham Rothward  and published in Critical Care Medicine in 2018, which showed that there's no real difference in mortality, in short-term mortality, between those patients treated with steroids  and those patients treated with placebo and the possibility of a longer-term outcome, a longer-term decrease in mortality,  with a confidence interval hitting one for treatment effect with the use of corticosteroids. However, while there may not be a mortality difference,  corticosteroids did lead to shock reversal, and this was the confidence interval that did not, the 95% confidence interval, did not cross one, suggesting that this is a real effect.  And, in fact, there were, along with this, a couple of potential side effects, including neuromuscular weakness. So what I hope I've shown you in the past few moments  is that there is strong biologic plausibility that vitamin C could be useful in patients with sepsis and septic shock, that the randomized controlled trials  with limited to moderate numbers of patients in sepsis and septic shock did not confirm the large treatment effect seen in non-randomized trials.  There were some differences in outcomes in clinical trials, and this potentially could be due either to differences in the timing of dosing of the vitamin C,  the comparator, including the use of steroids, or the primary outcome measure that was chosen. And there are ongoing trials that may provide additional data to inform clinicians.  I'd also like to highlight the fact that the treatment effect of steroids and whether or not steroids were given in the comparator group may confound the effect of vitamin C  in some clinical trials.  I would like to thank the 43 enrolling sites for the VICTIS trial, the Clinical Coordinating Center at Hopkins, the Data Coordinating Center at Vanderbilt,  as well as my colleagues at Emory and my colleagues at Grady for helping to complete the VICTIS trial. And I would be glad to answer any questions at the appropriate time.  Thank you.

Video Summary

The video transcript discusses the use of angiotensin II and vitamin C in different contexts. The first part of the transcript focuses on angiotensin II and its role in refractory shock. It explains the molecular behavior of angiotensin II and its downstream actions, such as increasing aldosterone, sodium water retention, and afterload. The transcript highlights the significance of angiotensin II as part of a complex biofeedback mechanism for blood pressure regulation. It discusses previous studies that have shown favorable outcomes when using angiotensin II in various types of shock. The transcript also mentions the importance of the renin-angiotensin cascade and how endothelial injury can disrupt this pathway, leading to vasodilation and hypotension. It suggests that restoring the biofeedback by giving exogenous angiotensin II can help balance the system and improve outcomes. <br /><br />The second part of the transcript focuses on vitamin C and its potential use in septic shock. It discusses the biologic plausibility of vitamin C in shock and its role as an enzyme cofactor for catecholamine production and anti-inflammatory properties. The transcript reviews several studies that have explored the use of vitamin C in sepsis, including the Citrus ALI study, the Vitamins trial, and the ACT trial. It summarizes the findings of these studies, which show no significant benefits in terms of primary outcome measures like change in SOFA score or mortality. However, some studies did show potential secondary benefits, such as increased shock-free days. Finally, the transcript mentions the ongoing VICTAS trial, which aims to provide more data on the use of vitamin C in septic shock.

Asset Subtitle

Sepsis, 2021

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 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Identify which patients are most likely to benefit from angiotensin II
Discuss the evolving role of vitamin B12 and methylene blue in vasoplegic shock
Review the physiologic rationale of ascorbic acid for the treatment of septic shock

Pressing for New Options: Angiotensin II in Refractory Shock Ashish K. Khanna Red, Blue, or a Combination of the Two: Vitamin B12 and Methylene Blue for Refractory Shock Joel Feih Is There Still a Role for Ascorbic Acid in Septic Shock? Jonathan E. Sevransky

Meta Tag

Content Type Presentation

Knowledge Area Sepsis

Knowledge Area Shock Non Sepsis

Knowledge Level Advanced

Membership Level Select

Tag Guidelines

Tag Cardiovascular

Tag Shock

Year 2021

Keywords

angiotensin II

vitamin C

refractory shock

aldosterone

septic shock

biofeedback mechanism

endothelial injury

VICTAS trial

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