prophylaxis, or I would say what a lot of us refer to here as stress ulcer prophylaxis. In terms of my conflicts of interest, I have nothing to disclose. And this is just a brief outline of what we're going to go through today. So I'm going to touch very briefly on the pharmacology of H2 blockers and proton pump inhibitors, since these are the two commonly used classes of agents for acid prophylaxis. The bulk of this session is primarily to focus on the evolution of evidence-based practice with regards to the acid prophylaxis or stress ulcer prophylaxis. So in terms of how our understanding has evolved or has changed throughout the years, in terms of the clinical significance of stress ulcers, in terms of the efficacy and adverse events of acid suppressive agents, and how that has impacted our practice in terms of managing stress ulcer prophylaxis. So it's really been a journey of acid prophylaxis, if we look at historically how things have changed. And I just want for us to take a step back and look at some of the history of acid prophylaxis and stress ulcers. So the interesting part is that this is way, way before we even think about stress ulcer, that they've identified the first ulcers. It goes back to the 19th century. So in 1842, Curlings described acute ulceration of the duodenum in a number of his patients that presented with extensive or generalized severe burns. They were both adults and pediatrics. And those patients had serious gastrointestinal bleeding, and some of them were fatal. Following that, in 1932, Cushings reported similar findings with gastroduodenal ulcers in patients with brain disorders. And again, cases that were serious and cases that were associated with significant GI bleeding. And then following that, there were several cases or several observations in various types of patient populations that had similar, where they reported similar observations of patients developing gastroduodenal ulcerations and erosions, some of which developed into clinically significant GI bleed. So it was reported in adults, in pediatrics, in patients post-surgery, pre-surgery, patients with respiratory failure, hypotension, sepsis, and again, many other patient populations that were critically ill and hospitalized. And that slowly evolved into what we refer to as stress ulcers. Now what's the pathogenesis or the pathophysiology behind stress ulcers? And why do patients develop stress ulcers when they're in critical illness? The exact pathophysiology is not clear, but it seems that it has to do with three main components. There's the gastric acid secretion. There's the gastric mucosal ischemia that's also been reported in patients that are critically ill, and also the impaired gastric mucosal barrier. Now initially, the focus of trying to prevent the stress ulcers was primarily focused on decreasing the stomach acidity, because that's initially what we had for prophylaxis. So the antacids were initially what was available for the treatment and for the prophylaxis. So that was initially what was used to prevent stress ulcers. And then after that, once the H2 receptor antagonists came out, they became another class of agents that were used for stress ulcer prophylaxis. But with both of those, the antacids and the H2 receptor antagonists, there was the concern about an increased risk of nosocomial pneumonia, that you're reducing the acidity, and so there's bacterial overgrowth, and that could increase the risk of nosocomial pneumonia. And so the attention became looking at another mechanism of action and trying to address another element of the pathogenesis, which is the impaired gastric mucosal barrier. And so when supraphate came out, that was another medication that was used for stress ulcer prophylaxis. Some of us remember that drug. Some of us may not have seen it. But that was considered as another drug that could target the mucosal, that could provide that protection for the gastric mucosa without reducing the gastric acidity, and therefore trying to prevent the risk of nosocomial pneumonia. And so at one point, the treatments that we had for stress ulcer prophylaxis were supraphate, antacids, and H2 receptor antagonists, and that was pretty much what the main three classes of agents that were used. And as with any treatments, we always question whether one is better than the other. So there were a lot of studies that came out also comparing those drugs and trying to find which one would be more effective. There are several studies that came out. I would say this is one of the main studies that helped us answer that question. It's a meta-analysis that included 34 trials and compared antacids, H2 receptor antagonists, and sucrophate, either comparing those classes together or comparing them with placebo. And what they found was that antacids or H2 receptor antagonists both can significantly reduce the incidence of stress ulcer and can reduce the incidence of significant GI bleed. In terms of sucrophate, the evidence was insufficient. And when it comes to comparing the H2 receptor antagonists with the antacids, the H2 receptor antagonists were more effective. And so that kind of moved us from having those three classes into mostly shifting towards H2 receptor antagonists being the main class of medications that are used for prevention of stress ulcers. And the focus, again, went back into reducing the acidity of the stomach. The injection pump inhibitors came out later as being more potent than the H2 receptor antagonists. So they were also being added as also a class of agents to be used for stress ulcer prophylaxis. This is just a very simple figure to demonstrate kind of briefly the mechanism of action of both the H2 receptor antagonists and the PPIs. So this is the parietal cell. As we all know, the H2 receptor antagonists bind to the histamine receptors that are on the parietal cell. And once they bind to it, then they prevent the acid secretion through that route. But keep in mind that there is also the gastrin receptors, and there's also the acetylcholine receptors that, when stimulated, they also secrete acid. So the H2 blockers don't completely block the entire cycle of producing acid. On the other hand, with the PPIs, they're considered more potent because they block the final stage of producing acid, which is at the level of the proton pump. They bind to the hydrogen potassium ATPase receptor, and again, they block the acid production through the proton pump inhibition. Now the question that came up is, if this is a more potent class of medication, would it be more effective for stress ulcer prophylaxis? And I'm sure a lot of us here are very aware of the numerous studies that came out comparing the H2 receptor antagonists to PPIs for stress ulcer prophylaxis. This is one of the meta-analyses that came out looking at 19 randomized controlled trials, over 2,000 patients. And the conclusions were generally similar to what others had reported, that it favors PPIs for stress ulcer prophylaxis in terms of being more effective for preventing a clinically significant GI bleed. And so with that, there was more shift in the practice to using more PPIs than H2 receptor antagonists. We still have the issue of nosocomial pneumonia, because again, there is the potential of reducing the acidity of the stomach and increasing the bacterial overgrowth. Even though there's been some debate about that, but that's still a concern with both the proton pump inhibitors and the H2 receptor antagonists. But there was a bigger price that we end up paying with the PPIs, is that there's additional numerous side effects that have been reported with the PPIs. So there is the C. diff, renal failure, both acute and chronic renal failure that's been reported with PPIs, electrolyte disturbances, vitamin deficiency, iron deficiency, and several other adverse events that have been reported. Now these adverse events are primarily with the long-term use of PPIs rather than the short-term. But as I mentioned in a few minutes, there are many times where our short-term stress ulcer prophylaxis ends up being a long-term treatment. So these adverse events are things that we also need to keep in mind as we're looking at the PPIs. Now taking into account the adverse events of the acid suppressive agents and the potential also for clinically significant GI bleed, there are several guidelines that came out from several societies and several associations trying to identify certain patients that would be eligible for stress ulcer prophylaxis rather than giving prophylaxis for all patients. And there are different recommendations that they had. They tended to agree on two main risk factors, which are coagulopathy and mechanical ventilation. And then they varied with some of the additional side effects, additional risk factors that were added there. But there's still uncertainty, even though the guidelines do provide some recommendations in terms of who's considered at high risk of developing a clinically significant GI bleed. And again, coagulopathy and mechanical ventilation are those that we tend to have kind of agreed upon among all the guidelines. There's still some uncertainty there. And I think this is where this study brought up another element of uncertainty. This is a study that was published a few years ago looking at predictors of gastrointestinal bleeding in adult ICU patients. And they looked at various factors and various predictors that were identified previously and whether they're statistically significant or not. The interesting finding is that mechanical ventilation, which we've always considered as a risk factor, showed no clear association with GI bleeding. So that kind of added another element of uncertainty in terms of trying to identify who's considered at high risk and what are the risk factors. Now, there's the misuse and overuse that I would say all of us would agree upon. And even though we have guidelines that are trying to kind of define who would be potentially at high risk of developing a GI bleed and who would qualify for a stress ulcer prophylaxis, and despite the adverse events that we've seen with the treatments, there's still considerable misuse and overuse of acid prophylaxis in all of our ICUs. And I'm going to use this study. It's not an old study. It's been published more than 10 years ago. But the nice thing about the study is it really goes through the entire cycle of the patient's admission. And it evaluates the ulcer prophylaxis, the appropriateness of the acid prophylaxis at each stage. And I think if we look at the data here, it probably is not much different than what we're seeing in general in most of our hospitals. So they looked upon ICU admission. They identified risk factors that are considered as risk factors for developing a clinically significant GI bleed. And then they grouped the patients into four groups based on the number of risk factors that they have. Now, the two groups that I want us to focus on are group three. So these are the patients who have absolutely no risk factor for a GI bleed. So they should not be receiving any GI prophylaxis. And then group four, this is the group that also has no risk factors. But these are patients that were taking acid prophylaxis at home, came in, and we just decided to resume their home medications. So if you look at the ICU admission and looking at group three, close to 70% of those patients who, again, had no risk factors for a stress ulcer were prescribed stress ulcer prophylaxis in the ICU. And for group four, it's pretty much everyone that came in got stress ulcer prophylaxis. Now, if we move down the line, so once the patient got transferred, and looking at those three groups, those two groups, group number three and group number four, again, group number three are those that had no risk factors. 60% of them continued to get stress ulcer prophylaxis on the floor. For group four, pretty much all of them continued with stress ulcer prophylaxis. And then upon hospital discharge, the same cycle continued. We probably did slightly better with group three. So it was 30% of those patients that were discharged home on acid prophylaxis. But group four, pretty much all of them, almost 85% of them, received ulcer prophylaxis. Now the interesting part is once those patients come back to the hospital, those that were in group three, so those are the patients that we started in the ICU, their acid prophylaxis and discharged home, they will come back as group four. So these are patients that will continue to receive acid prophylaxis probably until the end of their life. So it's an interesting cycle, just kind of the dynamics of how things work. And again, when we talk about adverse events, when we talk about costs, when we talk about a lot of the implications of misuse, yes, the patient is in our ICU for a few days. But specifically with acid prophylaxis, the impact is bigger than those few days that that patient is in the ICU. So if we look at the journey of acid prophylaxis and in terms of how things have evolved through time, initially, the earlier studies reported ulcers in about up to 100% of the patients. So they had reported erosions and duodenal ulcers that I mentioned earlier in almost every patient that comes into the ICU and as early as 24 hours after admission. And a lot of those studies were done with endoscopic examinations. So that's how they pretty much identified those erosions in patients that were admitted. And it was clear that some of those ulcers will progress to clinically significant GI bleeding. And so initially, the general approach was that the majority of the patients should be on stress ulcer prophylaxis. Because if all of those patients are having some kind of gastric erosions, and they may develop a clinically significant GI bleed, then we need to give GI prophylaxis for all patients. Well, our understanding evolved down the line that, yes, we do understand that that could develop into a clinically significant GI bleed. But the incidence of a clinically significant GI bleed is pretty low. Less than 4% is what has been reported. It varies depending on which ICU you look at. But it's less than 4% of what is translating or what is progressing into a clinically significant GI bleed. Clinical practice has certainly improved over the years. So our practice is not the same as it was 10 years, 20 years, or even 40 years ago. We do much earlier resuscitation. We do much earlier feeding. And so we expect that the gastric mucosal ischemia is less based on these points that I mentioned earlier. But we don't have any of those endoscopic studies that were done earlier to really confirm whether that has decreased or whether it has not. But again, what we know is that the incidence is very low in terms of clinically significant GI bleed. And so the attention started moving, or the practice shifted into more of focusing at the high-risk patients. And those high-risk patients, having them on stress ulcer prophylaxis. And that's what I mentioned earlier in terms of determining what are the risk factors, and then having those patients with risk factors receiving GI prophylaxis. Now recently, the evidence is kind of moving us into a different direction. And we're seeing more data coming out showing that the incidence of clinically significant bleeding is even lower than what we anticipated before. So it may be even lower than that 1.6% to 3.6% that I showed. And that it seems that it's not just gastric acid that contributes to the clinically significant GI bleed. Gastric acid is one part of the pathogenesis. But it seems that there's other contributing factors that stress ulcer prophylaxis may not be addressing all of those elements. And then there's certainly the adverse events that I mentioned earlier associated with acid suppressive agents. And so that, again, moved us into a different direction, where the question at this point is do we actually need stress ulcer prophylaxis in our patients? And that's really a big question in terms of going back to the basics of what's the added clinical value of stress ulcer prophylaxis. This is a study that came out which kind of triggered that thinking process. So this is the pop-up trial that came out. It was a single center study, randomized, double-blinded. And they took those patients that we would consider as high-risk patients for stress ulcer bleeding. So these are patients that are mechanically ventilated and expected to be on the ventilator for at least 24 hours. So again, a group of patients that a lot of us would consider as high-risk. And they randomized those patients to IV pentoprazole or placebo. The primary outcome was clinically significant GI bleed. And they also looked at C. diff and pneumonia. Now these are the results of the study. Clinically significant GI bleed, they reported no clinically significant GI bleed in either group. And in terms of the other endpoints, there was no significant difference. The incidence or the number of patients that developed over it bleeding in the pentoprazole group was lower than that in the placebo group, but it was not statistically significant. But the argument was that this is a fairly small number of patients, so most likely not powered enough to detect an event that doesn't happen very frequently in our patients. It was just a little over 100 patients in each arm, and it was single-centered. So maybe there is a difference, but we're just not seeing it with this study. So this is what triggered the other study, which a couple of years later, we had the sub-ICU trial that came out. This was a multi-center study, 33 centers in various countries around Europe and the UK, placebo-controlled, where they included adult patients that had at least one risk factor for clinically important GI bleed. So a lot of the risk factors that we're familiar with, such as mechanical ventilation, coagulopathy, renal failure, and other risk factors. And again, patients were randomized to either pentoprazole or placebo. The primary outcome was different than the primary outcome that we had in the previous study. So here, the primary outcome was the 90-day mortality, but the secondary outcome included clinically significant or clinically important GI bleeding, C. diff, and a new-onset pneumonia. They had a fairly large number of patients that were included in both arms, over 1,600 patients in the pentoprazole group and over 1,600 patients in the placebo group. They had patients who had risk factors. Around 20% of the patients had coagulopathy. And about 2 3rd of the patients were on mechanical ventilation and were on vasopressors. Looking at the outcomes of that study, the primary outcome, as I mentioned earlier, was the mortality by day 90. There was no significant difference between both groups. So in terms of primary outcome, there was no difference. The part that was a bit concerning to everyone was that the incidence of clinically significant GI bleed in the placebo group was almost double that from the pentoprazole group. So it was 2.5 versus 4.2%. That was a secondary outcome, so the p-value was not reported for that outcome. And so it's hard to tell whether it was clinically significant or not. But that was part of that study or part of the results that did raise some concern. The other part that was kind of concerning was that in the secondary analysis, they kind of took a closer look at the primary outcome, which is the mortality based on the severity of illness. And there appeared to be an interaction between the intervention effect and the disease severity, suggesting that there is an increased mortality in patients who had more severe disease and received pentoprazole. Again, that's a secondary analysis. It's hard to make any conclusions. But it was a signal that raised some concern at that point, that there was a potentially increased mortality with the PPI in patients who had a higher level of severity of illness. And that's what drove another study, the development or conducting another study, which is revising inhibition of stress erosions, or the revised study. This is a study that was just completed recently. The results have not been released yet, but we're all waiting for the results. The objective was to evaluate the efficacy and safety of pentoprazole for stress ulcer prophylaxis. It's a multi-center international study, randomized, concealed, stratified, blinded. And they're taking patients, adult patients, again, who we would generally define as high risk for GI prophylaxis. Those are patients that are receiving mechanical ventilation. And they're targeting a sample size of about close to 5,000 patients. So again, it's a fairly large study, randomized, placebo-controlled, and multi-center international. So it's really a study that we're all looking forward to kind of get some more insight about the use. The primary efficacy endpoint will be clinically important GI bleed. And they also have a primary safety outcome, which is 90-day mortality. So it's trying to answer that question about the efficacy, but also trying to address that part related to mortality as a safety outcome. The other part that's interesting and kind of different than what we've seen with a lot of the other research that's been done before is that there is a part of that study that will be looking at what's considered as patient-important GI bleed. So they'll be conducting some patient and family group interviews to get a better idea of what's considered as a clinically significant GI bleed for them. They'll be looking at, or they'll be including adult patients that were admitted to the ICU for at least 72 hours, as well as family members that had patients or that had family members for at least 72 hours in the ICU. And they're targeting a sample of about 50 patients. But again, this will give us, we've always been defining clinically significant GI bleed in a kind of a clinical way. We've always come up with our own definitions. This is taking another twist and kind of saying, well, what is important to the patients? Because there are patients where it's only transfusion that's important to them. And others, maybe it's the length of stay. So what is considered as a clinically important GI bleed that would require a GI prophylaxis? And the other important part is that there will be new guidelines coming out from the SCCM very soon, specifically for stress ulcer prophylaxis. Now the guidelines will not be incorporating the results of the revised study. So that part will not be included in the guidelines. But again, the guidelines will help provide some insight in terms of how to manage patients with regards to stress ulcer prophylaxis. So it's been a journey of prophylaxis. And I think it's a journey of uncertainty and will continue to be with a big element of uncertainty. To kind of summarize things, critical illness is associated with GI mucosal damage. And I think we all tend to agree with that. And it could progress to significant bleeding. The point is that the incidence of clinically significant bleeding is low. So the previous practice of where we would give prophylaxis for the majority of the patients is not something that is probably required at this point, based on the evidence. Acid prophylaxis is indicated in patients who are at high risk of significant GI bleed. And although we've tried to define those high-risk patients and those risk factors, I think there's still some uncertainty there. PPIs appear to be more effective than H2 receptor antagonists. But there's also the adverse events that I mentioned earlier. So it's also about weighing the risks and benefits. There continues to be significant misuse and overuse of acid prophylaxis in all patients. I think ICU is one. The non-ICU is another story. But there certainly is misuse of acid prophylaxis. There's certainly, with ongoing research and with the guidelines that will be coming out, we'll have better insight in terms of how to manage the high-risk patients. For the meantime, I think for all of us, as a multidisciplinary team, we can all put our efforts to at least make sure that those patients that are clearly not at risk of GI bleeding or significant GI bleed, that those patients not receive GI prophylaxis. I think this area remains having, there's still a gray part within stress ulcer prophylaxis. But there are certain parts that are very clear in terms of who should not be receiving GI prophylaxis. So it's something that we can all continue to work on to ensure that there is appropriate use of the medications. And with that, I get to the end of my talk. Thank you very much for listening. Thank you.

stress ulcer prophylaxis

acid suppressive treatments

H2 blockers

proton pump inhibitors

clinical guidelines

risk assessment