Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast hosted and supported by the Society of Critical Care Medicine as part of the Journal Club Critical Care Medicine series. In today's webcast we featured the authors of two viewpoint articles from the January issue of Critical Care Medicine. Each will present their case as to whether or not patients on vasopressors should receive enteral nutrition. This webcast will be available to registrants on-demand within five business days. Just simply log into MySCCM.org and navigate to the My Learning tab. My name is Tony Gerlach and I'm a clinical pharmacist at The Ohio State University Wexner Medical Center here in Columbus, Ohio and I will be moderating today's webcast. Thank you for joining us and just a few housekeeping items before we get started. First during the presentation you'll have the opportunity to participate in several interactive polls. When you see the polls simply click on the bubble next to your choice. Second there will be a question and answer session at the conclusion of today's presentation. To submit questions throughout the presentations type into the question box located on your control planner. Third if you have a comment to share during the presentation you may use a question box for that as well. And finally everyone joining us today's webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation. Your feedback is greatly appreciated. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter which may be helpful to others. The views and opinions expressed herein are those of the presenter and presenters and do not necessarily reflect the opinion and views of FCCM. FCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce today's two present presenters. First is Dr. Yassin Arabi who is chairman of the intensive care department as well as medical director of the respiratory services at King Abduziz Medical Center and a professor in the College of Medicine at King Sabin Abduziz University for Health Sciences in Riyadh Kingdom in Saudi Arabia. He received his internal medicine training at Wayne State University in Detroit, Michigan where he also served as chief medical resident and he obtained his pulmonary and critical care training at the University of Wisconsin in Madison. Dr. Arabi has more than 300 publications including articles in New England Journal of Medicine and he is currently the principal investigator or co-investigator on several multi-center randomized controlled trials. He also serves as an editorial board member of critical care medicine. And next and second is Paul Wischmeier who's a critical care perioperative and nutrition physician who serves as a professor with tenure of anesthesiology and surgery at Duke University School of Medicine in Durham, North Carolina. He also serves as associate vice chair for clinical research in the Department of Anesthesiology and director of TPN nutritional team at Duke Hospital. Dr. Wischmeier's clinical and research focus is in critical care nutrition perioperative care to help patients prepare and recover from critical illness and surgery. He has over 150 publications mainly focused on clinical nutrition and clinical care including articles in New England Journal of Medicine. He has an H index of 54. Thank you Yassine and Paul for joining us. Before we begin could each of you tell us if you have any disclosures to note. Yassine? My disclosure is that I was a PI on the permissible underfeeding trial and I'm currently a principal investigator for another feeding trial regarding the protein dose but otherwise I have no other conflict of interest. Well thank you very much and Paul? My disclosures are I have grants focused on nutrition and gut microbiome research from the NIH, Abbott, Baxter, Fresenius and Nutritia that relate to as I said nutrition and the microbiome and critical care and have also done some consulting to try to improve nutrition and and the outcomes of critical illness for Abbott, Baxter and Nutritia. Well thank you very much. Let's get started with the polling questions. So for everyone on what is your profession? Nurse, physician, advanced care provider or pharmacist which I would be, a registered dietician or student and others. It looks like we're evenly split between physicians, advanced practice providers, and dieticians, so a good mix of people today, about a third each. And now for Dr. Arabi's view on why patients on vasopressors should not receive enteral nutrition. Dr. Arabi? Thank you very much, Tony. So I think I'm going to start with the case. The first slide represents a case that we may be seeing on a daily basis. You have a patient admitted to the ICU with the community-acquired pneumonia and septic shock. This patient is on vasopressors. At present, if I can move the slide, this patient is on norepinephrine, relatively high dose, 0.6 micrograms per kg per minute, and he is on vasopressin as well, 0.03 units per minute, and his blood pressure is borderline systolic blood pressure in the 90s. The question, which it will appear, how would you think we would start feeding the patient? We have several options in this case. Maybe you should start feeding right away, on high-dose pressors. So the first question is about a patient we probably see on a regular basis, a patient with shock, high-dose inotrophs. How would you start feeding? The options we discuss every day on rounds. Should we start enteral feeding right away and try to advance to full target within 24 to 48 hours? Or perhaps another option to start at low rate, maybe trophic feeding or permissive underfeeding that is around 25 to 50% of the required requirement of calories and protein. Or perhaps if the patient is very hypertensive and high-dose pressors, an option would be number C, don't start enteral nutrition now and start when the patient becomes more stable. And the fourth option, when a patient with high-dose pressors like this one, don't start enteral nutrition now, but rather start pre-enteral nutrition now. So if we can get people's thoughts about this, it looks like 100%. So we don't need to debate this. Don't start enteral feeding now, start patient when it becomes more stable. So next question, next slide please. I think we are increasingly recognizing the importance of what happened to the gastrointestinal tract during critical illness. Our patients with critical illness have involvement of several organs and GI tract is definitely one of the involved organs in the critical illness. The GI tract is affected by the hyperperfusion. There are changes of the intestinal epithelial cells with apoptosis and atrophy. There is thinning of the mucous layer. There are important changes in the microbiome from the normal microbiome to pathobiome. And there are changes in the gut integrity. All these will lead to having toxic mediators and bacteria get access to the systemic circulation and therefore contribute to the multi-organ dysfunction. Next slide please. And this acute GI injury has been characterized in different grades. You could have a partial grade 1, which is mild degree of acute gastrointestinal injury. So this is a patient, for example, who has postoperative nausea. It could be more severe and affect the GI function. So a patient may have impaired digestion or absorption and manifest, for example, with gastroparesis or paralysis of the lower gastrointestinal tract. But in the grade 1 and 2, there are no systemic changes. In grade 3 is a more severe form where you start to have systemic changes. Example of this, if somebody has persistent feeding intolerance and you are not able to deliver enough calories for a long period of time, worsening bowel dilatation, abdominal hypertension. And then the most severe grade, which is grade 4, when you have GI tract is affected in a way that will lead to life-threatening condition. So for example, bowel ischemia, massive gastrointestinal bleeding, bowel pseudo-obstruction, abdominal compartment syndrome. These will be more severe forms. Next slide please. Now these grades have been tested or validated in observational studies where studies have shown that it's common to have moderate or even severe gastrointestinal injury. So in this study, which has 550 patients, grade 2 was as common as 50% of patients. Grade 3, 20% and grade 4, 5%. And increasing grades was associated with increased mortality and it was independent predictor for increased mortality. So I think we have evidence that GI tract is involved in the critical illness and it is associated with increased risk of mortality. Next slide please. Now where does intranutrition fit in this? So I think there's enough evidence to show that delaying intranutrition doesn't help. And in fact, it will contribute to the GI injury. Delaying intranutrition leads to atrophic changes in the intestinal mucosa, leads to impaired intestinal absorption, and it impairs the immune response of the intestine. And it will lead to impairment in the epithelial function. So delaying intranutrition is not a good thing. And studies have shown that if we start early intranutrition, it helps in restoring and probably preventing these morphologic and functional changes. So early intranutrition is a good thing. And this has been tested in multiple clinical trials. I have to say that most of these clinical trials are rather small, but collectively they have been examined together in multiple systematic reviews. I put here on the slide one of the recent ones where they looked at enteral feeding within 24 hours versus later feeding. And the systematic review among several showed that starting early intranutrition versus delaying intranutrition is associated with lower mortality. Several systematic reviews in different patient populations, including patients with elective abdominal surgery, major trauma, have shown similarly that starting early intranutrition is a positive thing. So I think there is good evidence that starting early nutrition generally in critically ill patients has a positive impact of clinical outcome. The second question would come is how much aggressive we should be pushing intranutrition in critically ill patients. And now this has been tested in multiple relatively large randomized controlled trials. I listed three trials. The EDEN trial, randomized patients with acute lung injury to trophic feeding versus standard intranutrition for six days. Our clinic, our trial, the PYRAMID trial, permissive underfeeding. The randomized patient permissive underfeeding, which is around 50% of caloric requirement versus standard intranutrition. And TARGET trial, the Australian trial, randomized patient to energy-dense versus standard intranutrition. And what you could see here on this table is that these trials collectively have tested almost all ranges of caloric intake. And all these trials did not show an improvement with more calories, giving more feeding, trying to push calories in the acute phase did not lead to an impact, positive impact on the short-term outcomes. In addition, the EDEN trial and the TARGET trial have a long-term follow-up. So the EDEN trial at six months showed no difference in physical, psychological, or cognitive outcomes at six and 12 months. And the TARGET trial functional outcome, which was published just recently in the Blue Journal, showed no difference in quality of life measures or disability. So the discussion that we have frequently at bedside that this patient, we want to give him more feeding quickly because we want to prevent disability or prevent the functional dysfunction. This cannot, this really has not been validated in randomized control trials at least. When it comes to giving more calories. For protein, I think that's a different question and it's being tested now in randomized control trials. I think we need to wait for the answer. So in systematic review that looked at dose of internal nutrition, generally there was no difference in mortality. In fact, when you try to push more feeding in these patients who are very critically ill, there's an increase in gastrointestinal intolerance, increase in insulin requirement, and some studies increase in renal replacement therapy. So the other aspect that we need to appreciate and understand when we talk about internal nutrition in patients on vasopressors is that what happens when internal nutrition is given in the GI tract. When we eat, there is an increase in the blood flow in the mesentric circulation. And it's part of the digestive process. So this study in 13 healthy volunteers documented blood velocity using Doppler ultrasound and documented that the blood flow in the celiac artery and superior mesentric artery increases within minutes after a meal. This also has been documented in other studies like this one in healthy volunteers and even in ICU hemodynamically stable patients. So what they've done in this study, they give them a meal either by oral or by NG tube and compared to a control group who are not being fed and another control group of patients who are given similar amount of calories periodically. And this table summarizes the results of this study. All the patients who received enteral feeding had an increase in blood flow in the superior mesentric artery while the control group obviously there was no change. And interestingly in the parenteral nutrition group, there was decrease. So in physiologic response to enteral feeding, you need to increase the mesentric blood flow. So the problem is when a patient person becomes hypotensive, part of the physiologic response to hypotension is there is a redistribution of blood away from the mesentric circulation. It's part of the compensatory mechanism. It is a good thing because it actually redistributes one liter of blood to systemic circulation to maintain blood flow to other organs. The price of this obviously will be on what happened to the bowel. So hypovolemias, patient with cardiogenic shock, clearly there will be significant hypoperfusion to the gut as part of this mechanism. This has, so when you add to this vasopressors, guess what's going to happen? You will have vasopressors will cause more vasoconstriction to the mesentric blood vessels. So this is a study in animals where they infused different vasopressors, epinephrine, norepinephrine, phenylephrine to increase the systemic arterial pressure by 20%. And obviously they were able to increase the systemic blood pressure. But this increase in systemic blood pressure was not associated with an increase in the flow in the mesentric arteries. In fact, some of these pressors diverted the blood away from the mesentric circulation. So the increment of the systemic blood pressure does not translate to improvement in the flow to the mesentric vessels. In fact, it might be the other way around. And it is, we know that some pressors are more, cause this more severely than others. Like this study in eight patients with septic shock in a crossover study design received an infusion of epinephrine compared to the vitamin norepinephrine. And this study documented that epinephrine is worse in this regard because it caused more hyperperfusion in the splenic blood flow, lower mucosal pH, and higher hepatic lactate. So some pressors are worse than others. Vasopressin also in this study shown also to cause redistribution of blood away from the gut mucosa as evidenced by increasing the PCO2 gap in the gastric mucosa. So vasopressin, epinephrine, probably more than norepinephrine causing redistribution blood away from the intestinal mucosa. So that's very important to know. So we have the changes that are related to the shock itself, which is physiologic, and then the pressors will add to the vasoconstriction. So in addition to these studies, which are based on blood flow, there are studies using biomarkers. There is a biomarker called intestinal fatty acid binding protein. And this marker is a marker of enterocyte damage. It's a marker of damage to the epithelial cells of the bowel. And this study looked at the levels of this marker in 103 patients and showed this marker is increased in patients who are on catecholamines. And that the levels of this marker are associated with increased mortality. This also has been shown in another study from the same group looking at the fatty acid binding protein, again documenting that this marker was higher in patients who are receiving catecholamines, and it is higher in a dose-dependent fashion. So in patients who have a dose of catecholamine of 0.48 microgram per kg per minute or more had higher levels. And the levels of this marker, the marker of the enterocyte damage, were independently associated with increased mortality, similar to SOFA. So damage to the enterocytes happen more with depressors and is an independent predictor. One of the best studies that looked at the vasopressors, looked at the aggressive enteral feeding in patients who are depressors is the NUTRIREA trial. And this is a large trial that I'm going to mention in a couple of slides later. This is a trial that randomized patients to receive early enteral nutrition with achieving the full target of enteral nutrition within 24 hours versus parenteral nutrition, full target within 24 hours, in patients who are mechanically ventilated and in shock. And this slide shows a subset, a substudy of the main trial where they did biomarkers. They did the fatty acid binding protein. So at baseline, patients, this marker was high, but it was similar in the patients who were randomized to enteral and parenteral nutrition. After starting enteral nutrition or parenteral nutrition, at three days, this marker, the marker of enterocyte damage, was higher, was higher in the patients who are receiving enteral nutrition. So we have a patient now who has reduced cardiac output, has a compromised circulatory status. Many of our patients already have vascular insufficiency. They may have atherosclerosis and changes in their mesentric arteries anyway. And now we add vasopressors. All these will lead to a reduction in the blood supply to the bowel. And when you add to this enteral feeding and the increased demand that is required, the enteral feeding, as we said, it will require an increase in the blood flow. Then this all will lead to supply-demand mismatch. And in some patients, it can lead to a non-inclusive bowel ischemia. Now this entity is not new. It has been described a long time ago. It was described mainly with jejunal feeding. So this is a review of nine studies where describing 32 patients who have bowel necrosis with jejunostomy or nasojejunal tube. And the incidence may be not very high, but it is very serious because the mortality is quite high, is 41 to 100%. And why jejunostomy in particular? It is believed that in patients, when you start them on enteral nutrition by, let's say, we start a patient on nasogastric feed and he starts to not tolerate and maybe vomit or has high residual, it is possible, I mean, if one can argue that this is a body reaction is that the patient is not ready to be fed. So in this patient, if you put a jejunostomy tube and feed him, maybe that will be problematic because already this patient is telling you that he cannot manage, he has a compromised gut, an ill, sick gut. This another study, this is another study of trauma patients, and these are young patients typically who don't have a lot of arteriosclerosis. And yet there were cases, not many, but there were cases of bowel necrosis with enteral nutrition. And what this study showed that there were no reliable clinical signs for early detection. The NUTRIA trial that I mentioned earlier, this is a randomized control trial published in Lancet a couple of years ago, a large French trial that took patients who are mechanically ventilated and in shock, and all of them were on pressure, 81% or norepinephrine dose. The average dose of norepinephrine was 0.56. So this trial enrolled patients who are really in severe shock, in severe shock. And I think I have to mention here that other trials for enteral nutrition, like the pyramids of underfeeding trial and Eden trial, would exclude, excluded patients who have this level of enteral, of vasopressor dose. So what this trial showed that if you randomize patients to early enteral nutrition, but here we are talking about aggressive enteral nutrition to reach the target within 24 hours, or parenteral nutrition, again trying to achieve the target within 24 hours, there was no difference in mortality, but there was significantly more gastrointestinal complications, enteral feeding, more vomiting, more diarrhea, and there was fourfold increase in bowel ischemia and fourfold increased colonic pseudo-obstruction. The incidence wasn't high, very high, it was like 1%, but it is serious enough to raise concerns, especially there was no benefit. So no benefit, potential harm, I think there's an issue here. So at present, there is a pilot study published on challenging the whole idea of feeding patients on enteral, on vasopressor. So this is a trial of early trophic enteral nutrition compared to no enteral nutrition in mechanical ventilation with shock. The pilot study, small, 31 patients, was published. The median dose of norepinephrine in this pilot study is 0.08. So interestingly, the studies, including patients who are mild shock, and I think it will be also very interesting to look at patients with more severe hemodynamic instability. So I can't make much out of the outcomes because it's too small. We always have looked at observational studies, but I think we need to be cautious when looking at these observational studies. This is one study that looked at enteral nutrition in patients with shock and mechanical ventilation. And yes, the study adjusted for confounding using propensity score, but I mean, we have this again and again, seeing that observational study can show effects that could not be validated in randomized controlled trials. So in this study, they found that enteral feeding was safe and was beneficial. This is another observational study looking at patients who are on VA ECMO. So they are severe shock to receive VA ECMO. And they said it was safe and enteral early nutrition was associated with lower mortality. But I could tell you the indication bias is really hard to adjust for in these cases, especially when you rely on retrospective data. So I think some of the limitation, and we wrote an editorial on this paper, the measured and unmeasured confounding. There are other issues, and especially related to the definition of bolus chemia, was all the cases documented, and this database is not clear. So putting this together, I think we need to keep in mind that non-inclusive bolus chemia in several of the feeding studies that's been published recently excluded patient in high dose pressures. So the EDEN trial, the permissive underfeeding trial, did not include high vasopressor doses. So in permissive underfeeding, for example, a subgroup analysis by vasopressor or no vasopressor did not show benefit or harm in terms of mortality. But again, the maximum dose pressure was 0.4 microgram per kg per minute of norepinephrine. Now so what should we do if we put all this together? I think if in a patient who is unstable hemodynamically and being actively resuscitated, I think it's very reasonable to postpone the enteral feeding until hemodynamic stability is achieved. And these recommendations, the slide and the one after, are consistent with the recent clinical practice guidelines. Patient who is on high dose of pressure or increasing dose of pressures or on multiple doses of pressures, I think it's better to postpone enteral nutrition until the patient is hemodynamically more stable. For a patient who is on low and moderate dose of pressures, I think it is very reasonable to start enteral nutrition at low rate and advance gradually. We need at the same time to monitor for symptoms and signs of gastrointestinal intolerance. So in a patient who has evidence or suggestive of compromised mesenteric blood flow, so example patient with intra-abdominal hypertension or abdominal compartment syndrome, it is reasonable to, in this case, to postpone enteral nutrition until the condition is treated. I think we need to keep eye on symptoms and signs of gastrointestinal intolerance. For example, unexplained abdominal pain, dilated bowel lubes, increased air fluid levels. In this case, I think most of us would hold enteral feeding and assess the patient for the underlying condition and possibly bowel ischemia, depending on the condition. If the patient has unexplained hemodynamic status, I think it's reasonable to again assess for bowel ischemia. Obviously, if the patient has confirmed bowel ischemia or pneumothorax intestinalis, because without saying, you hold enteral nutrition. So in conclusion, I think gastrointestinal injury in critically ill patients is common. Early enteral nutrition is generally recommended for ICU patients. I think we can all agree on this in general. However, in patients with high-dose pressures, trying to achieve full targets of enteral nutrition quickly is not beneficial, could be harmful, as shown in the NutriREA trial. I think we need to keep in mind that there are some patients who are at increased risk for non-obtrusive bowel ischemia. Probably a patient with high-dose pressures, probably a patient with epinephrine versus other vasopressors, jejunal or post-bioloric feeding, patients with underlying vascular disease, and also if we are trying to push calories quickly, I think that would be another issue. So that's, in summary, my view on this topic. Thank you very much. Thank you, Dr. Arabi, for that great presentation, and next I'm sure we'll hear a good presentation with Dr. Wischmeier, so my position, of course, is taking the role of that we should feed on vasopressors, and I want to say thanks to Tony and to Yasin, I learned a lot in that lecture, but advocating to feed on vasopressors, I would like to present the point that perhaps not only is it safe to feed on vasopressors, perhaps it also saves lives and improves survival to feed on vasopressors in the right patients, and so John Marshall and others and other mavens of our field have taught us, as Yasin started with, that the gut is a really key motor that drives organ failure, and this knowledge goes back many years to even the 1900s, early 1900s, when people described chronic intestinal stasis and the risk it posed to children, and even throughout the middle of the last century, we began to learn more and more about the role of the gut and the bacteria in the gut and how it drives illness, and so that's led to more recent publications by real experts in our field that really describe the gut perhaps being the origin of much of the multi-organ failure and the adverse outcomes our patients face when the gut fails, as you heard described in the last lecture, and I think no one better than our past SEC and present Craig Kubersmith has done more for describing the gut as the motor of multiple organ dysfunction and really the driver of much of the organ dysfunction and systemic inflammation we see than Craig Kubersmith has, and he has some really excellent review publications and articles for those who want to learn more about this, but to summarize that, I think we really see there as four key pieces in relation to how the gut drives organ failure and critical illness, and one is the dysbiosis or the deranged microbiome that we know happens, especially when we don't feed, and we'll talk about that, the increased intestinal permeability. We don't actually believe, and actually this is not able to be proven, that bacteria get through the gut barrier and into the bloodstream. Gene Moore at the University of Colorado where I was previously did a lot of work there and put catheters into portal veins and couldn't find any bacteria over many, many samplings, so we actually don't see or believe that bacteria escape into the bloodstream from the gut, but they do invade into the gut immune system, which is one of the largest in our bodies, and that leads to production of toxic mediators, inflammatory mediators that get not only into the blood but into the lymph, and the first organ that sees the lymph is the liver and then the lung, and so we think, as Dyche and others have taught us, that much of the injury to organs happens not just through the blood but through the lymph, and it's from the gut immune mediated systemic mediators, and then the last piece I think is important is we know that vagus signaling is affected from the gut, and the vagus actually can increase or decrease inflammation depending on how it's signaled, and I will talk about how intra-feeding actually improves the anti-inflammatory signaling of the vagus, and so we really have a new model of how the gut works. The gut becomes underperfused in shock, and then it doesn't lead bacteria into the blood but releases inflammatory mediators into the blood, and then subsequently ischemic reperfusion injury can occur from pressors or from under-resuscitation or from the severity of the shock, and that will augment the gut response and ultimately lead to the inflammatory response and the organ dysfunction that our patients suffer, and so lots of articles recently, but I think this is one of the best, have talked about how feeding the critically ill patient early intralutrition delivery in shock can slow the motor, slow the inflammatory response from the gut, and some of the damage it does to other organs, and so specifically getting at that intestinal permeability and the inflammatory lymph and inflammatory mediators into the blood, this is an excellent figure from that article of Steve McClave and Darren Highland and Bob Martineau and Todd Rice that looks at some of the key things intral feeding does. One, it actually increases the ability of the immune system to prevent bacteria from adhering to the gut wall and invading the gut and activating that big immune mass, and so by improving then not just the immune surveillance of the gut, but reducing the permeability of the gut, we ultimately reduce the oxidative stress and inflammatory stress that the body sees that is generated from the gut immune system, and so it actually changes the way the gut immune system functions when we give intralutrition, and so I think that's key, and I think it's key to say that there's a lot of anti-inflammatory and protective things that feeding does that go far beyond what nutrition does for the nutritional pieces of it. It's far beyond protein and calories, and in fact, gut perfusion is one of the key things. You saw the first hit and the second are often around gut perfusion, and this is an early study that was done a number of years ago that shows that early feeding actually improves gut blood flow and improves gut oxygen extraction, so that gut ischemia that leads to a lot of the downstream things you heard about in the last lecture, we believe can be improved by not necessarily goal feeding, but perhaps trophic feeding, and this was a model of that that was done. So then there's the newer knowledge we have of how clearly the microbiome and what the microbiome changes that we call dysbiosis or the pathobiome due to outcomes, and I published some of this data in a multicenter microbiome study, and we found, of course, that a healthy gut is a diverse gut with a very broadly diverse microbiome. Unfortunately, critical illness leads to a significant loss of diversity, down to where 95% of the gut's bacteria can be one organism, one organism. The gut loses so much diversity, and that we've associated that with poor outcomes, so lack of feeding leads to lack of diversity and loss of microbiome benefit, the beneficial microbiome and the promotion of a bad pathobiome or dysbiosis. John Alverde, one of the experts in the gut talk of bacteria, has even published data in his review article describing that even just delivery of 20% of nutrition, just trophic feeding, can prevent dysbiosis, attenuate loss of gut barrier function, and improve innate immunity, and so I think this is really a key opportunity we can use, just even trophic nutrition, and I'm going to keep coming back to that. I think the keys, in many cases, are to deliver not the nutritional value of nutrition, but the other effects of nutrition, to protect the patient from the shock state, if done correctly. And so, then the last piece that is worth knowing is, intra-nutrition has got some reasonable mechanistic data to show that it changes the inflammatory signaling of the vagus nerve, which runs to the brain and then out to the periphery, and that this was a very nice paper that was done where they fed animals different kinds of intra-nutrition, high protein or high lipid, and they found that it actually led to an anti-inflammatory response and reduced gut translocation of bacteria into that gut immune system, and it was mediated by the CCK receptor, which senses fat and other nutrients, and if you block the CCK receptor, the benefit of nutrition went away, and if you cut the vagus nerve, the benefit of nutrition in different forms of shock went away as well, so the vagus nerve clue plays a role. I think this is well summarized in this paper, that intra-nutrition modulates inflammation and preserves gut integrity via the CCK receptor, and that this gut-brain-immune axis that we're learning more about may be a key part of how we treat our patients with the therapeutic aspects of intra-nutrition rather than the nutritional aspects of when we give intra-nutrition. But then, of course, there is the nutrition piece, and I think it's important to realize it is vital for us to deliver maybe not even the calories the patients need, but the protein, the vitamins, and the micronutrients the patient needs. For those of you who haven't spent time talking or spent time at Greene-Vandenberg's ICU, she gives trace elements and micronutrients and vitamins to her patients' IV every day, and has done that for years, and maybe there's a role for that. And so, clearly, the malnutrition that we know is prevalent and pervasive in our hospitals and ICUs is essential to also be considering that needs to be addressed in our ICU care. And that not only translates to ICU outcome in the ICU and in the hospital, but what happens after the ICU as well. It's why it's so important to be studying outcomes that go well after ICU, because, of course, our goal is, some of you may have heard me say, is creating survivors and not victims. We want patients to go home back to a life that is worth all they suffer in our ICUs to achieve, rather than perhaps a life that's not. And I think it's, Jackie Shinawa has said it very well, that survivorship is the divining challenge for all of us in the ICU field in the next century. And he describes in these quotes well that the emerging picture of ICU survivorship is disturbing, deeply disturbing. Patients are ravaged following discharge. They can't walk. They can't think. Bodies don't function like they did before, and all of us have stories of patients like this. And clearly, we need to do better for them. And this is a prevalent problem. This is Wesley's slide, but we know that 60% to 80% of people on a ventilator more than a week will have this disability. Why does it happen? Well, we know that ICU patients can lose up to a kilogram of lean body mass a day, and they can remain hypermetabolic and catabolic for up to two years after a burn or a major injury. And so we're not evolved as humans to survive these injuries, and so delivering nutrition to overcome this catabolism, hypermetabolism, and muscle loss is key. Because this really is an epidemic, this post-ICU syndrome we hear us talk about, and we need to do better. And clearly, to do better for our patients, it's got to be a combination of nutrition, rehabilitation, and a lot of us believe some of the athletic training techniques that we're using around the world here at Duke and other places to try to recover patients and prepare them. But I think targeting our nutrition and personalizing our nutrition, as I've described here in this recent review article, is key. I think clearly we know the patients don't need as many non-protein calories early on. I think you've seen study shows that well, and I think even protein doses need to go up slowly over the first few days, as some of our European colleagues have shown us. But then clearly, we need to reach goal, and perhaps sooner in the malnourished patient, if we want to have a good outcome in our patients, and we know already we don't feed our patients well. Darren Hyland and others have surveyed, perhaps you have done his surveys, looking at how we feed patients. And we know we underfeed, not just for the first few days when they're on pressers, but we give less than 50% of their nutritional needs for up to two weeks, and the U.S. is always the worst for the U.S. listeners out there. And not only that, our protein delivery, which is probably what's essential to improving outcome, is a third of our goal recommendations. So we clearly are already underfeeding significantly, I don't think we need to take steps to aggressively do that. So again, this is the question we need to be posing, and actually, this was data from the REDOX trial. This was a trial that Darren and I published in the New England Journal studying glutamine and other things. But we looked at the very sickest patients, the ones with malnutrition for more than eight days, and we found the more protein and calories they got, the better their survival was. And more importantly, when we looked at them three and six months later, the patients who got more protein and calories had better qualities of life. That every 25% increase in nutritional adequacy over the first week, this is only over the first week, improved quality of life months and even perhaps years later, we would guess. So how you feed in the first week does change quality of life, we believe. And again, these patients got more protein than most of the trophic feeding trials you heard about in the last lecture. And so we think maybe some of these newer studies studying protein as the primary delivery agent to improve outcome might be essential, and so those studies will come. So early intralutrition, even trophic in shock, may be lifesaving, we would hypothesize. But what about the patient who's on vasopressors, who's still in that active shock, who's maybe resuscitated but still in shock, is it safe to feed? You'll often hear it's probably too risky, right? Well, I would say otherwise, and I think the data would support that it's not too risky to feed either if you're smart. So I think we can feed on vasopressors, we just have to be thoughtful about how we do it. And we do have a lot of literature to guide us. And so I've tried to summarize this, this is the review article, the viewpoint article that led to this lecture and this discussion. And this is where I show that it may not only be safe, but it may save lives. And the first study to show that, and this was an important study, Colleen and his colleagues looked at 1,174 patients in an observational trial, 700 of them got intralutrition in the first 48 hours on pressors, all the patients were on pressors. About 500, 450 of them got late intralutrition after 48 hours was when it was started. And the intralutrition started in the first 48 hours, that group of patients had significantly improved survival versus the patients who didn't get fed in the first 48 hours. And what was interesting was the sickest patients, when you adjusted for all the confounders, the people on multiple vasopressors experienced the greatest survival benefit from getting early feeding in the first 48 hours. So this was over a thousand patients observational in nature with this limitation, but showed that perhaps feeding on pressors had a benefit. And so a good number of other small trials have come since then, many of them retrospective, but looking at, I think, really good questions to help guide us. And this was one by Jayshi Patel, and he looked at 66 patients and looked at what happened to them in a retrospective study. And the patients were in three groups, those who got no intralutrition, those who got trophic feedings, basically less than 600 kcals, and those who got fed more in the first 48 hours. What was interesting, you can see here in the group that got trophic feeding, essentially less than 600 calories a day, they had a shorter time of mechanical ventilation and a shorter time of length of stay, even in the small group. And the patients who were fed more didn't necessarily benefit versus those who didn't get fed at all. So this gets to the non-nutritional value on protecting the gut and protecting the patient by feeding a small amount early. And so in septic shock, they found that there was improvements that could be had if you gave trophic feeding, perhaps even better than full feeding, of course, which makes some sense. So another trial, a retrospective trial done by two pharmacists, looking at 259 patients who are on vasopressors, and they looked at tolerance and complications, gut complications. And they defined tolerance as these kinds of adverse events like emesis and lactate, and 75% of their EN attempts on vasopressors were well-tolerated. They didn't have too many significant adverse events, a small amount of ballaschemia and perforation. But what they found was with patients tolerating internal nutrition tended to receive lower max doses of norepinephrine than patients not tolerating. So you can see that tolerance there on the one axis, and then the max dose, and you can see that tolerance goes way down as the dose of norepinephrine goes up. And so I think there's something to that, that at lower doses, there's potential tolerance to be had. So key factors associated this tolerance, and when you might think about feeding people, was a norepinephrine dose that was low, phenylephrine use, and no use of vasopressin or dopamine. Vasopressin and dopamine, as you'll hear me say later, have a much greater risk to the gut, we think, and are not great pressors to feed on, at least not as good perhaps as norepinephrine and phenylephrine, and we'll come back to that. And then this was a cardiac surgery study. These patients could be on mechanical circulatory support or on vasoactive drugs, and they looked at a retrospective, or I'm sorry, an observational study of patients who, as you can see, for those of you who work in the CT ICU, had this kind of support. These are very sick patients. And EAN was initiated without episodes of mesenteric ischemia. Some of them did have issues around constipation and other complications, but they didn't have vallaschemia. And so it was felt that even on hemodynamic support and mechanical support of the circulation, EAN could be safe. Again, many of these patients didn't reach nutritional goals, and I would advocate you don't need to reach nutritional goals to get the benefits, as we talked about, the non-nutritional benefits of this therapy. So maybe the dose matters. Maybe how much we give matters. This goes back to the NUTRIA trial that you've already heard Yacine talk about. I won't belabor it. This is the EAN versus PEN trial the French did. But I think, as we heard, there's this increased risk of GI complications, including vallaschemia versus TPN. So what you should know, especially for those of you in the US, the mean enrollment norepinephrine dose in this study was 0.53 mics per kilo per minute. And this is above what was permitted in most of the other trials. So this is much higher than I would feel comfortable feeding, and I think much higher than most of us would feel comfortable feeding. I'll be curious what you think. So I think that's a key thing to realize about this study. These were very sick, sick patients that are far beyond where most of us would be comfortable feeding when you look at this norepinephrine dose. But looking into other studies, this is another larger retrospective trial, 120 patients with septic shock, looking at the outcomes of these patients who received intralutrition. 60% of these patients with septic shock on vasopressors tolerated intralutrition. And I think what was key about this is they really looked at the dose, and I think that's what we're getting at here. The patients who tolerated in green, on average, had a lower initial dose of norepinephrine or vasopressor dose. The median doses were about half as high for these drugs, and the max doses were also lower. So I think it's important to realize that people tolerating are at these lower doses of vasopressors. The high doses, like we saw in the NUTRI trial, don't seem ideal, and these were statistically significant in the initial and median dose. And then I think the other key piece is, is they found that multivariate analysis demonstrated that patients were much more likely to tolerate if they were on 0.14 microns per kilo per minute, that should be microns per kilo per minute, of norepinephrine equivalent or less. And that might be a worthwhile number to think about in your practice, and we'll come back to that as well. And so I think the most important trial I'm going to show you, and one of the most recent, it literally came out just within the last year. This is a large health outcomes study where they looked at a large inpatient database in Japan. And the last author there, Dr. Yasunaga, is a very famous, very well-published, with over 500 papers, health outcomes researcher, and does a lot of critical care studies. They found 52,000 patients who were on different doses of vasopressors, and then they looked at whether they received early intralutrition or late intralutrition. And so I think this is a key piece here. And again, the two groups were started within two days with intralutrition or started after two days. Again, 52,000 patients, and then they looked at what happened to them and their outcomes at these different doses. And what they found was that patients who got fed early in the first two days had significantly improved survival in the low-dose and medium-dose norepinephrine-equivalent groups. So up to 0.3 mics per kilo were benefited in patients who were given intralutrition within the first two days. The high-dose group had no difference in mortality. There was almost an odd ratio of one. So no deficit or no detriment, but potential benefit in some very large group of care. Of course, it's a large healthcare outcome study, so it has limitations of that, but I think it compels us to think about the fact this could be beneficial in survival to our patients. So this showed that early intralutrition reduced mortality in the low- and medium-dose, but not the high-dose group. I think this is a very important paper, one of the really landmarks in this area. So maybe when we're increasing mortality risk when we do not feed patients on low-dose vasopressors, not when we do feed. And so then the question is, aside from the non-nutritional benefits, are there any nutritional benefits and are they absorbed? And so this has been studied as well, Metaburger and others have shown that nutrients are absorbed when patients are on pressors, the study they did in intensive care medicine a number of years ago. So they are absorbing them. And so I think to summarize and to finish here, this is the table and the recommendations that I made in the paper I wrote. And I think the markers you need to have before you even consider feeding are clearly you need a resuscitated patient. The lactate should be normalized, the vasopressor dose decreasing or stable, a good mixed venous, and reasonable amounts of fluid resuscitation going on. I think ideally patients on less than 0.1 mics per kilo are patients you should be feeding. I think the data would benefit towards a survival benefit amongst the other benefits you may give the patient. From 0.1 to 0.3, I think the jury's out. Above that, I wouldn't feed on that. And I think your choice is important, norepinephrine and dobutamine and phenylephrine clearly in the observational animal data seem safer, and you heard Yossine present some of this, than epinephrine, vasopressin, and dopamine. I think a trophic feeding strategy is essential. And then following for intolerance is also essential. And so I think the other key thing I would say that may be surprising is you should feed the stomach if you're going to feed on vasopressors. Don't ever, ever feed the small bowel. The only way you can monitor for GI intolerance and the other things you heard about in the last lecture is if you're feeding the stomach. You can't check residuals. You can get burned by feeding the small bowel. You should never feed the small bowel on pressors. I would advocate in septic shock or ongoing shock. Clearly, the CTICUS patients that are on continuous low doses of dopamine and epinephrine for cardiogenic shock, that's a different story probably, although I still would advocate to feed the stomach in those patients too and watch for signs of intolerance. This is the best monitor you have for internal nutrition safety. Feed the stomach. 95% of the world we surveyed feeds the stomach. So key take-home points in closing. Clearly the gut is the motor that we believe drives organ failure and inflammation in the body and there's lots of things that contribute to that from dysbiosis to vagus signaling to gut permeability. Early internal nutrition can slow this motor through lots of different mechanisms as we've talked about and I think it's key that we also be delivering nutrition because if you start feeding even trophically in the first few days, you're more likely to be able to continue feeding and not be having long NPO periods to improve outcome because it appears that how you feed in the first week may change people's qualities of life months later. And so I would advocate and conclude that feeding on vasopressors may not only be safe but may also save lives. And I think maybe we're increasing mortality risk when we do not feed patients on low dose vasopressors who are resuscitated. And I think we're not too far off my adversary and I, Dr. Rabi, even his paper implies that on low doses you maybe should be starting in and advancing gradually. So in the end, I hope we all can use nutrition both for its nutritional values and its non-nutritional values to create survivors and not victims of our patients and return them to a life that they came to us and one to get and one that's worth living. And with that, I think we're just left to make our decisions and see what our practice is going to be. And I will look forward to your questions and thoughts. With that, I would like to start with a polling question. Do you think patients on vasopressin should receive enteral nutrition after this talk and looking eagerly at this result? I do have a couple of questions from the audience. My first one kind of goes with the type of nutrition. Does the type of enteral nutrition matters? Should it be a concentrated or isoosmotic therapy formula versus a concentrated one? And does it really matter how many calories or proteins you get? I might say, and I'll be curious what you see in things, you know, I don't think we have a lot of data around which tube feed to use. I will tell you many practices I see and we often in our ICUs here at Duke use a peptide-based formula. Some of it's because it delivers better protein delivery for the calories you give. But I think it's very reasonable if you're going to feed on pressers and we know that it takes less energy to absorb peptides. And I think with the preponderance of peptide formulas available, I would choose a peptide formula. But that is absent, of course, actual literature evidence to support that. That's a study that hasn't been done. But I would tend towards a peptide formula knowing that's the most energy efficacious formula you can give to absorb protein, which is my goal. So I fully agree with what Paul mentioned regarding the second part of the question, the amount of calories and protein. I showed you the several studies that address the calorie amount. So these, basically all the studies suggest that lower amount of calories is as good as the higher amount of calories in patients who are not in severe shock. In terms of protein, I think the evidence is still limited at present. And there are several ongoing trials of high versus low amount of protein. There's the effort trial by Deryn Hyland starting early, high protein versus low. We'll be starting a trial where we have a step up increase in protein. So initially, moderate amount that on day five it goes up. So kind of step up approach. And hopefully we'll have better answer about the protein dose once these studies are concluded. Someone wanted to ask if arginine content or anything like that would matter or make a recommendation or a point in your recommendations. I might say in the patient on pressers, I would not give arginine to the patient on pressers. I think we had reasonable data years ago that implied that in the infected septic patient that the delivery of arginine may create a pathway down to nitric oxide that can not only increase instability and other negative hypotensive related events, but may also drive mortality being increased. So I think on pressers, I would try to avoid a high arginine containing feed. I think once patients are improved and perhaps moving into the chronic critical phase or once they're out of that acute shock phase, I think it's very reasonable to consider giving it. At that point, I think Fred Moore and others have shown us that the PICS or the persistent immunosuppressed state is real in ICU. And I think that's something arginine can help combat. But I wouldn't give it in the phase of presser receiving patient. Thank you very much. Just since we only have a couple more minutes for all those questions on here, we'll get them answered by the presenters and sent out on a group email. And if you have any new questions, you can always go to journals at fccm.org and ask them there and we'll get back to you. And right quickly, because you did mention about gastric residual volumes, would you use prokinetic agents in these patients? I don't think I would. I think, and I don't have any data to say that, I think if a patient started to acquire residual above 500 in the setting of a vasopressor dose, especially above 0.1, I might say that may be the first signs of meaningful gastric intolerance. And I think I'd want to maintain that marker, especially in the first 24 hours. Now that said, I think if the presser doses persist for a few days and you get out into the post 48 hour period, I think then at that point, if it's residuals over 500, again, the cutoff needs to be 500, not 250 or 300. If there's getting over 500, but there aren't other signs of distention or bowel problems, then I think it'd be reasonable to try some Reglan. But I think it's a really important marker. Those of us who worked in the burn world know that's the best marker for sepsis ensuing. And I think in the surgical world too, we really lean on that marker. So I think in the vasopressor patient, despite maybe not needing to check residuals and other things in other patients, I think in the vasopressor receiving patient, feeding the stomach and using your residual as a real marker, I think is very important. So basically, I think it's the theme that uses the high gastric residual as a marker of feeding intolerance, that you have a sick gut and trying to push more internal nutrition may not be the good thing. And I think that's a kind of change in the way we're thinking about gastric intolerance. Well, thank you to both of you today and our audience for attending. Sorry that we went a little long today. Again, everyone who joined us today's webcast will receive a follow-up email that will include an evaluation and the answers to the questions that we didn't get to. If you do have any more questions, please feel free to email journalswithaS at SCCM.org. And please take the time to complete the evaluation. Your feedback is greatly appreciated. And thank you very much for your attendance today. Thanks, everybody. Thank you very much.

Journal Club

Critical Care Medicine

vasopressors

enteral nutrition

Yassin Arabi

Paul Wischmeier

gastrointestinal intolerance

bowel ischemia

inflammatory response

gut translocation