with. So it's great to be with you here today and this will be a little bit of a different talk than you often will hear about immunonutrition. And rather than talking exclusively about fancy individual nutrients that may or may not do something, I'm going to get back to the basics of what we need to do well in the ICU feeding and the macronutrients like lipids and things that now new data is showing and new products are showing us we can do better for our patients. And so things that I hope will be practical for you clinically as well as scientifically. Briefly, if I can get an advance here, hold on, it's not Okay. Thank you. I'd like to call these my alignments of interest rather than conflicts of interest. I'd like to thank the RO1s from the NIH and the DOD grants and the industry grants I have. All of those funders are in alignment with all of us in that we're trying to improve patient outcomes and align to do better for our patients. And so as I always start my talks, I think it's key we always be thinking that it's critical that we take responsibility not just for what happens in the ICU, but every day on rounds we're also talking about what we can do that day for our patients that's going to help them recover after they leave us. And that's something I think we often forget until the very end of their stay. Because the reality is, of course, what our patients want is to go home as survivors. Patients go back to a life that's worth living rather than victims that perhaps go to rehabs and to long-term care centers or perhaps never go home to a meaningful life again. Because ultimately what our patients want, of course, is to be able to walk down the street with the people they love and to hold their grandchildren again. And I think that's what we're trying to do for our patients. And our patients are sicker than ever. Sepsis and COVID and the extent of comorbidities we're facing make our patients harder and harder to care for. And unfortunately, nutrition often falls by the wayside. And I think we need to, A, put it in the forefront of our minds, especially in their long-term outcomes. But also we need to realize that like any other therapy in the ICU, it must be targeted and that one size nutrition doesn't fit all. Just like we don't give the same dose of vasopressors or the same dose of antibiotics, nutrition needs to be targeted as well. And we need to give the right dose and the right patient at the right time. And so how can we think about this and put it into practice for our patients? And what are our guidelines and the latest evidence say? To do that, I want to tell you about a patient I took care of during COVID. I'm going to use a COVID patient as it's timely. It's a 49-year-old African-American science professor. I work at Duke. We have many universities around us. And unfortunately, many of our fellow faculty and staff got sick. And his family members were COVID positive as well. He got not so sick when he first came into the emergency department, but unfortunately, he progressed very rapidly. And as so many times we've seen, he decompensated and required intubation. Ultimately, on the vent, of course, he was severely ill. He had to ultimately be relaxed and ultimately proned. And so we have this very sick patient who's on levophed, although I often thought the levophed was for the sedation as much as the shock, who seems resuscitated, of course, with a good mixed venous sat and a reasonable lactate. So our guidelines clearly say we should be starting nutrition in all of these patients and feeding the stomach early. And so the question then is how much? And all of our recommendations now say, which may come as a surprise to some, is we're supposed to be starting very slow, perhaps with trophic nutrition for the first few days, and then slowly progress up. And I think this is critical. And why would that be? Why is our data showing that if we feed less early on, our patients do better? Why does trophic feeding improve outcomes? And particularly in the patient on vasopressors, is it possible that this trophic feeding not only is safe, but saves lives? And we're going to come back to that. And I think this gets back to the idea that we need to protect the gut. And you've heard a little bit about the gut in the last presentation, but Craig Coopersmith, a good friend and colleague of mine since my beginnings as a young intensive researcher, showed us the gut is the motor that drives organ failure. And so things that protect the gut and fuel the gut and allow it to function properly are critical. And clearly the gut suffers many insults that can drive inflammation throughout the body. One is dysbiosis and the alteration of the microbiome. Intestinal permeability increases, which allows the gut immune system to be activated. Many of the legends of the Shock Society and SCCM have shown us the lymph actually becomes toxic from the gut immune system dumping toxic lipid mediators in that the lung sees first as the lymph dumps into the lung circulation. And then ultimately vagus signaling, which we'll come back to, is critical in controlling systemic inflammation. And you want vagus signaling. And that comes in large part from your gut in many cases. So we've known that early internal nutrition, we believe, can slow the motor driving organ failure. But perhaps even trophic nutrition does this well with its non-nutritional benefits. We know that feeding even small amounts can reduce intestinal permeability and reduce the toxicity the mesenteric lymph sees. Further, it helps preserve the microbiome. This is data from our multi-center microbiome study that was published at M-Sphere a number of years ago that showed the severe dysbiosis. You saw it in the last talk as well in pediatrics with the red being the proteobacteria growing up. And in fact what we want of course is a diverse microbiome in our gut. And we know the loss of this is associated with poor outcomes. And you're going to hear about John already a lot. He was a mentor to me in medical school and in residency. Even delivering a small amount of feeding prevents dysbiosis, attenuates the loss of the gut barrier, and improves innate immunity. So even if you're just getting 10 or 15 cc's of feed in for your patients, you're doing good things for them and you're improving the things that create risk for them. What about the other things feeding does? Well it signals the vagus nerve, right? Everything, what happens in vagus affects everything. And it truly, truly does. And this is a critical thing that most of us would never think of when we think of feeding. But it does this as well. We know that vagal nerve stimulation, and there's lots of research by others in this, leads to a systemic anti-inflammatory effect and controls inflammation throughout the body. And there's a lot of data actually that feeding lipid and protein containing feeds, even in small amounts, reduces inflammation. And this is signaled by CCK, which is a vagal nerve stimulant. These are fasted cytokine levels in animals who've had hemorrhagic shock. You can see when a higher lipid feeding is given, these cytokine levels go down. If you block CCK, that effect is lost. And so in fact, nutritional activation by even dystrophic nutrition is a great way potentially to intervene in shock. It wouldn't seem like a direct therapeutic intervention. Nutrition wouldn't be, but it appears to be. And high lipid and high protein content seem to do this. Vagal nerve lysis blocks this effect. Really seminal study here showing that if you feed these animals when they're in shock, they have much lower cytokine levels. But if you lyse the vagus nerve, they lose that benefit. And so again, feeding into nutrition, even in small amounts, reduces inflammation for your patients distally and the distal organs. And it's mediated through the vagus. And so this really shows us what a fundamental role feeding plays in our lives. And it may affect other inflammatory conditions as well. This has also been done in humans. This is an LPS model in humans. And again, protein and lipid-rich EN reduces inflammation in humans who are exposed to endotoxin. And so what about intra-feeding on insepsis on pressers? Is it possible it's not only safe, but perhaps as I'll show you, saves lives. I was asked to review this actually for critical care medicine. Tim Buckman asked me to review this right before COVID started. So it was timely. And I learned a lot. In fact, I learned that it's probably lifesaving and something we should be routinely doing in resuscitated patients. So these are some of the examples. And what this first study shows, and it's a small study, and I'm going to show you a big study. In small studies, feeding trophic nutrition versus feeding full nutrition was looked at in patients who had septic shock. And what they found is the patients had the best clinical outcomes when they received trophic feeding, less than 600 calories a day in the initial part of time they were on pressers and being fed versus full feeding, interestingly. And so in septic shock patients receiving lower amounts had lower lengths of mechanical ventilation and lower lengths of stay versus not being fed or being fed more. So this is a study I didn't know existed when I wrote this paper, but I discovered is a really compelling study. 52,000 patients from Japan in their medical record on pressers fed at day two or fed after day two. And what happened to them? 52,000 patients, eh? So again, what they found was the mortality rate was significantly better in the low dose norepinephrine group, less than 0.1 mics per kilo per minute norepinephrine equivalents. Better in the medium dose, 0.1 to 0.3 mics per kilo per minute. And there was no difference in the high dose, although this was a small group. But this was fairly surprising to me. I wouldn't have fed someone in 0.25 mics per kilo per minute of norepinephrine, but this data might include the fact that you should. And so this shows that in low and medium dose norepinephrine up to 0.3 mics per kilo, there seems to be a mortality benefit in a large health outcomes study showing these results. If you're going to do this, how can you do it safely? And this was a chart from the paper, but I think the key is the patient needs to be resuscitated. The pressers need to be falling. I think 0.1 to 0.3 is probably even safe. And again, certain pressers are more toxic to the gut than others. Norepinephrine is the safest on the gut. Vasopressin and dopamine are the worst on the gut, and they are the most likely to cause gut ischemia. These are patients you want to start slowly with, start trophically. And I do check gastric residuals in patients on pressers. I wouldn't suggest you routinely check gastric residuals, but if you're going to feed a patient on pressers, feed the stomach only, don't feed post-pylorically, and check residuals. So again, watch for your residuals and there are signs of intolerance, and this is how you can do this safely. So we looked at this idea that perhaps early intralutrition can help in a lot of different illnesses, but we didn't have data for COVID. And so our group was really curious if, A, how are COVID patients being fed? We hypothesized poorly. And B, when you do feed early within three days, does it improve outcome? We used the premier database to do this. There was a 75 hospital cohort that had 265,000 patients in it. We found about 850 that were on the ventilator, and we looked at early and within three days, which seemed like a reasonable amount of time, versus late after three days. Sadly, we found that about 40% of COVID-19 patients are not fed anything, PN or EN, for more than three days, and the average time to start any nutrition at all was 10 days. So that's tragic. That's starvation and nitrogen is at its worst. This was really a tragic finding and something we were surprised by. As you might imagine, patients who got early in had lower mechanical ventilation days, lower days in the ICU, and lower, less days in the hospital, and less hospital costs. And so there were great benefits to this, but this is really tragic. And I think this led to things that told us we need to be feeding these patients better, and that just like in other ICU illnesses, in COVID and in sepsis, feeding early is beneficial. Now, because we feed so poorly entrally, waiting 10 days in many patients, SECM recommended we start per nutrition sooner. So if you're going to do that, first off, are you increasing the risk of infection or not? And I hope all of you know that there is no increased risk of infection from PN any longer. There are four large trials and journals you've heard of, New England Journal, Lancet, JAMA, that show in thousands of ICU patients, it's just as safe to put TPN through a central line as it is saline through a central line. And so there's no reason for you not to be starting it. Why is that? Well, there's a lot of reasons. We control hyperglycemia. Most of the studies that showed infection didn't do that. We have better central line care, but we have better lipids. And lipids have a great impact on inflammation and the immune system. We'll talk about that. The new Aspen ICU guidelines even suggest there's no difference between EN and PN, and you can do either. You can start with either, and you can start early with either if you need to. This is an interesting study benefiting that's in JAMA surgery, just published a few months ago, looked at large surgical patients who randomized to an early supplemental PN versus late supplemental PN. There was a significant reduction in infections in patients who received early supplemental PN in this study. So what about lipids? Is there a best choice? And finally, we have alternative lipids to give in the U.S. I hope all of you are using one of the new olive oil or fish oil lipids. And is it important in illness? Well, clearly different lipids have different inflammatory profiles. The soy lipid we've given for 30, 40 years that I got as a kid on TPN when I was on TPN as a kid in the 85 and the 80s is not the lipid you should be giving anymore. Olive oil and fish oil are much less pro-inflammatory, and you truly are what you eat. And so again, we want to be driving an anti-inflammatory phenotype for our patients. And unfortunately, the soy lipid that I know 60% of hospitals in the U.S. are still using routinely in all of their patients is like the Big Mac and fries down the IV tubing, right? We know they intercalate those bad lipids into the cell membrane, and they drive inflammation in our patients, and they drive organ failure through the NFKappa B and other pathways. And so this is an adverse potentially outcome driving pathway, which is one of the reasons TPN was not as safe when these lipids were used in the past. Of course, we know if, and then of course it amplifies itself, if you use a fish oil-based lipid or an olive oil-based lipid, fish oil in particular, that intercalates into the membrane and can slow or reduce or modulate this pathway in a much more beneficial way. And so this is why these new lipids exist. They do more than just decrease the inflammatory response. They generate resolvents. Charlie Serhan will likely win the Nobel Prize soon. We're just in a meeting together, and this data continues to grow. Resolvents help resolve inflammation. They're really critical, and our patients can go down this long-term organ dysfunction pathway in sepsis, or they can resolve that inflammation. And the fish oil that we give them as part of their nutrition when they're TPN perhaps, or in their feeding, can help drive that. So what are the key effects of the new lipids? These are lipids you shouldn't be using anymore. These are the interlipid soy lipids. They're immunosuppressive. We weren't giving lipids for many years. Many of you probably remember that. This was the trial that drove that. It was the Batalista trial. It gave a fat versus no fat lipid, and what they found was patients getting these soy lipids had adverse clinical outcomes, longer lengths of stay, more infections, poor natural killer cell activity, and this was based on that lipid. So these have a lot of negative effects, and there's no patient really other than people with fish allergies or olive oil allergies that should be getting these. The mixed fish oil lipids are much better. These are now large meta-analyses in thousands of patients that show significant reductions in infections when these mixed lipids that contain omega-3s and other fish oils are used. They reduce ICU length of stay by multiple days. They reduce hospital length of stay by multiple days, and they reduce sepsis and sepsis outcomes in these studies, and so all of our recommendations are now suggesting we move to these lipids. We also have an olive oil lipid available in the U.S. It also has benefits on lymphocyte function and immune function. As you can see here, there's quite a protection of lymphocyte function and proliferation when olive oil lipids are used, as well as immigration and adhesion, and so again, I can't say it enough. There's data to show that these olive oil lipids also improve outcome, and so there's trials with all of these lipids now that say that, and if you come on Monday night, we're going to present new data from Duke where we switched from soy lipid to a fish oil-based lipid. We had marked improvements in outcome in our patients at Duke in a before and after study. So again, our recommendations say we should avoid these poor older lipids. This matters to outcome. If you're still using a soy lipid in your hospital TPN, how many of you still use interlipid? Raise your hands in your hospitals. How many of you don't use an alternative lipid? I can't see all, but I see a few. Stop. Your patients deserve better, and so use a new fish or olive oil-based lipid to improve outcome. One of the last things I'm going to tell you about is one of the other things this patient faced, and I see more often, sadly, than I wish I did. It was when the patients develop renal failure, as this patient did, and go on CRT. They have other complications that we don't always attribute to nutrition or even to perhaps what the CRT did to the patient. This patient got that. He developed pancytopenia with a neutropenia and low white count. We ruled out all the drug-related causes for this patient, and we thought, what could be causing this? And I've seen this a few times. There was a nutritional loss that can cause pancytopenia immune dysfunction, and it's copper. So the CRT machine is a dumb kidney. It filters all water soluble micronutrients and vitamins quite nicely, and they get very deficient very quickly within five days. We gave copper chloride, and all this gentleman's counts recovered. Everything but zinc is lost in CRT that you see on this screen. I checked these levels. We have a routine pathway at Duke where we check these levels of many of these nutrients after five days of CRT, and we replete them. These can cause serious complications. These nutrients, the bees and the copper, can cause pancytopenia. I've seen patients that look like they had a stroke. They got two or three MRIs. Their B6 level was zero from CRT. Give them B6. Costs about 50 cents. They wake right up. I see this a lot. Prolonged weakness. If you let copper or carnitine sit low for long periods of time, permanent weakness, especially from copper, ensues. So how much of our ICU-acquired weakness is actually missed copper deficiency? I don't know, but we're studying that. And then lactic acidosis from thiamine deficiency is lost too. One of our former ICU fellows at Duke looked at all of our data at Duke on these levels, and this was just published in Clinical Nutrition, and we found that 90% of patients are deficient. These patients are very commonly deficient in copper and other nutrients, and that these nutrient deficiencies are associated in some cases with mortality risks. And so this is a review article if you want to learn more about how to check these of things you can check. So the last thing I'm going to say is as patients recover, are they going to eat on their own? They're not. They're not likely to eat, so we routinely use a high-protein oral supplement with one fancy nutrient I'll tell you about called HMB. It's an anabolic agent. I've been taking it myself since 1996. It was developed for athletes. It occurs in catfish and avocados. You'd have to eat hundreds of them to get enough, but it stimulates muscle growth through mTOR, and it reduces inflammation through NF-kB. It's quite potent at doing this. There's a lot of trials looking at this, and it breaks this vicious cycle that our patients need to get through to recover. So it affects NF-kB signaling and mTOR signaling to build muscle. There's many, many studies of this. It was originally studied in cancer and HIV patients. This is a study by one of the premier muscle physiologists in the world, Mick Deutz. He's the head and chief of clinical nutrition. Patients who are late in bed will lose significant amounts of muscle, especially elderly. If they're given HMB, this is a very highly controlled study, they completely lose that loss of muscle. They block that loss of muscle mass. This is a very potent nutrient that we can give. They 92% decline. This has been looked at in reducing SERS and improving nitrogen balance in trauma patients. You can see the HMB group there on the right has the best SERS incidence. It's been used in COPD to help get patients off the ventilator, and it reduces CRP in CRPD patients, helps make them stronger. But this is the only oral nutrition supplement that exists that has a large multi-center randomized trial showing reduced mortality at three months post-discharge, and I think that's the most potent data I can show you. The number you need to treat was 20 for about a $1 and $2 drink, and so I encourage all my patients to do this. It also increases strength. So this is really essential in our patients. So in summary, if we're going to create survivors and not victims of our patients, we need to show one size does not fit all, and we need to be better at feeding our patients. Ten days to feed a COVID patient is not acceptable. We need to be giving the right doses and the right patients at the right time. We need to be measuring. These are the strategies we use. We ramp up both our calories and our protein early on. You should ramp your protein up as well. There's data for that. And then later in care, of course, the calories need to increase, and we need to be using good lipids for our patients. So this is really critical. So we need to be taking responsibility, not just for what happens to our patients in the ICU, but after, and if we do so, we can take patients who look like this, have them looking like this, and then have them go home and hopefully look like this. And if you don't believe me, listen to my favorite mentor, Yoda, as he tells us what we need to do. Make sure there's volume, please, on the sound. And with that, that's what we're left to do. I encourage you guys to follow on social media, and feel free to email me for these slides or with any questions. Thank you.

immunonutrition

ICU patients

macronutrients

enteral feeding

gut

COVID-19 patients