SCCM Resource Library-Nutrition Therapy and the 3Ms: Microbiome, Mitochondria, and Muscle

Video Transcription

Hello, and welcome to the 50th Clinical Congress for Academic Care Medicine.  It's kind of an auspicious way to spend our 50th anniversary in a virtual Congress, and hopefully this is our last one, and hopefully this experiment in virtual  conferences that we've all done this year, we've done multiple, have shown us that, you know what, we're better together. We're better getting to meet and know colleagues,  and we'll get through this together. So hopefully for 51, we'll all be together, and I can't wait to see everybody again, so it's going to be a great time.  So what are we going to talk about today? This session actually is something I'm really excited  about. We've been trying for the last few Congresses to get this on the agenda. We were  finally able to get it on. It just had to make sure it fit correctly, but nutrition. Nutrition  is super important to me as a surgeon and an intensivist. I have that saying in my ICU. I may be the only one that says it, but I'm trying to spread the word, so to speak,  and it's that you walk and eat your way out of my ICU. If you don't have the nutrition and the  protein to heal, then all our outcomes are going to be worse, and we really don't use the metabolic  cards. We don't use the nitrogen 24-hour collections and do the nitrogen calculations  like they used to, we say, in the old days, but really in the end, we cause a lot of malnutrition  in our patients with their NPOs and holding two feeds and their injuries and their illnesses that lead to that, and so we really got to look for ways to optimize nutrition,  and what better way than to arm ourself with more knowledge. So today is going to be a great talk.  I'm really, really excited about it. What are we going to talk about? We're going to talk about  supplements and specialty feeding and the gut microbiome. There's some strong feelings on supplements and those specialty tube feeds, and the gut microbiome, especially some great  data is coming out about that. As a surgeon, I'm really interested in that gut microbiome data,  looking at these bowel anastomosis and things like that, and there's no shortage of argument  and debate on those specialty formulas, so that should be interesting, and then we're going to  look at the impact of nutritional therapy and mitochondrial function. This is a really growing area. It's looking at the food sources and energy sources for the mitochondria,  so that will be interesting, and then,  sorry, I apologize for my laugh there, but the last topic is something that is controversial. We do debate it. Actually, it's not that controversial. We know what's better. It's  getting to it. It's continuous versus bolus feeding, so we know what's the right thing to do,  but how many times do we really achieve that goal of that bolus feeding as early as we should have?  We do miss that mark sometimes, so join me in welcoming these three great speakers, and it should be a great session. All right. Thank you so much, and hope to see you next year  in person. Well, good afternoon. I'm Bob Martindale. I'm from Portland, Oregon, and today I've been asked to speak about modulating the microbiome in critical care.  I think this is a very interesting topic because we can go either way. We can make things better  or make things worse if we try to modulate maybe too much, maybe too little, so we'll talk about  where some of the action is in this area. We know that this fits well in the critical care nutrition realm, and if we look at critical care nutrition, we've really evolved from  sort of the 1960s to 80s. We talked about getting enough nutrition in. It was TPN-based,  and then from 82 to 2014 or somewhere around 14, we've started understanding the importance of the  gut, some early work showing the benefits, and then we started talking about the microbiome,  but we knew very little in the early 2000s until recently. Recently, this area has literally  exploded with how can we alter it, what can we do, what about fermentation fibers, what about  minimizing different foods we may give to our ICU patients, and then really questioning the theory  of should our current nutritional regimens really work, and do they work? You know, the microbiome  concept really has been talked about since, you know, Metchnikoff in 1906 brought the concept  forward, but really the concept of the entire microbiome was really brought to us by Joshua  Lederberg. He was a Nobel Prize winner for his work in genes, swapping genetic information of  viruses, swapping bacteria, swapping genetic information, and really said the microbiome  should include not only our own cells, but the bacteria live within us and within us, and includes  the bacteria, the fungi, etc. And at birth, we're really absent of about 99% of our genome in that  case because these genes play a role. Well, what happens today in the ICU? Routine ICU care today  causes many detrimental changes, not purposely, but certainly as an artifact of what we're doing.  Broad-spectrum antibiotics, within hours we see these changes. Oral antiseptics, PPIs, you know,  H2 receptor antagonists, vasopressors, opioids, you know, decreasing luminal nutrient delivery  with parenteral nutrition, decrease in bowel salt production, all these things come into play,  and then invasive devices. I won't bore you with too much animal data here, except to show you that  within 24 hours, not only do the bacteria diversity changes, but also the bacteria phenotypically changes. The actual pseudomonas becomes an aggressive pseudomonas, and this  paper here shows very nicely, this paper published in 2017, where you can see very easily here,  animals were inoculated with pseudomonas in this case, and then they gave them 24 hours, okay, after sham operotomy versus the hepatectomy. And the bottom line was, that stress of a  hepatectomy changed the phenotypic expression of that same bacteria. As you can see, the sham operated left the same smooth shape to the morphotype, and the other one changed, it's  actually changed the shape. But look at, here's the key, the animals that, with the changed phenotype  from the stress of a hepatectomy had 100% fatality, and those in the sham operation did  not change on 100% survival. So the same bacteria's lethality is what changed, not the bacterial  species, but the lethality of the same bacteria. We see the same thing here with the expression  in pseudomonas, when they're exposed to opioids, what happens? We know that we see these viral,  these tissue factors, which is in the tissue of the surgical patient, you can see causes exposure of this host factor, which causes clumping of the bacteria, and the bacteria  basically become pathogenic bacteria with just exposure to opioids. We know from this nice work  by Wischmeier's group and Rob Knight's group that comparing an ICU patient's microbiome to the  American Gut Project, which is basically a bunch of healthy individuals who've sent in their  bugs and they've measured them, and showed that we see, what do we see? Rapidly in changing,  a decrease in diversity, overgrowth of pathogenic species, and the ICU versus healthy, there's a  strong separation in their bacteria. But really the next slide sort of summarizes all of this.  If we look at the normal commensal bacteria drop off as a patient becomes critically ill, these opportunistic infections and the phenotypic change of the bacteria, like pseudomonas,  klebsiella, et cetera, you can see increase, and we see these phyla changes. Firmicutes goes down,  bacteroides goes down, and proteobacteria significantly increases. Why we see a drop in the protective mucosal layer in these ICU patients, and so what do we see? Mucus layer,  short-chain fatty acid production drops, and epithelial integrity is altered, permeability  increased, there's a pro-inflammatory response, absorption of nutrients is altered, so it's a  major sort of shift change we see in all of the microbiome. Now, what do the current ICU formulas  do? Well, we wrote this paper a couple of, about two years ago actually, because when we looked at  the literature, the current literature is sort of ignores this idea of microbiome, because why? We  said, why with so much importance now, they're forgetting about it? Well, the current dogma, basically, worries about macronutrients, the lipids, the carbohydrates, the proteins,  and the micronutrients, vitamins and trace minerals. They were starting to consider these metabolites of bacteria, but we didn't really have a focused attention on that.  So, the amount of interaction and crosstalk between the microbiome and these metabolic products of bacteria is where we need to focus, and that has not been the case. Only now we're  beginning to see those differences. We know the mechanisms of the microbiome and how we can  manipulate those are incredibly important. We know there's competitive inhibition by the pathogens  when we see the right microbiome. We enhance heat shock protein, tight junction protein synthetic  machinery is upregulated by some bacteria. Stimulating gut immunity, it's a myriad of effects there. Butyrate production we'll spend some more time on. So, there's really numerous  mechanisms, which you know about now, or are beginning to understand. First, let's talk about some of the potential mechanisms, including prebiotics. Remember that prebiotics now  is the fermentable substrate, which is not absorbed in the proximal gut, gets to the colon,  where it becomes fermented to produce multiple metabolites, which are beneficial to the host.  Butyrate being the big key we'll talk about as a model for this. But we know, for example, human milk has got milk sugars in it, which selectively enhance a beneficial bacteria for  the baby's GI tract. These other fermented products maintain optimal pH to prevent dysbiosis.  They alter glycosylation of the epithelial cells that limits the infections and pathogen binding.  So, just the prebiotics, the right diet, not necessarily a macro, not necessarily giving  a probiotic, but giving a fermentable substrate can make a difference. We want to use butyrate  as that sort of example here. We know that butyrate about, you know, we know a lot about  short-chain fatty acid fermentation now and starting to understand it's important in critical  care. We know that butyrate is one of the three major short-chain fatty acids produced, acetate,  butyrate, and propionate. Short-chain fatty acids make up about 70% of the primary energy for the  colonocyte, proximal dysacolline. But here's the key, they're targets for G-protein receptors. As  you can see here, G-protein receptor 43 has the highest functioning at stimulating the immune  system. We see G-protein 41 widely distributed, also activating inflammatory changes as is G-protein  109. Also, they enhance the hydrogen-sodium transport system, which keeps the optimal pH at 5.4. You know, we go on down, we look at butyrate decreasing inflammation through two  major mechanisms, three probably, increasing the M2 macrophage, which is a resolution macrophage.  We know butyrate stimulates that. We know we reduce the pro-inflammatory cytokines TNF, IL-6, IL-12. We know that we activate IL-22, which stimulates antimicrobial peptides from the  mucosa. So, there's all sorts of benefits to this, and we see numerous mechanisms now being described.  What about models, animal models? Well, certainly in sepsis, giving butyrate in sepsis in animal  models, starting back in 2007, we saw that butyrate given IV actually improves survival. And we saw multiple mechanisms. We also shot a 2010 article by Zhang that, you know, the  sequel ligation function model giving IV butyrate attenuated ARDS in that model. But the newer data, you can see in this 2019-2020 data, again, we see a myriad of mechanisms.  You know, the COP, the sequel ligation function model has been a nice model to see what happens  in sepsis and renal function. You can see very nice data, which continues to grow. We also know now that short-chain fatty acids actually enhance muscle function and the  mitochondrial biogenesis in the myocyte. So, systemic effects of these short-chain fatty acids actually altering the mitochondria and allowing biogenesis of these mitochondria in  the myocyte. Again, very interesting data, which can really show us maybe we can see significant benefit in our ICU population. What about in the surgical ICU population? Well,  how about giving it prior to surgery? A couple of papers here, this nice meta-analysis, the bottom part of this. You can see 14 trials, 1,500 patients, 28% decrease in surgical site  infections, number needed to treat 18. Very nice paper. Again, what about here in sepsis? Same thing here, prevents it, probiotics. This is now, what about probiotics for staph  aureus infections? Beneficial. Probiotics and symbiotics in post-op infections? Beneficial. So, the literature is now ripe with these, but here's probably one of the best.  This perioperative delivery of probiotic or symbiotics, remember, symbiotics is a combination  pre and probiotic. You can see very nicely, 34 randomized clinical trials now in the annals of  surgery, 2,700 patients, probiotics and symbiotics decreased infection length of stay with no adverse  effects. Very simple, very inexpensive, and potentially altering significance. This paper,  to my mind, is probably the most significant benefit for ICU populations. This is a randomized, double-blind, placebo-controlled trial giving L. plantarum and fructooligosaccharide,  a pre and a probiotic, to 4,000 normal-weight infants, healthy babies at birth, 35-week  gestation, because this was shown in rural India had a significant high rate of sepsis in these  infant children that are born healthy. This is WHO criteria for sepsis. This is a well-controlled  study, obviously in the journal Nature, very popular, 42% reduction in sepsis one week of  therapy costs a dollar, a shocking benefit, 42% reduction in sepsis in these babies. Remember,  this is 4,500 little infants, major difference in sepsis. So, we got lots of data here. It continues to go on. You can see associated diarrhea, C. diff, VAP, abdominal transplant,  sepsis, trauma, multiple papers now. So, the time has come that we should consider the microbiome  as prevention and as treatment in the ICU. In my mind, this is what we now need to think about. The problem is it's still pretty complex. Now, this shows a nice paper here by John  Alverde's group where they fed mice an obesogenic diet versus rat chow. They gave antibiotics and  then subjected them to a sterile surgical procedure. Those that got the obesogenic Western  diet developed lethal septicemia with multi-drug resistant pathobionts compared to the rat chow,  mouse chow. So, could it be that we're setting ourselves up for more trouble in the ICU  because we're not eating the right diet, not preparing, not considering the functions of the microbiome? Remember, the microbiome metabolizes drugs, produces vitamins and minerals,  short-chain fatty acids, maintaining a healthy mucosa, anti-inflammatory, stimulates hormones,  modulates immune function, maintains mucosal barrier. If it's not maintained, we see a rapid  drop in diversity and we see the phenotypic expression of the microbiome becomes a pathobiome.  I think the summary and takeaways today, we should attempt to minimize or control the least of the  cues given off by the host, by the human to the microbiota. You know, we know that opioids cause  these cues. We know that we need to minimize and prevent antibiotic use, overuse. Obviously,  we need it in most cases, but overuse is a key. We need to use foods which support the microbiome  and produce short-chain fatty acids. But currently, unfortunately, we have inadequate data to completely understand the impact of metabolic manipulation. So, we need some work.  Where are we going in the future? Certainly, animal models with epidermal growth factor, membrane permeability inhibitors, we've got those, vagal nerve agonists, mucosal surrogates,  mucus surrogates, we've seen those, the early work now in animal models. Other novel approaches  we might see is synbiotics we just talked about, maintaining colonic luminal phosphate levels. This has been brought to us by John Alverde and his wonderful work over the years,  showing us that if we can let the bacteria in your colon think they've got adequate phosphate,  which would be obviously for their energy production, if they feel they've got adequate phosphate, they don't become a pathogen. They stay in their normal microbiome. The tributrin,  where we give three butyrate molecules off a glycerol backbone, again, nice way, early cleavage,  IV butyrate, fecal microbiome transplant, possibly even changing our concept of ICU formulas,  and maybe just grinding up good healthy food-based formula, blenderized foods, maybe what we're,  we currently have a protocol, I know Mayo Clinic's got a protocol ongoing, so the next generation  technology will allow us to understand this better. It'll bring together the metabolomics  of the bacteria, the bioinformatics will be able, large enough computers to figure out what it all  means, because we've got a thousand species, let alone the viral products that are produced,  and they become a very issue. I think we need to change our thoughts. I think one of the most  dangerous phrases in the English language is, we've always done it this way, we've got to consider  the microbiome and change the way we're doing things. Thank you very much. Hello and thanks  for joining us in this symposium today. As it turns out, as an organelle, mitochondria are  exquisitely sensitive to oxidative stress and critical illness, so it should be no surprise  that its deterioration and functional structure have tremendous implications for the ICU patient.  In 15 minutes, I want to share with you a few facts about the normal role of mitochondria,  and then we'll learn how mitochondrial dysfunction and critical illness leads to its own hibernation  and multiple organ failure. Then we can appreciate how this dysfunction impacts nutritional therapy  through the different phases of critical illness. Now, it's hard to talk about this subject without  mentioning Mervyn Singer. This is a phenomenal researcher and clinician in London, close a colleague of Zutton Puthacherry, who's with us today on this symposium,  and he describes himself as a mitochondriac, and 90% of the information I'm going to share  comes from his lab. When he talks about causes of organ failure in the ICU, he says, far and away,  shock is the most common cause, but there are other factors that contribute, such as breakdown  of gut barrier to function and the formation of toxic lymph, immune dysregulation in gut sepsis,  the conversion of a microbiome to a virulent pathobiome, and then added to that list is  mitochondrial dysfunction. Now, we all think of the mitochondria as the powerhouse of the cell or  the battery of the cell. It's responsible for producing ATP. One of my mentors, Mitch Kaminsky,  used to say, when the body does work, like maintain an electron potential gradient across the membrane or make new proteins, that work generates a bill, and the currency with which  you pay the bill is ATP, and that's what the mitochondria are responsible for.  Now, normally, all three macronutrients can be broken down into a form that eventually  enters the mitochondria and takes advantage of the Krebs cycle and the electron transport chain,  which is this luxurious production of ATP, but with increasing oxidative stress and critical  illness, the mitochondria are malfunctioning, and that entry into the mitochondria is limited,  so the patient becomes overly dependent on carbohydrate metabolism, and the patient cycles out here in glycolysis, which generates far less ATP and generates lactic acidosis.  With the inflammation of hypoxia of critical illness, you induce inducible nitric oxide synthetase, which generates excess superoxide radicals. That, in turn, stimulates superoxide  dismutase enzymes, which produce hydroxyl radicals, and these superoxide radicals  overwhelm the defense system of glutathione antioxidant systems, and that contributes further to oxidative stress. The hypoxia, the high levels of reactive oxygen, nitrogen species,  and then gaseous molecules produced mainly in the gut, carbon monoxide and hydrogen sulfide,  further inhibit the electron transport chain. The patient instead cycles out here in the cytosol.  Hyperglycemia and insulin resistance is tied closely to this process, and with hyperglycemia,  you get the formation of these dicarbonyl compounds, and the dicarbonyl compounds further inhibit the electron transport chain.  Mitochondria are responsible for triggering cell death pathways. So with increased oxidative stress,  production of ATP falls. And when it falls below a certain level, that triggers these cell death pathways. Now, if the process is early and less oxidative stress, then autophagy,  or programmed cell death type 1, can clean up the mess and the cells can survive. But as the oxidative stress gets worse, it'll first go to apoptosis, programmed cell death type 2,  or if it's too great, the cell will just implode with necrosis and non-programmed cell death. And  the mitochondria are responsible for directing this. In response to oxidative stress, mitochondrial  function is compromised. There's loss of mitochondrial volume, the number of mitochondria diminished, and there's morphologic change. So here on the left, we see a normal muscle,  the muscle striations, and these little marbles in between the columns of muscle are normal  mitochondria. In critical illness, their numbers diminished, and look at, they're misshapen,  they're lumpy and clumpy. And in the non-surviving ICU patient, their numbers are even fewer, and the morphologic changes are even more grotesque.  When you get structural damage, then these mitochondria will begin to light leak mitochondrial  DNA. And this mitochondrial DNA enters the circulation and acts as damps, or danger-associated  molecular patterns. These will bind to dendritic cells and activate pro-inflammatory lymphocytes  and inflammatory cytokines. The higher the level of the damps, the lower the survival. And as these mitochondria spill their contents, the process is linked to organ failure and  reduced survival. There are several protective mechanisms that help minimize this effect.  With these damaged, leaking mitochondria, one process is fusion, where it will take two defective mitochondria, fuse them together, and then fission. It'll split them and somehow  concentrate the defects in one mitochondria and generating a new, undamaged mitochondria. Then you bring in mitophagy, which is the autophagy version directed just at mitochondria,  where you surround the mitochondria, bring in lysosome enzymes, and get rid of it.  Another protective mechanism is the process of uncoupling. Uncoupling means that several steps in the Krebs cycle and the electron transport chain are inhibited or diminished.  And that causes or generates less efficient metabolism and reduces the oxidative phosphorylation.  The proton gradient, which is a measure of the energy stored in the mitochondria, mitochondria is lost as heat, and that's called pyrexia. Now it's organ dependent. In the heart,  there's much less of this heat loss, only 15% of the energy, but it's higher in skeletal muscle  and liver. But in fat, it's really important. In polar bears and other mammals in a cold environment, there's excessive brown fat because the uncoupling there and the pyrexia that's  generated causes non-shivering thermogenesis, and that's how the mammal stays warm. But back to the ICU, this uncoupling process is protective. So the amount of respiration that you  would normally utilize for ATP production is reduced by this uncoupling by as much as 50 to almost 90%. And with reduced mitochondrial membrane potential, there is less generation  of reactive oxygen species. So that helps diminish their contribution to the oxidative stress.  But one of the most important protective mechanisms is the concept of hibernation and subsequent organ failure. With all the insults of critical illness,  excessive inflammatory mediators, oxidant stress, uncoupling, the genes that would transcribe  mitochondrial proteins, those are all diminished and they compromise mitochondrial function.  So what happens is a cell-adaptive change, they shut down the mitochondria, that's called  hibernation, at the expense of organ maladaptive processes, which is the normal organ failure.  Now, the example of this organ failure is seen in the ICU. We just didn't realize it was part  of this protective mechanism. The kidney, for example, would expend 98% of its energy filtering  every drop of plasma that comes through the kidneys. If it reduces, say, to 60% of the plasma  being filtered, then we see that clinically as AKI, but it preserves energy and saves structure.  In the heart, myocytes will hibernate after an acute MI. You may need more drugs to maintain  cardiac output, but it reduces myocyte cell death. In the liver, you simply decrease protein  synthesis or secretion of bilirubin. The patient may get jaundice, but it preserves liver. And in  the lungs, they describe hypoxic conformance, in which the ATPase-dependent pumps are reduced.  You get a little bit of pulmonary edema, but again, it saves on structure of the lungs.  In lab animals, this is even more dramatic. They'll take rats and give it sepsis, 40% mortality, and compare it to controls. When they look, when they biopsy the failing organs,  compared to controls, look at that. They're beautiful. There's very little inflammation, very little structural damage. And the organ failure in the critically ill patients and in  these rats recovers quickly when you treat the sepsis and completely in a very short period of  time. Now, it's interesting that we have examples of this in nature, this adaptive hypometabolic  states. Mammals like bears will hibernate. Reptiles in a desert environment will cause, will do estivation at the heat height of the hot season, which they'll crawl under a rock.  In both situations, they decrease motility and activity and preserve what little energy they have  for cellular processes. These are seasonal changes, but there's also a process called TURPR, which is described in lower primates, in which genes are actually transcribed,  and they will slow the heart rate. They'll slow the metabolic rate. The patient will become, the primate will become hypothermic. But at the same time, it boosts immunity,  boosts resistant ischemia reperfusion injury. These situations are similar to our ICU patient. If there's reduced energy production, you have got to decrease demand  in order to reestablish balance and provide survival.  Now, when you look at critical illness, the insult of the inflammatory mediators and the hypoxia are what caused this mitochondrial inhibition. And then things we do in the ICU,  like sedatives, propofol is notorious for inhibiting mitochondria. In fact,  propofol infusion syndrome is complete inhibition of mitochondria. Antibiotics are notorious for  binding to the cell wall of bacteria. Well, we think mitochondria at some point started out as  bacteria and entered the cell. So sure enough, antibiotics will bind to the walls of the mitochondria. The mitochondria shut down or hibernate, that leads to the organ failure.  At some point, there's a transition and the patient begins to recover and there's biogenesis of new mitochondria, repair of damaged mitochondria and the recovery of function  and the organ failure resolves. Unfortunately though, we don't have any clinical signs or viable biomarkers that can tell us where we are in this transition point.  Now, the implications for nutritional therapy are tremendous. There's evidence of futile substrate cycling or impaired utilization of all three macronutrients in critical illness.  Nothing works. Carbohydrate, we have insulin resistance. Protein, we have anabolic resistance.  The beta oxidation of fat can only take place in the mitochondria. So that is diminished to  an extent that the patient again becomes almost entirely dependent on carbohydrate metabolism.  And Paul Wischmeyer has shown that the recovery of fat metabolism may take months after the patient  gets out of the ICU. Arthur Van Zanten, in a beautiful review article, pointed out that a  number of micronutrients are cofactors in the antioxidant glutathione antioxidant defense system.  So deficiencies there can compromise the patient's ability to deal with oxidative stress.  When you look at the function electron transport chain, it's even more complicated. And toxicities or deficiencies of these micronutrients, malfunction of enzymes like  carnitine, acetyltransferase, all these things can compromise the function of the electron transport chain. What do you do about it? Depends on which society you listen to.  Metaburger has shown that you can enter the ICU with normal levels of antioxidants and then through the duration of oxidant stress these micronutrients are depleted.  Aspen, SCCM, we said we'd give an empiric cocktail. Aspen agreed, but said we'd measure vitamin D specifically. Canadians used to say that, but then reversed their position.  So there's no right answer. There is specific therapy for mitochondrial failure and different strategies, but whether they're appropriate for the ICU is not clear. You can directly  stimulate mitochondrial biogenesis through agents like resveratrol or PPAR gamma agonist ferrosaglitazone or low-dose carbon monoxide. You can promote antioxidant defense by giving  melatonin or these micronutrients that we mentioned. You can directly activate autophagy through agent like rapamycin or anthracycline, but these have unacceptable side effects.  Or you can induce the unfolded protein response, which goes and stimulates autophagy. It removes  that buildup of unfolded protein. And there's a drug, 4-phenylbutyric acid, that's used in urea cycle abnormalities. That drug could do this, but whether or not it's appropriate  for ICU is just not clear. So in conclusion, these treatment strategies are oftentimes  sensitive through the phases of critical illness. Early on, we want to do reduced macronutrient  provision. In other words, a slow ramp up of our macronutrients and calories. We want to avoid  perinatal protein because that's the strongest inhibitor of autophagy. We want glycemic control because that decreases the flux through that glycolysis, decreases the formation of  dicarbonyl compounds that are going to inhibit electron transport further. There are certain  clinical conditions where we actively decrease the metabolic rate, hypothermia for acute MI,  low-dose carbon monoxide, and hydrogen sulfide in certain neurologic conditions. We certainly  want to promote judicious use of antibiotics and avoid excessive use of sedatives like propofol.  At some point, we may figure out how to maximally provide protection for the mitochondria and  stimulate progenesis, but I think we're early in these concepts and their application to critical  care is still yet to be seen. Thank you very much. Hello, everybody. My name is Zuden Pithacher. I'm  a clinical senior lecturer in intensive care medicine at Queen Mary University of London.  I'm going to talk about continuous or intermittent feeding and how this choice could impact on  skeletal muscle of our patients. These are my disclosures. I work with all these companies in trying to develop interventions to prevent acute skeletal muscle wasting in critically  ill patients. So muscle wasting occurs rapidly in the critically ill patient. On the x-axis,  you can see days from distance from ICU admission, and the y-axis here is change in muscle mass.  And as you can see, patients in single organ failure lose no appreciable muscle mass,  but with increasing organ failure, you see more muscle wasting. So if you're in two to three organ  failure, you will lose about 20% of muscle mass in the first 10 days, and with increasing organ  like four to six organ failure, you lose 26 to 30% of your muscle mass in the first 10 days.  Why does this occur? This is because of an imbalance in muscle protein homeostasis. So all patients, all humans, all vertebrates, their musculature muscle is balanced between making  muscle pre-synthesis and breaking down muscle breakdown. So this balance is affected by a lot  of things that occur in critical illness, yet actually skeletal muscle in some ways is quite  simple, and muscle protein synthesis is often the facilitative thing that happens. If you have an  anti-anabolic stimulus, then muscle protein synthesis decreases, muscle protein breakdown decreases, but not as much, giving you a net catabolic balance. So immobilization is an  anti-anabolic stimulus, leading to decrease in muscle protein synthesis and the net catabolic  balance, as is inflammation. Okay, so remember, not breakdown that's not increased, it's synthesis  that's decreased. And surprisingly, critically ill human beings are just like normal human beings,  where muscle protein synthesis is depressed on the first day of critical illness, which you see here,  despite the provision of adequate nutrition. And there's this variable recovery over the first  seven days, and Lena Gammon-Grippenberg went on to show that this muscle protein synthetic problem  continues to exist all the way up to about beta 30, so it affects the vast majority of our critically  ill patients. Now interestingly, one of the drivers of a decreased muscle protein synthesis is  continuous feeding. So if you continuously feed somebody, then you get the muscle full effect,  whereby the amino acids can no longer be taken up by the skeletal muscle. And so then muscle  protein synthesis starts to decrease. And this is what's shown by Julian Burhey in parenteral  nutrition and Phil Atherton in enteral nutrition. So you've got this window about one and a half to  two hours of continuous feeding, and then after that, you lose ability to make muscle protein.  So we, this is the basis of our trial, of the trial we did, the IV CTAR intermittent versus continuous feeding and muscle wasting. This is a phase two clinical trial of intubated,  ventilated patients, multi-organ failure, who are likely to be in ICU for up to seven days and to  survive. We randomized them to six boluses in 24 hours via an NG tube versus continuous feeding,  and the outcome measure was change in rectus femoris cross-sectional area at 10 days.  Now, what we managed to assess for eligibility, over 3,000 patients, randomized 127 patients, giving us sufficient power for our primary outcome and an intention to treat analysis  with over 30 odd patients in each arm. Fortunately, there was no difference in change in muscle mass in patients randomized to intermittent feeding or those in continuous  feeding. So muscle wasting did not change. Intermittent feeding did not affect skeletal  muscle wasting as measured by muscle ultrasound. However, what we saw was this. Interestingly, what we found is that if you were fed intermittently, you were far more likely to  hit your protein target. So if you hit this, if you look after 60% of your protein target,  which is a real world sort of target, then you are 1.89 times more likely to hit that. That's  your odds ratio. And if you work for 80%, which is your, which is really what most of our guidelines  find, then you will have an odds ratio of 1.5. The same is true for energy, where we saw the  same pattern. You are far more likely to hit your energy targets if you use an intermittent  feeding regime rather than a continuous feeding regime. While we saw peaks and troughs in our  amino acid profiles within the feeding patterns, the overall concentrations within plasma were no  different. We looked at branch chain amino acids, non-branch chain amino acids, and specifically  at leucine. Okay. So we did not change concentration of amino acids over a period of time  using an intermittent feeding program, but we did get a cyclical change in amino acids, which potentially may or may not stimulate muscle protein synthesis.  Intermittent feeding certainly did lead to more variability in glucose control, and there were  more hyperglycemias in the intermittent arm than there were in the continuous arm. But interestingly,  as feeding was extended over time, by day seven, patients who were fed continuously needed more insulin than those who were fed intermittently. And this is another well-known  phenomenon with continuous feeding, where you develop insulin resistance and therefore need insulin, whilst intermittent feeding obviously does not promote insulin resistance.  So, our conclusion of our phase two trial was that intermittent enteral feeding did not preserve  muscle mass as a sole intervention. It's safe and it's feasible, and a greater achievement of nutritional targets than a continuous feeding regimen. Now, of course, you don't  publish a trial without everyone saying, oh, that's not the right thing to do. So, there  were some questions that were asked, and I think there were questions we would ask ourselves about  this. And this is, I guess, our first trial in trying to prevent acute muscle wasting.  And so, these are the questions that we ask, and I think the reviewers ask, and the commenters and  the letters ask, is muscle also the right outcome measure? Well, it may be the right outcome measure,  but our original effect size of 0.5 was pretty unrealistic. Looking back in retrospect,  if we knew then what we know now, why they picked a smaller effect size, and it may be that we picked  a smaller effect size, then actually muscle ulcer may not be sensitive enough, and we don't know  that. We only recruited patients in multi-organ failure who were intubated and ventilated. And, of course, this was over the period of time that high-flow nasal oxygen came in,  and it may be, I think, in future trials, I think I'd probably stick to multi-organ failure,  but I wouldn't require them to be intubated and ventilated. I'd require them to be nasogastric fed.  And like in all nutritional trials, actually our median delivery of intervention was only four  days, and this is extremely common in nutritional trials, in vitamin C trials, and all these  supplementation trials. It's difficult to get a long period of intervention, and so we then run  into problems with our signal-to-noise ratios. And this is some, it's like this conceptual thing that  we put together when we look at equations, or physiological equations, the Sackett's equation,  and when it comes to critical illness, I think we need to think a bit more when it comes to nutrition trials and matching intervention to outcome, so effect size, and then trying to  understand the noise that affects this. So intermittent feeding, the dose that we do, the route and timing, all these things come in to affect the confidence in our ability to  interpret the result. So I think this is a first trial of intermittent feeding. I don't think it'll  be the last trial. I think our colleagues in Belgium are probably quite interested in doing  one. So watch this space. One of the interesting things that we're also seeing, if you go back and  we're doing secondary analyses, is looking at other markers of catabolism and muscle wasting.  So the urea to creatinine ratio is a very old marker of catabolism, but more recently some  colleagues of mine, Ryan Haynes and John Prowell, used the urea to creatinine ratio and demonstrated this  to be a good marker of persistent critical illness, a biochemical signature of persistent  critical illness and catabolism. If you remember, persistent critical illness is often undermined  by muscle wasting. Others have gone on to show the same thing, that the urea to creatinine ratio  defines persistent critical illness in other groups of patients, such as sepsis, and what we're  probably seeing is this, that the urea reflects ammonia, intramuscular ammonia, which is obviously  a waste product of protein and toxic. So ammonia depletes TCA cycle intermediaries you have. So glutamine comes in on the side and gives you alpha-ketoglutarate and keeps your  TCA cycle going. This is called catapheresis, sorry, anapheresis, sorry. And if you have  ammonia, you get the reverse and you get catapheresis, where alpha-ketoglutarate is taken out  to cause, to form glutamine, glutamate, and therefore you deplete the TCA cycle of intermediaries and you're unable to produce ATP. Ammonia is specifically toxic to many components  of the anabolic signaling pathways and ammonia is toxic to muscle function, which we know, again,  is affecting the critical patient. So this is why we measure urea and the urea to creatinine ratio, perhaps  being a surrogate measure of ammonia, because you can't measure ammonia in muscle easily and plasma  ammonia is not a reflector of tissue ammonia. And so in a preliminary assessment and some data from  Ryan Haynes, who published the original study, and Luke Flower, those are doing some work in urea to  creatinine ratio, they looked at the urea to creatinine ratios in the intermittent versus  continuous feeding trial and this is what they saw. So if you had intermittent feeding, we saw this flat, flat-ish line of the urea to creatinine ratio and the urea, and if you had  continuous feeding, you saw this, where there's a rapid rise in urea to creatinine ratio, so your  market of catabolism as a result of continuous feeding, and you end up having more catabolism  in the continuous arm. This is despite the delivery of more protein in the intermittent arm,  allowing us to conclude, or hypothesize more specifically, I would say, that the extra protein delivered in an intermittent feeding regimen was not diverted to urogenesis, but in  fact, potentially taken up by tissues. Now there was a whole series of other things that need to  happen with that, I mean, with those amino acids and muscle to be generated and recover, but it's  perhaps the first step. Ryan and Luke went on to use a agnostic clustering tool and looked at  different trajectories and found the same thing. If you had a flat trajectory, you were far more  likely to have intermittent feeding with renal replacement or without renal replacement therapy,  and actually all the continuous feeding patients all had, a vast majority, 70% of them had this  rapid rise in trajectory, giving us some confidence that with two different clustering programs,  that we see the same patterns. So to conclude, intermittent enteral feeding did not preserve  muscle mass as a seldom intervention. It's safe, it's feasible, and it gives you a greater  achievement of nutritional targets than a continuous feeding regime. Intermittent feeding results in a  decreased rate of urogenesis and creatinine loss, suggesting greater amino acid uptake into tissues.  Thank you very much.  Thank you.

Video Summary

In this video, three speakers discuss different topics related to nutrition and its impact on patients in the intensive care unit (ICU). The first speaker emphasizes the importance of optimizing nutrition for patients in the ICU, specifically focusing on the role of nutrition in healing and recovery. They discuss the impact of malnutrition on patient outcomes and highlight the need for more knowledge in order to optimize nutrition in this setting. The second speaker focuses on the role of the gut microbiome in critical care nutrition. They explain how the microbiome can be affected by antibiotics, antiseptics, and other factors in the ICU, leading to dysbiosis and potential complications. They also discuss the potential benefits of prebiotics and butyrate supplementation in supporting gut health and overall patient outcomes. The third speaker explores the impact of mitochondrial dysfunction on patients in the ICU. They explain how oxidative stress and inflammation can result in mitochondrial dysfunction and subsequent organ failure. They highlight the importance of understanding and addressing this dysfunction in order to improve patient outcomes. Lastly, the video concludes with a discussion on the choice between continuous and intermittent feeding in the ICU. The speaker explains that intermittent feeding may be more effective in achieving nutritional targets and suggests that continuous feeding can have negative effects on muscle protein synthesis. They present the findings of a clinical trial comparing intermittent and continuous feeding and discuss the potential implications for preventing acute muscle wasting in critically ill patients. Overall, the speakers underscore the importance of nutrition in the ICU and highlight the need for further research and optimization in this area.

Asset Subtitle

GI and Nutrition, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Examine supplements and specialty formulas that modulate the gut microbiome
Identify the impact of nutrition therapy on mitochondrial function
Discuss the potential impact of continuous versus bolus feeding on muscle synthesis and function in critically ill patients

Does Modulating the Gut Microbiome Shift the ICU Patient Toward Recovery? Robert G. Martindale Mitochondrial Dysfunction in Critical Illness: Implications for Nutrition Therapy Stephen McClave Continuous or Intermttent Feeding: Could the Choice Impact Our Patients' Muscle? Zudin Puthucheary

Meta Tag

Content Type Presentation

Knowledge Area GI and Nutrition

Knowledge Level Advanced

Membership Level Select

Tag Enteral Nutrition

Year 2021

Keywords

nutrition

ICU

malnutrition

gut microbiome

mitochondrial dysfunction

continuous feeding

intermittent feeding

clinical trial

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