SCCM Resource Library-Hot Topics in Critical Care Nutrition: What Recent Data Tell Us

Hot Topics in Critical Care Nutrition: What Recent Data Tell Us

Video Transcription

Good morning, good afternoon, or good evening to you. Hola, bonjour, and konnichiwa. My name is Dante Yeh, I'm a trauma surgeon at Rider Trauma Center in Miami, Florida,  and it's my honor and pleasure to welcome you to this current session entitled Hot Topics in Critical Care Nutrition, What Recent Data Tell Us.  So a pulmonologist, an anesthesiologist, and a trauma surgeon walk into a bar. Well, I wish we could meet at a bar, but instead here we are in cyberspace coming together  to talk about the science of ICU nutrition. We're in for a treat today, as my two speakers are well-published and world-recognized experts in the field.  I personally have been following them for years, and I learn something every time I hear them speak.  Dr. Jay Patel is an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, Wisconsin.  In his lecture, Dr. Patel will review the phases of critical illness and introduce the viewer to some exciting new theories about the gut that are reshaping our understanding  of how it behaves in critical illness. He will be discussing the current controversies surrounding the timing and dose of enteral  nutrition in the early acute phase of critical illness, and also review several recent high-profile randomized trials on this topic.  Dr. Paul Wischmeier is a tenured professor of anesthesiology and surgery at Duke University with a unique expertise in utilizing innovative and integrative interventions.  His research is on the cutting edge of medicine, and his lectures are always entertaining and inspiring.  Today, Dr. Wischmeier will be teaching us about personalizing ICU nutrition and also combining exercise with nutrition in the ICU, something that rarely occurs to me when I  am attending the unit. Using research and evidence from diverse sources, Dr. Wischmeier will provide compelling arguments  for reframing our whole approach to nutrition in the ICU and also beyond the ICU. His lecture will also give us some insight on how to manage critically ill COVID patients  and give us practical recommendations that you can use tomorrow at the bedside. So without further delay, let's get to it.  Thank you to our moderator, Dr. Jay, and SCCM, and the program committee for the invitation to speak to you today.  My name is Jay Patel, and today I'll be talking to you about when less may be more, reaping the benefits of early, perhaps low dose, enteral nutrition. Here is my disclosure.  I am a consultant for Baxter and Nestle. Here are the objectives for today's talk. There's certainly a ton to unpack here, and the next 20 to 25 minutes, I'd like to focus  on two key areas. Number one, describe the rationale for feeding in the early acute phase of critical illness.  And two, we'll discuss the optimal timing and dose of nutrition in the acute phase of critical illness. Let's consider this case.  You have a 50-year-old man with esophageal cancer who was admitted after a witness aspiration, leading to pneumonia with acute hypoxemic respiratory failure and septic shock.  He's had poor oral intake with a 10-pound weight loss over two months. His current BMI is 24.  Ask yourselves, what is going to happen to this patient that enteral nutrition may prevent or attenuate? And so here's a question to ponder over in part one.  What are drivers of multiple organ dysfunction syndrome? And certainly choose more than one answer. Take about five seconds to look over the answer choices.  Now these are the phases of critical illness. The ESPIN guideline, which was published about two years ago, nicely outlined these phases.  You'll notice that there are two phases, an acute phase and a late phase. And the acute phase is partitioned into an early acute phase and a late acute phase.  In the early acute period, it's really defined by metabolic instability and a severe increase in catabolism.  The obvious consequences of the early acute phase are, of course, hypercatabolism, which  then leads to a caloric debt, but then a proteolysis, which then our patients acquire sarcopenia as well. Perhaps the silent component of the acute phase is this gut dysfunction.  And that's what I want to talk about and focus on a little bit more in this first part of this talk.  Now in 2007, Clark and Coopersmith introduced intestinal crosstalk, whereby there's a partnership between epithelium, immune tissue, and gut microbiota.  In effect, each element modifies the others via crosstalk signaling. The purpose of crosstalk signaling is to maintain the epithelial barrier function.  Now as you'll recall, the epithelial barrier function is composed of three layers. The first is a biochemical mucus layer here.  The second is a physical barrier of columnar epithelial cells that are bound by a tight junction. And the third is a sub-epithelial network of immune cells.  So here's an example of crosstalk. These are all molecule-associated molecular proteins, also known as MAMPs. Now these MAMPs interact with epithelium.  Now the MAMPs are not actual organism, but pieces of the organism, such as flagellae. When they interact with intestinal epithelial cells, they do certain things like increase  tight junction protein productions. When they interact with patent cells, they serve to increase the production of defensins.  When they interact with goblet cells, they can increase mucus production, again, increasing the barrier layer.  And then when they interact with dendritic cells, they can promote T-cell differentiated to strengthen the sub-epithelial immune network.  Now if we think about critical illness, you get a breach of this epithelial barrier function in multiple ways. Number one, mucosa thin.  Number two, there's reduced defensin production. Number three, there's impaired tight junctions. And number four, enterocytes are more likely to apoptose.  And some of this is mediated in part by the high TNF-alpha concentrations that are observed in conditions like septic shock. And overall, repair mechanisms are compromised.  The other thing that happens is dysbiosis. Now the emerging dysbiosis project looked at changes in the gut microbiome at the onset  of critical illness, defined as within 48 hours and at ICU discharge or day 10. They looked at 115 adults who were mechanically ventilated for at least 72 hours.  Now this slide that you see here shows the American Gut Project, which looked at the range of bacteria that are observed in healthy Americans.  Now as you can see here, most of it is in green and blue, which represents formicates and bacteroides.  Now enter critical illness and you get this very stark transition to dysbiosis. And all of that green and blue is replaced by this red area here.  And this red area is nothing more than proteobacteria, which are predominantly gram negative rods.  In other words, within 48 hours of critical illness, bacteria transform from a symbiotic, you know, formicates and bacteroides to dysbiotic proteobacteria.  And greater severity of illness promotes the emergence of pathogens capable of dysregulating this epithelial barrier layer.  On the bottom right here, the colonizing pathogens become opportunistic, sensing that the host can no longer obtain the resources necessary to remain healthy.  In other words, severe stress from critical illness leads to a dysregulating phenotype and gut bacterial induced cytokine release can promote systemic inflammation, responding  to adherence and invasion by intestinal pathogens or microbial products. So the loss of epithelial barrier function, coupled with the emergence of a pathobiome  that subverts immune responses, and in fact, promotes gut derived inflammation is thought to promote multiple organ failure.  So gut dysfunction simply as a result of critical illness can promote multiple organ dysfunction syndrome.  So if we go back to our patient for just a moment here, he's received three liters of IV fluids and his blood pressure is 120 over 50, and he's on norepinephrine at 0.2 mics  per kg per minute. So let's think about this question now. Where do you deliver nutrition? So let's take about three or four seconds to look over the answer choices here.  Let's look at our guidelines for just a minute. What do guidelines say about the timing of nutrition?  If we shift our thinking a bit and consider timing and dose, all major nutrition society guidelines, even the recent ESPN ones, support the use of early internal nutrition.  And they support it over early parenteral nutrition. And I think we have ample data to say that early EN is better than no EN or late EN,  with late being defined as more than 48 hours. This is a meta-analysis of 13 trials comparing early to late or no EN that showed early  EN as compared to, again, nothing, had 15% absolute risk reduction in infectious complications.  When they looked at 21 trials that described mortality, this meta-analysis showed that early EN had a lower mortality as compared to no or delayed EN.  So again, I think we have ample enough data to say early internal nutrition is better than nothing in the gut, or if we delay something in the gut by more than 48 hours.  Now I would contend that the mechanisms for benefit are at least partly related to attenuating gut dysfunction.  Preclinical and clinical data shows EN is associated with preserved epithelial barrier function. A lot of this data comes from the University of Michigan.  And EN has been shown in animal models to preserve epithelial barrier function, while deprivation of EN led to loss of it.  Furthermore, gut dysbiosis with parenteral nutrition as compared to EN was observed, with impaired barrier and immune functions, and supplementing just 20% EN reversed some  of these changes that are seen. Certainly I'm advocating for early EN here, but some of you listening might say, wait  a minute, this patient is in shock and he's on a vasopressor and I certainly can't justify putting something into the gut.  And you're very right, because progressive gut hyperperfusion increases a risk for the gravest consequence, which is non-occlusive mesenteric ischemia and non-occlusive bowel  necrosis, with the latter having a mortality rate in excess of 80%. So if we look at the benefits of EN versus PN, in fact, some of you might be saying,  if I'm worried about introducing something into hyperperfused gut, I may consider PN. So if we look at the benefits of each of these, both of them certainly provide calories during  this hypercatabolic state and may help close that caloric debt just a little bit. And both of them may provide substrate to increase protein synthesis.  But if we think about the use of early PN in enteral nutrition, the NeutroREA-2 trial examined this question, whether PN will be superior to EN in hemodynamic instability.  And so what's the question that they asked? They said, in critically ill adult patients receiving mechanical ventilation for at least  48 hours, who are on vasopressor support, does intervention with early full-dose PN, as compared to early full-dose EN, improve outcome of 28-day all-cause mortality?  And here was the trial design. They randomized about 1,200 patients in each arm, one to receive EN, other one to receive PN.  Note, GRV, or gastric residual volume monitoring, was not done in the early enteral group. And PN could be added at day eight if the investigators thought it was necessary.  In the PN group, they received it until the patient was off vasopressors for 24 hours and the lactate was under two.  And when we look at who were the patients that were studied in this trial, now, many of them were those that we would see in our ICUs in their mid-60s.  They had a SOPA score around 11, so sick patients as well, and about two-thirds of them were in septic shock.  And if we look at the results of this study, we can see that there was a significant increase  in bowel ischemia in those who got early enteral nutrition as compared to those who received parenteral nutrition.  Now, note, there was no difference in 28-day mortality, which is what the study was actually powered for.  And there was also an increase in the number of colonic pseudo-obstruction in early enteral group as compared to the parenteral group.  So let's look at a couple of take-home points before we build on this just a little bit. Again, even though there was no difference in the primary outcome of 28-day mortality  in early EN versus PN, there were more serious adverse events in the early EN group. Now, the high rate of non-occlusive bowel necrosis made me scratch my head a bit.  What was it about this trial? What was so different about NutriVit 2 that led to a statistically significant increase in non-occlusive bowel necrosis and colonic pseudo-obstruction?  So we went back and looked at all the contemporary RCT data that included at least one arm that provided EN to patients with circulatory shock.  And we found that non-occlusive mesenteric ischemia and non-occlusive bowel necrosis incidents did not exceed 0.3%.  And this was in over 12,000 patients from contemporary randomized controlled trials that provided, again, EN to patients with circulatory shock in at least one arm.  Now, this may be sort of the key in figuring out why patients in NutriVit 2 developed a non-occlusive mesenteric ischemia. Look at the dose of norepinephrine.  It was a pretty high dose at the onset, meaning at randomization at 0.5 mics per kg per minute.  Furthermore, the adverse GI effects may be related to the end-trial nutrition dose along with the norepinephrine dose.  Because recall, the early EN group received a mean of about 18 kilocalories per kg without GRV monitoring while they were on that high dose of norepinephrine.  Certainly, more data are needed to compare different EN doses and explore mechanisms for benefit in hemodynamically unstable patients.  Now, this was an ancillary study of the NutriVit 2 trial, which compared, again, early EN to PET and circulatory shock.  This study aimed to determine the effect of the route of nutrition on gut mucosa by measuring plasma citrulline, which is a marker of enterocyte mass and function.  So, the higher the level of plasma citrulline, the higher the enterocyte mass and function are intact.  Now, notice the white bars represent the citrulline concentration for those who received early PN and the gray bars in those who received early EN.  As you can see, by day three, plasma citrulline was higher in the EN group as compared to the PN group and many more patients in the early EN group achieved a plasma citrulline  of greater than 20, which is considered to be a normal range. This data suggests that full-dose EN may restore enterocyte mass and function faster than early  PN, but this isn't to say that lower doses can't, and it's unclear if lower doses of enteral nutrition can preserve epithelial barrier function while avoiding the complications  that were observed in NutriVit 2. The question is, well, if it's not full-dose EN, how much can we get away with to reap the gut benefits of early enteral nutrition?  Before we examine other data, let's clarify a few semantics. Note the terminology here, and many of you have heard some of these terms, trophic EN,  hypocaloric, permissive underfeeding, and then, of course, full calorie. And note that trophic just means nourishment or growth, and it's low volume of continuous  feeding to nourish the intestinal mucosa. In fact, in pig and dog models, 10 to 40% of goal calories was enough to really nourish the intestinal mucosa.  Hypocaloric in trials has been defined as less than 70% goal calories, but it maintained the protein dose, the high protein dose.  Permissive underfeeding was a reduction in calories, again, another form of restricted feeding, but it was also a restriction in protein as well.  And of course, full calorie is pretty self-evident. When we look at newer data comparing low-dose EN, especially in those with circulatory shock, this was one such trial.  This was a pilot feasibility trial that compared early trophic-dose EN to no-EN in septic shock. This was feasibility for protocol compliance here.  Now, here was the process by which the trial ran, and note that trophic dose here, most patients got isocaloric, about 20 cc's an hour, which equated to about less than 600  kilocalories per day. And by this, here's the table of who were the patients. Now, there is an error in this particular table, and it's highlighted here in this rectangle.  This BMI in the no-EN group should actually be 29, not 39. But otherwise, if you look at the norepi dose, the total IV fluids, time to first antibiotic,  and the SOPA score, they're all similar in both the early trophic-dose EN and no-EN group.  And again, this was a feasibility trial, but nonetheless, note that there was more vomiting in those who were randomized to late-EN.  Again, I remain curious as to whether this is related to early-EN preserving enterocyte architecture, mass, as well as function.  So far, we've talked about our hypothetical patient in circulatory shock, where less may indeed be more, but what about the general ICU patient?  What about somebody who's, say, not in shock, somebody who has ARDS or single organ failure? If we go back to the guidelines for just a moment, you can see that the 2016 ASPEN-STCN  nutrition guideline recommends either trophic or full-dose nutrition using EN in those with ARDS and suggested, based on expert consensus, high-dose nutrition patients get advanced  towards goal in the subsequent 24 to 48 hours. So, in other words, in those patients who are deemed high-nutrition risk or severely  malnourished, those patients are recommended to get to goal pretty quickly during their critical illness stay. So, what new RCTs have evaluated trophic-dose-EN?  So, if we look at trophic-dose-EN, again, which is 10 to 30 cc per hour, simply to lubricate the gut, we can see that there's two trials.  The first was done to test the hypothesis that trophic-EN would decrease GI complications. This was a single-center trial by Rice.  The second was done to see if trophic-EN would improve ventilator-free days in those patients who received six days of EN.  And when those two trials were put into a meta-analysis, you can see a signal favoring trophic or full-dose-EN did not emerge.  Look at these force plots you can see here. So, again, trophic versus full-dose-EN, a signal did not emerge for one or the other.  What about hypocaloric-EN? Which randomized trials have evaluated hypocaloric-EN? You can see all of them right here from 2011 to 2018.  We have eight studies comparing some form of lower-calorie to higher-calorie nutrition. But note, there's heterogeneity in the patient's populations that were studied,  mixed medical-surgical versus pure medical populations.  Notice that some were single-center trials that was done in emergency surgery patients in this trial study, for example.  Notice there were differences in the protocols and the number of days that patients received therapy as well. And the reporting in terms of mortality was different.  Some reported 60-day mortality. Others reported 28-day mortality. And then the types of infectious complications were a little bit different reported as well.  But when we put those studies into a meta-analysis, again, you can see a signal did not emerge  of favoring trophic or full-dose nutrition in this patient populations. So now we have eight studies that have compared, eight contemporary studies that have compared  hypocaloric-EN to full-dose-EN. And we have two that have compared trophic-EN to full-dose-EN with no signal that's emerged  for full or trophic or let's just say restricted-dose enteral nutrition.  Since the publication of these trials, observational data has been published as well. Zussman and colleagues evaluated over 1,100 patients between 2003 and 2015 at a single center.  The reason why I like this study was because they used indirect calorimetry to assess calorie targets for patients who had more than a four-day ICU stay.  There's two take-home points here. First is that underfeeding and underfeeding, you can see, are associated with harm.  And number two, and this is important, those who achieved 40% to 60% goal calorie had a better chance of 60-day survival.  And when Zussman excluded those patients who had an ICU stay of less than two days or more than two days, that 40% to 60% signal persisted.  What are some other rationale for why less may be more in the early acute phase of critical illness? Well, there's actually five key reasons. Here's the first one.  Feeding intolerance in the acute phase of critical illness may be higher. Take Nutria-2 as an example, where GI complications like vomiting, diarrhea, non-occlusive  bottom necrosis, colonic pseudo-obstruction were higher. If you look at reference number three here, this is a meta-analysis that compared trophic  to full-dose EN, and it found that more serious GI intolerance was observed in those individuals who achieved full-dose enteral nutrition in the early phase of acute critical  illness.  The second reason is endogenous glucose production in critical illness is increased. Now, recall the combination of heightened catabolism, proteolysis, as well as insulin  resistance will lead to hyperglycemia that's observed in critical illness. Well, if we give a lot of nutrition early on, that can increase the, excuse me, compound  the hyperglycemia that's already observed as well.  Number three is refeeding syndrome in malnutrition.  There was a randomized controlled trial by DOIG that randomized patients to restrictive feeding and standard feeding for seven days, and they ramped up nutrition based on the  phosphate levels.  The primary outcome was survival to ICU discharge at 60-day follow-up as well.  In the right here, you can see that there was a clear separation in this Kaplan-Meier curve when feeding was advanced slower, again, based on serum phosphate levels.  This blue line on the left side shows that the patients who had a slow ramp up really didn't get to their goal calorie intake, probably till about the end of the first week  of critical illness as well.  The fourth reason is mitochondrial failure. Remember that mitochondria are sensitive to increased oxidative stress, which is a hallmark  of critical illness, and aggressive feeding in the early phase of critical illness may increase the mitochondrial workload really when in fact they are dysfunctional, which  can further lead to their dysfunction and contribute to mitochondrial, excuse me, multiple organ dysfunction. And then the final reason is this concept called autophagy.  Autophagy is a housekeeping mechanism, which removes unfolded proteins, viruses, and bacteria.  And the amino acids that are generated from those unfolded proteins are used to generate energy. Now, it's thought by some that excessive feeding during the first week of critical  illness can suppress autophagy, which can then perpetuate the increase in oxidative stress as a result of suppressed autophagy and lead to multiple organ failure as well.  And so the question that I would ask you is, is the pendulum swinging for nutrition dose during the early phases of critical illness?  You've already seen the 2016 SCCM Aspen guideline, but if we look at the Aspen guideline, they're very clear.  They say, they recommend hypocaloric nutrition should be administered in the early phase of critical illness as well.  Now, yes, again, EN and PN can provide calories and perhaps increase protein synthesis. I would submit to you that the rationale and goal for early restricted dose EN during  the early acute phase is to preserve gut integrity, reduce inflammation, maintain gut immunity. In other words, mitigate the gut dysfunction that's observed.  Now, for the sake of time, I will let you review these take-home points. Thank you very much for your attention. It was an honor to speak to you today.  Hello, my name is Paul Wischmeyer, and I'm a professor of anesthesiology and surgery at the Duke University School of Medicine, where I also direct the Duke University TPN  and nutrition support team. And I'm thrilled to be here with you here today to talk to you about personalizing ICU  nutrition and critical new tools for the objective assessment of nutrition and muscle mass. Briefly, my disclosures are what I'd like to call my alignments of interest.  And I think the key message that I want to convey throughout my talks today is that we must not only take responsibility for the outcomes that occur in the ICU, which we round  on our patients, but we always must be thinking about how the care we're delivering and the care we give each day, how it affects what happens after the ICU to our patients as well.  Because ultimately our goal is to create survivors of our patients, survivors that go back to their families rather than victims that perhaps stay in rehab and perhaps never go home  or have a meaningful quality of life again. Because ultimately we would love for our patients, or our goal for our patients is to have them walk down the street again  with the people they love and hold their grandchildren again which is what they came to us to give back to them in the first place.  But in the era of COVID-19 and advanced critical care, this is becoming more and more challenging. And in particular, how we deliver nutrition  and physical therapy in an objective fashion where we can measure our outcomes much like as we give pressers to patients, we measure the blood pressure,  how can we give nutrition and physical therapy in that same manner? And I would like to believe that we, especially in the nutrition field,  and perhaps in the rehab field as well can do better, but how can we do better? Well, I think the first realization, I think we all know this to some degree  is that one size does not fit all of our patients, particularly when it comes to nutrition. Just like it's true, as I said, we wouldn't give vasopressors  without measuring a blood pressure that we then adapt and change those vasopressors to as the blood pressure changes. We should be personalizing our IC recovery  and nutrition strategies, giving the right nutrition and the right strategy and the right patient at the right time. And we need to be able to measure that.  And I'm excited to be able to tell you about a lot of exciting new technologies and interventions that you can begin using in your hospital tomorrow  to help you make these measurements and to help you objectively define how much nutrition your patient needs and the effect that nutrition is having on them as we move along.  So first, as we begin to think about the nutrition risk state of our patients, do we know who our most at-risk malnourished patients are? And can we monitor the nutrition delivery  they're receiving and what tools, what new tools do we have to assess? But first, who's most at risk? So as we think about who is going to survive ICU  and perhaps recover meaningful functional quality of life, who do you think is most likely to recover? This thin, healthy-appearing gentleman or this obese gentleman who perhaps  has some other comorbidities related to obesity? Well, we know from many different diseases that the higher weight or the higher BMI patient  with a BMI of 30 to 35 is the best BMI to survive just about any illness, injury, or even critical illness you can have. And this includes COPD, atrial fibrillation,  cancer, trauma, lots of different things. The obesity paradox with the best survival being at a BMI of 30 to 35, much better than a BMI less than 25 in most cases, is true.  And this is true in critical care as well. We can see in ARDS that there is a pretty sharp linear curve downward in mortality as BMI increase,  with the highest mortality being at lower BMIs and the lowest mortality decreasing all the way up to a BMI of even 40, something we wouldn't think otherwise would be an advantage.  This is true in general ICU patients as well. You can see there's a significant increase in mortality with a steep upward curve in the BMIs of 25 and less.  Unfortunately, most of our ICU nutrition trials have been done with an average BMI of 28 to 32. So they've been done in our more obese patients who are at lower risk of death.  And so it's harder to see signals of benefit, whereas we really also need to learn to focus on our most at-risk patients. And this may also include low lean body mass,  which is a whole nother issue outside of BMI. And I think it's something we need to be thinking about and we'll talk about more. But in terms of not just survival, but recovery,  there was a great study in that top reference in the Blue Journal that showed that for every drop of one point in your BMI, you had a 7% decrease in the probability  of meaningful functional recovery of quality of life or meaningful quality of life recovery. So a woman who weighs 130 pounds with a BMI of 22  is 60% less likely to recover a functional quality of life than a woman who's 175 pounds with a BMI of 30. Conversely, again, the more obese patient  is much more likely to recover functional quality of life as well as having a lower death risk. And so I think this shows us they're likely  to be able to do something to the idea of metabolic reserve and perhaps the relatively obese or moderately obese patient that's diabetic  and perhaps in front of you in the next marathon you run or next race you run is a lot more fit and has a lot more muscle mass perhaps than you think.  And it makes us rethink about how we think about what a healthy, for the ICU at least, metabolic reserve is. And so what makes someone metabolically nutritionally fit  and how do we assess that objectively? So first, is it muscle mass? I mean, clearly we know that when we use CT scan to measure lean body mass,  we know that muscle mass predicts survival. This is great work by Peter Weiss that shows that significant increases in mortality occur as people's muscle mass or lean body mass  declines at ICU admission. This has also been shown by work by Rosemary Kozar who I work closely with. She looked at 150 or 149 elderly trauma patients,  free living, out driving their cars, who had underwent trauma. 71% of these patients were sarcopenic by definition. And again, you couldn't eyeball them and tell who they were.  They could be underweight, they could be normal weight, they could be overweight, but you couldn't tell which of those patients had low lean body mass.  The eyeball test doesn't work. But what we did find is the sarcopenic patients had double the mortality of the non-sarcopenic patients, other things being taken into account for  just on the sheer fact they were sarcopenic at admission alone. So this is a major risk factor, the metabolic reserve you enter the ICU with.  And so can we do better to assess this risk and metabolic risk and are there better tools to measure this that we can use at the bedside?  And so we've typically used CTs and perhaps BMI, but perhaps we can be more objective and more hands-on with our measures by using ultrasound. And not just to measure muscle mass,  but to measure muscle glycogen, muscle quality, fat mass, and other things as well. Again, Marina Motsikas and I published that this was an easily done technique.  It can be done by an RD, it can be done by a nurse, a physician, anyone on your team can be trained to do this successfully. It takes just a few minutes to do  and can be very straightforward. Zutin Poojachery, who's giving one of our named lectures, which we're all very excited about, has been a pioneer in showing us  that the severity of illness contributes to the loss of muscle mass and that muscle atrophy is associated with survival and multiple organ failure in these patients.  And so there's a really seminal JAMA paper that he published. And Darren Highland and his group has shown  that there is some correlation of the ultrasound with the CT scan, but we need more data. I think some of the limitations here where the CT and the ultrasound imaging  could occur as much as 72 hours apart. And we know that within the first week, you can lose 10% of your lean body mass. And so even just a few day difference  from when one test was done to say when the ultrasound was done can lead to significant variability in this setting. But I think this was a great start for our specialty.  But can we take it a step further? Can we learn from elite athletes like Tour de France athletes like this using ultrasound testing they use to help our patients?  So this is an actual Tour de France athlete using what's now known as a muscle sound ultrasound. It's a new muscle specific ultrasound to help guide his training  and his competing on the Tour de France course. And how does this technology work? Well, this takes essentially a muscle biopsy and measures things like muscle glycogen,  muscle mass and muscle fat right to your eyes and converts it to colors. You can actually see gray scales, not so good with the human eye, but these colors are.  And it can really give us a picture, almost a biopsy of what's happening in the muscle. And it's very simple. It's a handheld ultrasound that fits in your pocket  and plugs into your iPad or iPhone. And it can in minutes, give you a whole wealth of information about the patient's metabolic reserve, about their glycogen levels,  which is sensitive to nutrition delivery on a day-to-day basis and really give you nice printouts of data that we've not been able to get before. You can see it's very easy to use.  It actually self-corrects and tells you when your image is correct. It knows what the correct muscle image should look like.  And so it's really user-friendly and straightforward to use that anyone can be trained to do. And so I think what's really exciting about this is,  is we can not only get muscle mass, but we can also get muscle glycogen, which is reflected. The darker those areas of muscle are, the more glycogen they contain,  the lighter areas contain less. And this muscle glycogen is really important to understanding the metabolic state of our patients and how effective our feeding is  and where they are in the acute and chronic phase transitions. Glycogen storage is very important to endurance. Again, the glycogen is used first  and the more glycogen reserve you have, the better your performance and the time to exhaustion will be much longer. And so our patients will be able to perform  more rehabilitation and more exercise and be more apt to recover. Unfortunately, glycogen depletion leads to muscle damage and poor muscle function.  And it forces the muscle then to begin to use amino acids to be catabolic because it doesn't have the glycogen it needs.  And so with muscle glycogen depletion, the body can't be anabolic. And so we're not going to be able to help our patients preserve and recover muscle. And now we can measure this.  It's been validated by muscle biopsy. So what happens to muscle glycogen levels in ICU patients? This is what a perfectly trained athlete looks like.  You can see how dark the muscle is, waterfalls, glycogen, and you get a very high, almost perfect score. This is the average individual at rest, 65.  This is what happens with different kinds of training. These are the averages and athletes, sedentary individuals. This is following two and a half hours of cycling,  not riding around your block, but in a Tour de France ride. This is after a marathon. This is the average in our critically ill patients. So being critically ill is like running  five or 10 marathons. And again, if you look at their ultrasounds, it's complete white, complete whiteout. There's no muscle glycogen there. You can see compared to the dark muscle  of the elite athlete. And so again, this is dramatic differences that we can see with our eyes. And now with color, it looks even different. This is a sepsis patient at ICU admit.  You can see by day 10, they have a lot less dark areas of high muscle glycogen, and they have a lot of muscle necrosis. But different critical care states have different responses.  And this is a neurotrauma patient with much better glycogen versus the sepsis patient. So every ICU patient is different, and we can see that visually in minutes.  Unfortunately, our data showed that in our surgical and medical ICU, 70% had glycogen scores of zero at admission. So it was rapidly depleted within as fast as 24 hours.  So it's incredible hit the body takes. It's like running the marathon of one's life. And it puts the muscle at great damage for risk of muscle damage and lack of muscle recovery.  But what we can see is some of these patients, this was a shock patient that began to recover. You can see the glycogen score begins to go up.  And this may be a signal that this is a time when rehab and anabolic interventions and increased feeding may be able to be started on the patient  because the muscle is able to use substrate now. And I think this may be a signal for moving from the acute phase to the chronic recovery phase.  But of course, muscle mass is not the only thing we wanna measure. Muscle quality also matters. Lipid infiltration and fat infiltration  really tells us a lot about muscle and about outcomes. This is a autopsy segment of someone who has much more fat on one side because they had a hip replacement on that side.  And so that's very poor quality muscle with a lot of fat infiltration. And we know that Peter Weiss's group has also shown it's not just mass that matters,  but muscle quality predicts survival as well. So poor muscle quality leads to increased mortality. And we can measure that through intermuscular adipose tissue  and other measures of muscle quality and muscle fat. So this is a new biomarker that we've been working on as well. And it actually measures the muscle fat content  using the ultrasound, as well as the more quality muscle that's within the muscle. And so you can see in these different patients  that the device can integrate the areas of muscle fat versus connective tissue and give you a quality score.  And we were able to show that compared to athletes and normal controls, that there was a significant loss in muscle quality very quickly within seven to eight days in our patients.  Excuse me. And so muscle quality is likely significantly we've seen changed in ICU patients with not only muscle mass loss, but subcutaneous adipose tissue increased.  And this is as Zutin Punjacheri has shown us and taught us that the body is not able to use lipid. The muscle is not able to use lipid. It's likely mitochondrial dysfunction  and other metabolomic dysfunction. And so this fat accumulates in the muscle when it can't be used. And this is one of the derangements that critical illness brings upon us  and Zutin has been a pioneer in this. So now we have other tools that are new as well. A tool you've probably heard of, the bioimpedance analysis  has been something that we're beginning to use more as well. Again, the old fashioned scales used to stand on are not what we're talking about here,  but that's the basis of how those work as well. They have limitations of course, and are not nearly the degree of the devices  that now we have, and we have a number of these at Duke. And we're using muscle sound at Duke as well. And you can see that these are the BIA devices,  multi-channel, much more advanced devices that are used throughout the world in ICUs and other settings, cancer as well, to measure much more accurate measures.  So there's some promise for the phase angle, which is a composite measure that the BIA yields and some of our really strong researchers in cancer and critical care are using.  This gives you a sense of what the readout of a BIA gives you. I'm gonna show you an individual, I won't name who it is, but that we did some measurements on  and this person looks overweight, they have a high BMI and they have a high weight, but they have a very high skeletal muscle mass with a very low body fat.  And that's some of the interesting things this device gives you. And this actually was an amateur bodybuilder that we were measuring, who has this very high BMI,  and this is a very high skeletal muscle mass with a very low body fat. And that's some of the interesting things this device gives you. And this actually was an amateur bodybuilder  that does this very high muscle mass despite having high BMI and very low body fat. So we'll talk some too about our patients. This is a patient we'll talk about in the next lecture  that we'll talk about for exercise and nutrition. This was an individual who had a much lower weight at a very high body fat, 40% and a very low skeletal muscle mass.  And this is a cachectic sarcopenic post-ICU patient. And we'll talk more about his course and his care in the next lecture. So, but again, this is a real opportunity  to learn a lot about the muscle and you can really see changes. These are cachectic patients versus septic patients and the changes of fat infiltration that they can have.  And we can bring those modalities together. So we do all these modalities together, which I'll tell you more about in a study we're doing in COVID-19,  where we bring a lot of objective modalities together to help us understand the metabolic phenotype of our patients. And so again, this is the muscle ultrasound  with the BIA in the same patient or the same individual. And then we get to the question of when we diagnose malnutrition and have a sense of the patient's metabolic status  and reserve, how much do we feed in critical care, right? And we need objective measurements to guide us. We can't rely on equations anymore. We need to move way beyond that.  Again, we wouldn't give pressures without blood pressure measurement. We shouldn't be giving nutrition without measuring metabolic needs and energy expenditures.  So, and that may be especially true, I'm gonna show you in COVID-19. So again, I think nutrition therapy in the patient with COVID-19, we've made some recommendations.  Again, these are very similar or almost the same as what our recommendations are in general, for critical care patients. And so I think, again,  we perhaps need to evolve beyond this. And let me come back here. And so we actually need to be measuring energy needs. This is a new pandemic disease  and a new opportunity that we really need to have more data on to know how to feed correctly. Again, metabolic heart and endocrinometry is recommended by all of our guidelines,  both ASPEN, SCCM and ASPEN and should be done routinely. And I think, again, even in COVID, we're finding this can be done routinely and be done safely.  And I'm gonna show you how that's going, can be done in just a moment. I'm gonna show you why it's so important. And the other interesting data we have  is that clinical trials that use indirect calorimetry to guide the higher nutrition groups versus the lower nutrition groups have a much stronger signal  of showing benefit of nutrition than trials that just guess at how much nutrition the patient needs and hope for the best in the higher nutrition groups. And so you can see  there's some nice meta-analysis data here that shows this really may have promise in how we care for our patients. But the limitation has always been they've been too hard to use,  they're too expensive, they can't be calibrated, no one can use them, they're impractical and they're not accurate. Well, that needed to change  and led by people like Claude Bruchard and Elizabeth Davale and Pierre Singer and Meta Berger, a group of us from all around the world came together to work with industry  to build the much needed new generation metabolic heart that was simple, easy to use and practical. And this has occurred and has now been validated  in a multi-center trial around the world. We did, it was just published last year. And it's this Q-energy device, this next generation device. And I will disclose that Baxter does  support our research using this device. And so Baxter and Cosmed are the developers and I'll disclose that they are working with them and they're supporting research,  which I think is great. And I'll show you some of that research in a moment. But these are exceedingly accurate, they're validated against mass spec gold standard measurements,  they warm up rapidly, they don't require calibration, but once a month, they're easy to use, they are very small, they can roll around in a cart and they're quite affordable.  I think they've really addressed, Claude and his group really brought it together to get us what we finally needed. This is what we've all said we've needed for so long  is this rapid measuring, it can measure in 10 minutes, our data would validate accurately and can be easily moved from patient to patient. And again, it's got a touchscreen,  it's very simple to use. So we have the opportunity to have these devices at Duke for some validation studies, the iCALIC trial you just saw in March when COVID hit.  And so we proposed to study very quickly and got up and running to define the metabolic phenotype of COVID-19 using BIA, using metabolic cart,  using muscle ultrasound and other devices. This is Jeroen Mullinger who showed incredible commitment and sacrifice doing these measurements day and night, weekends, holidays,  and he's continuing to do that in COVID rooms around our hospital at Duke. He's done innumerable measures for hours at a time in these high risk rooms  and I owe him a lot of credit, we all do. And this has been published initially in a research letter, our initial findings, which you'll see here.  So again, we didn't have longitudinal data and we needed that data about what the energy needs of our patients with COVID really were.  And so we brought all these instruments together and did every three day measurements from ICU admission or intubation all the way through hospital discharge.  And we used all these devices, including Echo to gather this data. And so the real question is, are COVID-19 patients hypermetabolic in the acute phase  and what are their real energy needs? So here's some of those patients. Again, this is a patient in the first week, a mid-50s long-term care patient from a long-term care center  who was spontaneously breathing and only showed a resting energy expenditure of 913 calories or 71% of predicted. So this patient was hypometabolic  versus the Harris-Benedict equation or other predictive equations in that first week. Again, this is another patient, this was a prone paralyzed patient  who again showed hypometabolism less than 100% predicted by Harris-Benedict in that first week. This patient was prone and paralyzed on a PEEP of 12.  You'll see the new metabolic carts can measure up to FiO2s of 70% and PEEPs up to 16. So they really extend our ability to accurately measure sick patients.  But what about in the second week and the third week? What happens as we go along? This is the same patient you just saw who's now at age 12. Now he's quite hypermetabolic.  Unfortunately, he's being underfed because we didn't have another data point for that patient yet, but now we do. And you can see they're needing 35 kcals per kilo  by indirect calorimetry and quite hypermetabolic. And so we had to adjust their feeding. Just some progression, this is the next day.  We saw that big jump, we wanted to be sure it was correct. Now they're 200% of predicted, 44 kcals per kilo. And again, we needed to adapt for that.  This patient was febrile essentially all day long for a couple of days in this setting and had significant increase in needs. A few days later, they were improving  and weaning a bit on the vent and their caloric needs dropped. So you can see the variation from day to day. Every few days, they change pretty dramatically sometimes.  But unfortunately, this patient got sicker on day 23 and jumped back up to significant caloric needs. And this patient was very hard to feed  and ended up needing supplemental parental nutrition. This gives you a sense of the variability that we've seen. And this was our first 22 patients overall,  average age of about 60, about half male, about half African-American, BMIs of around 31 on average. So again, obesity and COVID sadly go together.  Our average ventilator days were 14 to 20. Our initial mortality in the study period was quite low, but that increased by the time hospital mortality was recorded about 22%.  So you can see our nutrition data, normal metabolism or even hypometabolism in that first week, but then that increased dramatically over the second and third weeks.  And you can see even in obese patients, significant hypermetabolism based on weight and needs over time. And these patients were very hard to feed.  We averaged about 50% of their caloric needs. So significant changes across the board.  This is Dr. William Whittle, who's now back in England. Sadly, we miss him at Duke. He helped lead this project, myself and your own and others.  And you can see the average VO2s and VCO2s and RQs in these patients over time. This is the average caloric expenditures over time in all patients.  You can see the incredible standard deviations. There's no way equations can predict this. A lot of variability from patient to patient. These are the non-obese patients.  You can see here as Benedict sort of predicts a flat line. It can't account for this hypermetabolic state these patients face. And in real marked increases in hypermetabolism  with a lot of variability after the first week. These are obese patients. You can see measured by both adjusted and actual body weight. Significantly above aspen SCCM guidelines  of 11 to 14 kcals per kilo. So significantly increased needs in these obese patients with COVID-19. The obese and non-obese weren't all that different. They were fairly similar.  You see a little more of the hypermetabolism in the obese patients, but again, not that big a difference. This is Chris Haynes, one of our intensivist surgeons  who's working with us on the nutrition team. Incredible variability. She did this data in day-to-day and week-to-week measurements making it very hard to predict.  And I'm gonna show you some new data. It's not published that we just finished looking at how this measured data compares to equations. You can see the proning and paralysis use  was pretty consistent throughout the study that didn't seem to affect the nutrition needs or contribute to the hypermetabolism. SOFA scores are very similar week-to-week  in these patients without a lot of variability. They were very, very sick patients, as you all know. You can see the number of patients remaining in the study over time  and the use of proning and paralysis over time. These weren't statistically different from week-to-week. And again, the SOFA scores were not different either. So our initial data,  normal metabolism to almost hypo metabolism in the first week, 17 to 20 kcals per kilo with significant hypermetabolism in the second and third weeks,  25 and even up to 35 or more kcals per kilo. So I think it's reasonable to look at 20 kcals per kilo in that first week as a reasonable place to start.  And then again, I think it's reasonable to feed 70% of that for the first few days and ramp up the calories as the patient's endogenous  calories are produced by the muscle breakdown. And then that's lost and we have to get to goal in three or four days. So again, the other piece is  there's lots of variability after day seven. It gets very hard to predict without a metabolic cart. The caloric needs are a little lower in patients that are over 70.  They're a little higher in obese patients, especially after the first week and fever significantly increases those. And some of these patients are febrile for long periods of time.  The other interesting findings I think were it does not, this hypermetabolism is not related to severity of organ failure. That didn't seem to be relation.  And then the hypermetabolism doesn't have much of any relationship to paralysis and sedation. So don't go reducing your calories if the patient's paralyzed or deeply sedated.  And we're not the first to show that. Arthur Van Zanten showed that paralysis only led to about a 6% reduction in resting energy expenditure  when you measured people before and after paralysis. So this is a very minor effect you should not need to account for. So when actually tracing out what actual needs are  based on our previous guesses, we can see this is what the actual needs for calories appear to be. So how well do these predictive equations perform compared to measured needs  with the equations we're routinely using in COVID-19 now in practice. And two of our outstanding star dieticians that do research with us,  Hilary Miller and Laura Nieder did this work and we've submitted this for publication. They did a great job. We now have 34 patients in fairly similar demographics.  You can see our remdesivir insulin steroid use was very high at Duke. Our length of ventilation now is longer and our length of stay is longer  as we get better at caring for these patients. And this is total mortality of these patients even followed to post-hospital setting. You can see we have a fair number of deaths  that occur after hospital discharge and readmission. So again, you can see that the indirect country showed an increase in hypermetallism  that neared statistical significance across week one. This was not at all predicted by any of the routine equations used in care today. The Penn State, there's Benedict or the MSJ.  None of these could account for the hypermetallism or even suggested. Most of them went down actually in their predicted needs not up like the resting energy expenditure showed.  So there's a dramatic difference. These are the average K-cals per kilo. Again, none of the equations at all reflect the hypermetallism these patients are actually showing us.  So they're not useful in these patients and you can see significant differences. This is what the obese patients versus non-obese patients showed us in resting energy expenditure,  a little bit lower needs in the obese patients on K-cals per kilo actual and some statistical significant differences now that our patient groups expanded.  And you can see now where all the red values are, where all the statistical differences were between what was measured at resting energy expenditure  in both obese and non-obese patients and what the equations predicted. The only equation that even predicted reasonably well was the Penn State equation,  but it could not account for the hypermetallism at all. So indirect commentary is essential for accurate nutrition targets in COVID-19,  especially if this can be done repeatedly and longitudinally as the predictive equations can't predict the actual needs and they cannot account for the hypermetallism.  If you're gonna use an equation, the Penn State equation should be used as it appeams to perform the best. So again, if you wanna see a summary of how we can consider integrating  the metabolic cart into our care all the way through hospital discharge and ICU, post ICU phase, and we are measuring people out on the floor using metabolic cart,  you can see that there's ways that we are suggesting, and this was just accepted for publication in nutrition and clinical practice. This figure is in there  and I'm happy to share this figure with you by email. So in summary, how can we create survivors of our patients and do better and not create victims?  I think we all need to realize we have chances to do better. I think we can have more accurate nutrition targets for our patients using indirect calorimetry.  I think we must begin to personalize our feeding, the right dose in the right patient at the right time and we need to be measuring.  We need to bring ICU nutrition up to the standard of other systems within the ICU, cardiovascular ID and renal and the like, where we make measurements every day  to guide our therapy, nutrition, we can do that as well. And we have many new devices that can help us do that. And we need to objectively assess this longitudinally  throughout ICU stay and post ICU stay to optimally recover our patients. So again, there's many opportunities for new devices and new treatments to help us do this  and to help us target this. I think to close, I think these are what we found at least in COVID patients, that we need to ramp up calories and protein  as Arthur Van Zanten has shown us. And then these need to continue to increase on the hypermetabolic phase. And then we need to be looking at high intensity exercise,  I'll talk about next lecture and even anabolic agents, which I'll talk about as well. But the hope is if we can get better at targeting this,  we can take patients who look like this, have them up and mobile like this, and then ultimately look like this, or at least like this when they go home.  And so with that, I thank you all for your attention. And please feel free to reach out to me with questions any time by email and follow on Twitter and Instagram  for new papers and new data that are coming out all the time. Thanks very much. And look forward to talking to you in the next lecture as well. Take care.  Nutrition and exercise and how they go hand in hand, even in the ICU. And I wanna review the current knowledge we have around this. So again, these are briefly my,  what I'd like to call my alignments of interest or my conflicts of interest. And I think, as I've said before, the key piece that I wanna convey is we must take responsibility,  not just for the outcomes that occur in the ICU, but also what happens after the ICU. And so that is every day as we're on rounds, we're always thinking about  what are the things we need to do today to not only ensure what we need to do to have the patient survive and recover from the acute illness,  but recover their quality of life afterwards as well. And are there exercise, nutrition, and other care therapies that we need to be being sure our patients are receiving?  Because again, our goal is ultimately to create survivors of our patients to go back to their families and not victims that perhaps never go back to a meaningful quality of life  or remain in rehabilitation facilities for the remainder of their lives and never go back to walking down the street with the people they love again or holding their grandchildren,  which is what they came to us to give back to them in the first place. Because the reality is surviving and recovering from the ICU is often a marathon of many patients' lives  or of almost every patient's life. It is the ultimate marathon of their lives. And what happens when we ask our patients to run the marathon of their lives  without the right training and nutrition, perhaps both before and after the ICU stay? And so perhaps this is the marathon to table or the marathon to ICU, we call it.  And I have to thank your own Mullinger and John Whittle for this wonderful way of thinking about it. And to describe that, I wanna tell you about a patient  that we cared for not so long ago and I've become quite close to his family. His name was Elijah and he was an 89-year-old who came to us for partial colectomy for rectal cancer.  And he'd lost about 10 kilos of weight over the last three months prior to his operation due to his cancer. And he definitely said, I feel weaker than I used to.  But this was a very active individual at 89. He was on the ladder fixing his church roof at home the day before his surgery occurred. And then he said to us, as he went to surgery,  I can't wait to travel to see my new granddaughter after his operation. I wanna be well enough to see her and watch her grow up. And the one question is, is he ready for surgery,  which is a prehabilitation question beyond the ICU. But the reality is he went to surgery and he probably wasn't ready. We're trying to find better ways to optimize patients,  but he went to surgery, did okay for a few days, but on post-op day three, had acute abdominal pain, rectal bleeding, and acute decompensation.  He went to the OR and on his way to the OR, of course, he had a CT scan and he was shown to have ischemic bowel. He developed hypovolemic shock. And in fact, while in the OR,  he had a brief cardiac arrest with one round of CPR. And I remember this is an 89 year old. And so they found out an asthmatic leak and then also ischemic bowel.  And so he came back to the ICU with an open abdomen, very weak on the ventilator. And of course he's already got malnutrition from his prolonged weight loss and lack of nutrition.  And so the real question that came up on rounds was can he survive this? And probably appropriately so, people on rounds began to ask,  he's too old and too sick to recover from this. Perhaps we should talk to the family about withdrawing care. And sometimes I think that is the appropriate decision,  but I can tell you that many of us as physicians, both the surgeon and myself, having gotten to know the family said, no, I don't think this is what they want.  I think they want us to fight for this patient that didn't seem to be his wishes. And so he gets his abdomen closed. He's extubated now day three  and the family and the patient agree they want to keep fighting, that they are not ready to give up. They said he wants to go back to his church.  He wants to go back to seeing his granddaughter and he was very active before. We think he can get through this and he thought he could get through this.  So we all agreed our team would fight for him. And the question is, can we save this patient and give him his life back? And what do we need to do to do that?  Because I think to save patients like this and to save all our ICU patients, we need to continue to do better for their ICU recovery  or as Jackie said, for their ICU survivorship. And how can we do that? And I think it's going to take a combination of nutrition, therapeutic nutrition, targeted nutrition,  good physical therapy and rehabilitation and then perhaps some learnings from elite athletes and how they train and how they optimize training.  So what are our exercise and nutrition goals to prepare and recover an ICU patient? Well, clearly we need to recover muscle mass and we need to recover, forgive me, aerobic fitness.  And so again, this needs to be a personalized recovery plan, giving the right nutrition and exercise dose to the right patient at the right time. And we need to be measuring.  We can't just say go and exercise or go and eat. That is not going to work. So if we're going to measure things, what were this patient's muscle  and body composition measurements in the ICU? So in the last lecture, you heard me talk about the devices we're using at Duke to measure these patients.  This is the BIA measurements. Again, he had a very high body fat mass, very low skeletal muscle mass and very low muscle mass by ultrasound with poor muscle quality.  So we had a lot of work to do, but we had a starting place. We knew there were measurements, we knew where we were starting. And so we knew how to objectively follow  on a week to week basis our progress. And so starting with his nutritional needs, of course, protein is essential to recovery. Can't build a house without bricks  and you can't rebuild lean body mass or muscle mass without protein. And this is an outstanding paper from Peter Weiss and Stuart Phillips, who's a real expert in the muscle field  and the nutrition muscle field, really somebody I look up to, published in Current Opinion that really shows us the idea of anabolic resistance.  As we age, it takes more grams of protein to gain the same amount of muscle as it did when we were young. And so not everyone who ages loses muscle.  This individual's maintained a lot of muscle mass at age 70 and that is not just eating well, it does that or exercise. But we can learn a lot from these athletes.  They take in a lot of protein, they take in boluses of protein, not continuous and Zutin and Puducherry's Danny Bear has done some research now in bolus feeding  and I think it's got a place. Then they give themselves a lot of leucine and HMB and other essential amino acids, often taking in a large amount before they go to bed  when they're anabolic. And then it has to be combined with exercise and strength training. Because the anabolic resistance of critical illness is quite a bit more severe  and it takes a much more protein to gain muscle and likely it's going to take other anabolic agents and substrates like HMB, oxandrohone and anti-catabolics  like propranolol to recover. We'll talk a little bit about that later. But what are we feeding patients now and are we giving them at least the base requirements  that they need to begin to recover before we add exercise and anabolic agents perhaps to those things in rehab? Well, we know of course from Darren Highland's data  that we don't feed our patients adequately, especially in the US. We underfeed for two weeks. We give our patients half of the nutrition they need,  not for a day or two, but for weeks. And so it's no wonder it's very difficult to recover. And our protein delivery is even worse. We give a third of the protein,  we say our patients need a half to a third for not a day or two, but for weeks in the ICU, which without the fundamental building blocks of muscle,  it's going to be virtually impossible for our patients to recover. And so this is really, I think, a contributor. And so if we're going to create survivors,  can improving nutrition and protein delivery help? Can it help patients gain muscle? Well, there's some hints at this data from the early PN trials done in Australia  by the ANZICS group that showed that early protein nutrition and protein delivery reduced muscle wasting in the patients that got the early PN.  So here's some signals of reduced muscle wasting with better amino acid and protein delivery. This was data from the REDOX trial that Darren Highland and I did.  And this was the subgroup that were on the ventilator more than eight days. And we, his group was able to show that patients who got more than 80% of calories and protein  had the highest survival. But more importantly, we had SF36 scores on these patients after three and six months. And for every 25% increase in nutritional delivery  over the first eight days, these patients had significant clinically meaningful changes in their physical function by SF36 after ICU. And so again, we can make a difference  in what happens to our patients with how we feed them in the first week or two of ICU, perhaps months or even years later. And so again, this affects what happens to them,  this data would show. Now, especially in COVID patients, but as I showed you in all ICU patients, getting to go into nutrition is very difficult.  And there's a lot of GI tract involvement in COVID-19. And so the question is, should we be starting protein nutrition sooner? Especially in those that are malnourished  or that we expect a longer MPO period in. And that brings up the question is, does TPN and kernel nutrition increase the risk of infection in ICU patients?  And I'm curious what all of you think as you listen. I hope you answered this correctly. The answer is clearly no. There are now four large randomized trials  of many, many patients in journals you've heard of, New England Journal, Lancet and JAMA, that show it has no association to infection risk in 2020.  It is just as safe to put TPN through a line as it is to put saline through a central line in modern ICU practice. And I can't stress that enough. Why is that?  It's different from what you're probably taught in medical school or in other training. TPN is no longer related to infection because we don't hyperallocate anymore.  We don't give 35 kcals per kilo on day one. We control hyperglycemia. Most of the infection related morbidity from TPN was done in studies before glucoses were treated.  We didn't use glucoses over 300 when I was a resident. That wasn't that long ago. We have better protein delivery. We have better central line care with our checklists.  And we have better lipids. We now in the US have fish oil and olive oil based lipids. If your hospital is not using one, change it now.  It is one of the best things you can do for your patient. The meta-analysis data clearly shows reduction in infections. Everyone should be getting a new lipid  and no one should be getting the routines inter-lipid omega-6 lipids. So what about our patient? He's starting to recover. And will he eat enough on his own? Not likely.  We know that the average intake of a post-ICU patient is about 700 kcals per day, which I can tell you is not nearly enough.  So we're going to need to use oral nutrition supplements. And that's what we did in this patient to get to post-ICU needs. We know there's a lot of data to show  they reduce mortality, they reduce complications. Every dollar you spend on these little nutrition drinks reduces costs or saves hospital costs quite significantly for our patients.  And in fact, that number comes to, hold on, let me get my cursor back.  It saves, for every dollar we spend on OS, we save $52 in hospital costs. Let me get my cursor for a moment. And there's now a large randomized trial of heart protein,  HMB containing oral nutrition supplement that shows a significant reduction in mortality at 90 days post-hospitalization. So now we have large randomized controlled trial data  showing improved outcomes, and this showed improved muscle strength as well. And so I think the post-op use and the post-ICU use, sorry, of oral nutrition supplements  is essential to recovery. But is the right nutrition enough to win the war? Is nutritional alone going to do it? The answer clearly will leave us no.  Calorie delivery alone won't stop lean body mass loss. Giving enough nutrition will slow it. And I think that's the baseline we all have to achieve.  We have to give good basic nutrition if we want any of our other exercise or anabolic interventions to work. But by itself, we all know it's not gonna do.  You can't eat your way to being fit and to gaining muscle by itself. And again, we're not evolved to survive these kinds of injuries.  Our body doesn't know when to turn off the catabolic signal. Hypermetabolism and metabolism can persist for months to years after ICU stay.  A burned child will remain catabolic for two years after an ICU stay. And so this can be quite dramatic. So is there things we can learn from elite athletes  to help our patients? And I think there are, and I think taking the right anabolic agents can help. And so I think we need to find ways to consider that as part of our care.  And one of those agents is testosterone. And again, this shouldn't be given in the acute phase or the first few days of ICU, but the post-acute phase data for this  is much more promising. So again, testosterone levels in the ICU drop dramatically. And so I check them often. And almost everyone I check is severely deficient  or even zero within three to five days. And this has been published. I'm not the first to show this by any means. We know that within three to five days,  everyone's testosterone level is exceedingly low. And when this has been given back using oxandrone and burn injured patients, we've seen dramatic improvements in survival  and reductions in time of wound healing and numbers of surgeries. There's lots of positive data and also for functional recovery in burn patients.  So this is widely used and standard of care in burn centers around the world, even in third world countries, South Africa, India, and other places. But is it safe?  You always are gonna get asked the question, is it safe? Does it increase cardiovascular risk? Is it going to be okay for my patients?  Well, the answer is it does not increase cardiovascular risk and it is very safe. It in fact reduces cardiovascular risk. And I can't say that strongly enough.  Testosterone supplementation in deficient patients reduces cardiovascular risk. This is one of the many studies that show that. This is 43,000 subjects studied in the Kaiser studies  and they are in the Kaiser healthcare system. All testosterone deficient randomized or it was an observational study, sorry, receiving either testosterone replacement  or not in an observational way. And the patients who received testosterone replacement had significant reductions in combined cardiovascular events,  stroke events and cardiovascular alone events by 30% by a third on average. So significant reductions in cardiovascular adverse outcomes  in our mountain health has shown the same data, even in patients with coronary heart disease, they should reduce risk of cardiovascular events  and stroke events in these populations. So this protects you actually, it looks like when you were repleting people who are low. So again, I think a total testosterone is fine.  You don't need to check a total or free it costs more. Total testosterone has come back very quickly.  94% of patients when this is studied are severely deficient by day three. These are the doses you can use. Oxandrolone 10 milligrams, POVID is perhaps the best.  It's purely anabolic and can be given orally, which is really a plus. Testosterone suprinate is the standard. There shouldn't be an R in there.  Testosterone suprinate is the standard 200 milligrams IMQ two weeks that's been used for many, many years in the outpatient setting. And then you need to ensure adequate nutrition  or this is not going to work. This is a recent publication that myself and Rosemary Kozar and others, Steve Wolf have put out and we cover the different testosterone agents  and how to think about using them and sort of how they're used in other settings with references for all of this, if you want to learn more about this.  And this was the sort of etiology and treatment for the post ICU physical disability that we proposed that clearly all the factors that ICU brings upon the patient  lead to catabolism muscle weakness. And this leads to physical dysfunction that we must address. And so again, we need therapies, structured exercise, physical therapy,  we need anabolic agents and we need protein. We need all three to recover our patients. And so I think this is our best chance,  this triad of recovery interventions to improve outcomes. So again, this is the patient we want to get. We want to get a patient back to their exercise,  back to their quality of life. And what role does exercise play in all of this? Well, there are already studies combining exercise and nutrition.  This is the NEXUS trial some of you may have heard of. This is Darren Highland and Dale Needham and Renee Stapleton. And it's a multicenter trial looking at in bed ergometry  with amino acid IV supplementation. And it's ongoing at multiple sites across the U.S. So it's funded by NHLBI and Clark Files.  I have to thank he and Dale for this slide and information. They're doing also some mechanistic trials looking muscle biopsies and other mechanistic outcomes.  So this is a really exciting trial. It has a great paper if you want to read about how they designed this trial right there. Now, this has actually been looked at  in a neuro ICU population in a pilot study, looking at neuromuscular electrical stimulation cycling and looking at high protein supplementation.  So electrical stimulation and high protein supplementation and the patients who got the neuromuscular electrical stimulation and high protein had improvements of post stroke day 90  or post bleed day 90 on the SBBP, which is a standard physical function test in the modified Rankin scale. And they also had less muscle atrophy, right?  For muscle to grow and for to maintain a muscle size, you have to have contraction. You can't just passively be cycling. You need contraction and motion to optimally grow muscle.  And that's why contraction is so important. That's what electrical stimulation does. So this is a nice paper that Dale Needham shared with me.  So again, this appears to be feasible and safe in post-stroke patients and may reduce muscle wasting and have some benefits long-term for our patients.  So again, combination of protein and neuromuscular stimulation. So this is another great concept paper for those of you interested in this topic that Darren Hyland put out.  This was in the preparation for the NEXUS trial. And then in terms of how you look at outcomes for these trials, the NIH has funded Dale Needham and his group  to create an outstanding improve LTO, improve long-term outcomes core set that we all should be using in our research for our patients. And so I encourage you to join this website.  It's free and see all the amazing work that Dale and his group have done to help us think about how to measure and do studies in this area. So, but can we learn from elite athletes  to take this to the next level? If someone was training for the Olympics or for a marathon, they would do things that we aren't doing for our ICU patients,  but that could perhaps benefit them a great deal. And it doesn't involve sitting on a cycling recumbent bike like this. It involves getting tested and studied like this.  And this is cardiopulmonary exercise testing that we're doing at Duke and lots of other centers around the world are doing as well. And it measures all kinds of exciting things.  And it really gives us a lot of information, VO2 max and our weight threshold. And it lets us target exercise in a way I'm gonna show you.  And it teaches us about how patients are metabolizing and how their mitochondria are functioning. Why is this so important? Well, let me tell you about another patient.  This was a burn patient I cared for a number of years ago. His name was Joshua. He's an amateur athlete in Colorado. Had a full thickness burn, 37%. He got better very quickly.  He was only in the hospital 24 days. So less than we would expect. And he went back to his life and a few months later tried to start cycling  and riding his bike even again and exercising. And he had incredible difficulty. Let me go back. He couldn't even ride up a hill outside his house  without having fatigue and having to walk his bike. He couldn't ride for more than five minutes. And he was stunned by this and he tried and tried  and tried to improve without success. So he came to Colorado and underwent an exercise test with Inigo Sammola, one of our real elite.  He was a Garmin Tour de France coach, CPET testing expert. And what CPET testing can tell you about is you can actually look at substrate utilization.  And again, remember fatty acids can only be used in the mitochondria where glucose and carbohydrates can be used in the cytoplasm. So you can learn a lot  about mitochondrial function from this testing. This is a world-class athlete looks like on this testing. They can use fat, as you can see in that red line  out to very high workloads and they'll maintain the ability to use fat and only shift to carbohydrate oxidation at very, very high workloads as they get to max effort.  So they have a very high mitochondrial density and ability to use lactate and fat very efficiently. So what an obese diabetic patient looks like  when they're tested, they have a very poor fat utilization, only at very low workloads can they use fat, which is why it's hard for them to exercise  at much intensity for any length of time. And they quickly increase their carbohydrate utilization and their lactate generation. So again, this patient who's unable to bike up  even a hill six months after they leave the hospital, what was his data on CPET testing? So you can see he could use no fat utilization at any workload, even very low workloads.  Inigo Sammola tested 10,000 people at this point. He's never seen a patient like this, but he'd never tested an ICU patient. And so no fat oxidation at all at any workload,  only carbohydrates. His mitochondria will not function in any way, shape, or form. We retested him twice trying to show this was true. And we saw the same result a few weeks later.  So again, no mitochondrial function. And so he was placed on a heart rate specific HIIT training program using nutrition and exercise, which we'll talk more about.  And a few months later in October, his fat oxidation returned. We were able to rehabilitate his mitochondria using HIIT training and return to fat oxidation in this patient.  And he was able to recover this, where before he was not able to use it at all. So this was, again, treating the mitochondrial dysfunction  of critical illness with targeted training. He's now a competitive cyclist, competing 160 kilometer bike races. He got his life back,  but it took this kind of testing to target our care. And so how many of our patients will continue to suffer from the post-exercise and post-ICU exercise dysfunction  and never walk or even run or bike again? So personalized exercise and nutrition training is becoming a reality. We can do this. The future is now. We're doing it at Duke.  We're planning it for trials. And here's some personalized prehabilitation data that we want to show you. This is John Whittle and Jeroen Mullinger again,  who you've heard me talk about. This was a trial to optimize very large, high-risk surgical patients before surgery using this technique. This is one of the patients we optimized.  Michelle was coming for bladder cancer, for cystectomy. She was very debilitated, was on oxygen using a walker. When she came to us,  we put her into a four-week high-intensity training protocol basing her heart rate targets and her goals three times a week at home on her CPET testing.  So we structured and targeted or personalized her exercise based on her first CPET. And then she came in three times a week to an outpatient rehab center  and did these with a little card you put in the bike that took her through an exercise routine, a HIIT routine. And so there's a protocol for this that Mike Rochot and Denny  and his wife in England have developed. We use that. We included high protein ONS with HMB after training and in the morning on training days  and then twice a day otherwise during the week. And you can see that she started out with a fairly high body fat mass and a fairly low leg lean mass.  And in four weeks, just under four weeks, we reduced her body fat significantly and we increased her lean leg mass by almost two kilos, by over a kilo.  And we did this in a very short period of time in a very debilitated patient. And we increased her VO2 max and her METs significantly. You can see we increased her VO2 max  by about 200 plus 250 plus, and we increased her METs by over one. So again, a VO2 peak by a whole measured exercise unit increase. So that is equal to a 15% reduction  in mortality risk lifetime if she can maintain it. So this is a big effect in a very short period of time. We're taking this to the next level we hope  with a post COVID study where we're going to do CPETs at discharge of COVID ICU patients and then put them on a home monitored using iPhones and iWatches  in high intensity training program. They do three times a week monitored by a physical therapist in their homes. We are grateful to have received the 2021 Discovery Award  from the Society of Critical Care Medicine for a grant that we submitted, both myself and Wes Ely submitted. And we're going to be training  a really exciting young person, Matthew March, who's a new attending at Vanderbilt, who's very interested in this. And we're gonna look at cognition and physical function  looking at this, and we hope to submit to the NIH as well. This is a, again, we're going to do face mask portable CPET testing, which is now available.  We're going to buy instruments for all the centers and they do a step test in their hospital room before discharge. And then they go home with an iPhone and iWatch  and they do sessions three times a week for three months. And this actually was developed by a cancer physician, a BMT physician at Duke, Tony Sung. And we have preliminary data  in debilitated cancer patients that shows incredible adherence and compliance with these sessions and a 25% increase in VO2 by four weeks.  So you can see the patients have a target zone in green and we monitor them beat to beat with the iPhone and iWatches.  And we actually can coach them on the best ways to do this. They do this through stepping, they do this through walking, they can do it through cycling if they want,  but they're monitored and doing this. We had incredible adherence and compliance with this. And so this is the plan. We're gonna, sorry, I'm gonna go back to that.  We're going to do a structured plan where we follow these patients out to three months, and we're gonna bring them back and do CPET testing  and measure and do six minute walk testing and do measurements both at hospital discharge in three months following that. And so if you wanna read more about this,  these are some of the recent papers we've published on combining nutrition and exercise and some of these novel interventions, including anabolic agents.  I'm happy to share these articles with you by email. But in the end, what did it do for our patient we've been talking about, Elijah? So again, we've kept fighting for this patient  and what do we do to help this really, really aged patient who really was desperate to recover, recover. So we put him on the high protein ONS with HMB,  two grams per kilo per day of protein. He was on TPN for a short time. We started testosterone cypionate. We started creatine for this patient.  We replaced his vitamin D that was quite low. And then he started very aggressive exercise and recovery  doing walking and chair sit to stands. His family brought in their own dumbbell weights. He had exercise bands in the bed and he aggressively combined all of these interventions  and walked out of the hospital 28 days later on his 90th birthday. So the patient was committed. We were committed. We did structured exercise for him.  We did structured nutrition for him. We made measurements and he left the hospital, which many people said there was no way we'd ever get him well, but it is possible.  This is actually him. He gave me permission to use this picture. He lived for another year and a half. Ultimately was able to see his family, was able to spend time with his family  and they were all incredibly grateful for the almost another year and a half, over a year and a half that he got to spend with his family. So this was really a gratifying save.  So in the end, we must train our ICU patients recovery because this is the marathon of their lives. And that change needs to start with us.  I think we need to be good examples for our patients. Because in the end, as I've said before, we need to be creating survivors of our patients and not victims.  And we need to do better than we're doing and use all this opportunity, all this new technology to prescribe the right nutrition exercise doses  in the right patient at the right time and be able to measure it, which we can do. And these are all the new technologies that are available to all of us.  And I think very soon, I think all of these things are things we can be doing and all of the different other interventions that are possible. Again, this is the nutrition delivery  that we're suggesting and feel free to ask for this. I'm happy to send you this slide and this picture. And then of course, exercise in addition to nutrition  is essential and it's something we all struggle with in the US and around the world. I think this is something that just shows us we can all be better.  This next video is from a very small third world ICU in the rainforest of Brazil. This is a patient doing bed squats on the ventilator  in a government hospital that doesn't have the resources most of the hospitals do. So if they can do it, we can do it. And then I think the other thing  that we all hope to dream to have is these exercise weight training beds to increase strength where you can do squats right in the bed.  And these devices are actually available commercially. I hope, I dream of us getting one soon. So again, I hope we can take patients using all these technologies,  combining nutrition and exercise to have them again, be walking very soon and then actually save some lives and give back quality of life to patients like Elijah  and have them leave the hospital looking like this or at least like this. So again, thanks for your attention. Feel free to follow on Twitter and Instagram  for more of this research and more findings that we share all the time in our data. And feel free to email me for any of these papers or email me any questions at any time.  Thanks for your attention and enjoy the rest of SCCM. Take care. ♪♪

Video Summary

The video features two sessions on critical care nutrition. The first session, led by Dr. Jay Patel, focuses on the timing and dose of enteral nutrition in critical illness. Topics include gut dysfunction, early enteral nutrition, and the use of trophic and hypocaloric nutrition. The second session, led by Dr. Paul Wischmeier, discusses personalized nutrition in the ICU and the combination of nutrition with exercise. Topics include assessing muscle mass and quality using technologies like muscle ultrasound and bioimpedance analysis, measuring energy needs with indirect calorimetry, and optimizing nutrition therapy. Dr. Wischmeier highlights the potential benefits of these measures in improving patient outcomes. In another part of the video, Dr. Paul Whipple discusses the importance of personalized nutrition and exercise plans for ICU patients. He shares his experience with a patient named Elijah and discusses the use of modern technologies to track progress. Dr. Whipple presents data showing the benefits of nutritional supplementation and high-intensity exercise for ICU patients. He also discusses the use of cardiopulmonary exercise testing to target exercise interventions and rehabilitate patients' mitochondria. Dr. Whipple emphasizes the importance of comprehensive nutrition and exercise programs in creating survivors and not victims of ICU patients.

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

Differentiate the pathophysiology related to continuous and intermittent enteral nutrition
Appraise the evidence behind prepyloric versus postpyloric feedings
Assess the risks and benefits related to permissive underfeeding
Explore best practices related to enteral nutrition administration

When Less May Be More Jayshil Patel Personalizing ICU Nutrition: New Tools for Objective Assessment of Nutrition and Muscle Mass Paul Wischmeyer Nutrition and Exercise Go Hand in Hand Even in the ICU: Review of Current Knowledge Paul Wischmeyer

Meta Tag

Content Type Presentation

Knowledge Area GI and Nutrition

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Enteral Nutrition

Tag Calorimetry

Year 2021

Keywords

critical care nutrition

enteral nutrition

gut dysfunction

trophic nutrition

hypocaloric nutrition

personalized nutrition

ICU

muscle mass assessment

indirect calorimetry

nutrition therapy

exercise plans

patient outcomes improvement

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