You've given the title of therapy to nutrition and that puts a big onus on us. It turns us from cheerleaders to stewards of this therapy. And I think in the next 15 minutes I'm going to try and push us to examine the true evidence for everything that we believe nutrition does. And I hope that in the interest of time, I will use my own personal synthesis of the available evidence and tell you how I have interpreted the various guidelines in a stepwise fashion as I am at the bedside. I don't have any conflicts of interest and I won't endorse any commercial products, but I have been chair of the Pediatric Guidelines Committee for both organizations, SCCM and Aspen and I continue to be. So maybe some experience with how this process works and I may show you a little bit of that. So as I said, to follow on from Dr. Irving's big responsibility that she's lumped on nutritionists, I'm hoping that we go beyond intuition. We go beyond the pathophysiologic premise for the benefits of nutrition. We go beyond anecdotes and observational data to actually assess the true evidence for nutrition. So we look at the hierarchy of nutrition studies out there and like anything else in our field, it is a pyramid and right at the base is the preponderance of expert opinion, myself included. Case reports, cross-sectional studies, well-conducted cohort studies, these observational studies are not to be dismissed. But as you go up the pyramid, not only do the number of studies with higher confidence in the results decrease, but also the bias decreases. So there is the desire to form evidence-based guidelines that incorporate some of this high-level evidence. Now for the purpose of this talk, I cannot possibly show you individual studies. There are, I counted, 436 printed pages of evidence-based guidelines in just the last seven or eight years. On the left, you see some of our adult critical care guidelines, both from SCCM, Aspen and Aspen, our European colleagues. And then on the right are our pediatric guidelines. One thing that's common between them is the level of evidence that's available and it's frustrating with every guideline, there is a rider that says, however, we need more evidence. So at some point, you expect the guidelines to change your practice and you need to be patient, but at that point in time, how do we incorporate what's available with the best of our scrutiny into bedside practice? So here's an example, the Aspen Pediatric Guidelines are the latest in pediatrics that came out a couple of years ago. And a lot of overlap with our Aspen Guidelines that were three years earlier. They made 32 recommendations, but 80% of those recommendations, 85% were either level C, level D, or what we call just best clinical practice, which means a bunch of so-called experts got together, came to consensus and says, you know, guys, this seems prudent based on what we have. So that's fair. And then on the adult side, the Aspen update, which was in 2022, put in even a harder scrutiny and said, we are going to look at the randomized control trials. Dr. Patel was one of the co-authors and he might have more insight into the rigor for this, but it appears that when you actually test for the high level evidence, we still don't have strong differences between intervention and control for many of our so-called beneficial therapies. So we start with that premise, but having said that, how do we incorporate what's available? Guidelines process is interesting. In addition to the evidence, one needs to be providing clinical context because one size does not fit all. And in addition, patient values and preferences are not adequately accounted for when we come up with systematic guidelines from organizations like SCCM and Aspen, and we need to do better. You take the best available evidence and try to put them through a systematic process. So here's an example wherein on the left, you take every level of evidence, which includes meta-analysis, the highest level of incorporating all RCTs, all the way down to expert opinion. You put them through a quality rating because you can have a very superior, high quality observational study, and you at the same time can have a poorly done randomized control trial. This process allows you to provide a quality rating, and based on that, the evidence table then allows a group to form consensus around practical guidelines. This is an example of how a quality of evidence can be downgraded or upgraded based on the clinical context, which means if the net benefit completely outweighs harms, even though the level of evidence was not very high, it can be upgraded to a strong recommendation. I show you this just so the curtain is lifted behind the guidelines process, and when you read guidelines, it's important to note the process that they undertook in order to fine-tune the studies into clinical concepts. The European folks used the Scottish intercollegiate guidelines, which is a similar framework. So having said that, let's now begin to explore what is out there. Before we go into stepwise guidelines, the goals of nutrition, as beautifully outlined by Dr. Irving, are to try to offset the metabolic stress burden. You heard, you saw the cartoon, and our goal is while critical illness imposes that burden, can I offset some of it so that the patient escapes the ravages of that metabolic stress? Can I do that safely, which means I will handle the specialized nutrition therapy with minimal complications, ENPN, and then I will hold myself to accounting for the outcome that was improved or not based on that therapy. And therefore, the three main questions that we ask in guidelines are the classic questions that you ask for any therapy, whether it's nutrition or any other pediatric critical care therapies, what's the dose, what route am I giving this dose, and when. And unfortunately, while we try to parse them in a randomized controlled trial and create an artificial situation where we control for one or the other, these three are intricately linked and they don't exist in isolation. So let's get started with some of these questions and how we individualize them for patient and disease characteristics, knowing fully well that not only are children not small adults, but even adults in themselves are not all the same. So here's the task. So let's start with some of the questions that practice recommendations put forward, and like I said, 438 pages. So I'm going to distill it into slides that will take you through a patient at the bedside. So we'll talk about screening, nutritional assessment. We'll talk about the prescription dose, predominantly focusing on macronutrient dosing and maybe some micronutrient concepts, and then the route and timing intricately linked together with some controversies and some new insights. And finally, some special considerations, some areas which are exciting but don't have a lot of evidence, so we need to tread cautiously. So as you go from left to right on that previous slide, the strength of evidence is expected to be better, but the research is scarce, and therefore the confidence in the guidelines or recommendations become diminished. What we all agree on, adult or pediatrics, is one must make every effort to assess every patient that comes to the door in a critical care unit and try to identify those that are at high risk. Patients who are malnourished at baseline, at high risk of becoming malnourished, or at high risk of patients who may have poor outcomes. The concept is that these are the patients that we would try and target with limited resources to provide the nutritional therapies with intended outcome improvement. There are lots of different scoring methods out there in adults. There are none in pediatrics that are validated, but the NRS, the nutrition screening, and the ICU nutrition screening, and the subjective global screening, and the global leadership in malnutrition screening, these are all existing out there to help us identify these patients. Essentially, what you need is a nutrition focused exam and a history that allows you to identify vulnerability, and anthropometry continues to be used. We now use these scores of anthropometric parameters, knowing well that some patients with fluid shifts may have inaccurate anthropometry. Finally, this is not complete until you also assess for comorbidities, which might alter nutrient requirements, GI function, which might alter your ability to provide nutrients, and aspiration risk, which might give you unintended side effects of nutrition. Finally, risk of refeeding, Dr. Evans will go through some of it in terms of refeeding and nuances of how we monitor for it, and all this in the context of time. Let's talk about the concept of time. This has been a big shift in the last 15 years. We now believe, it's still a strong belief, that there is a so-called acute phase of critical illness, and then there is a so-called non-acute phase. The acute phase is divided into early and late, and it's been talked about for decades, but what we understand from Dr. Irving's cartoon she showed of metabolic stress is that during this acute phase, three things are happening. The first one is that there is profound catabolism, so there is breakdown of essentially protein, predominantly, but every other substrate in your body, as some kind of an ability to deal with the nutrient intake deficiency. The second thing that's happening is that there may be alterations in the requirements because there may be inflammation and metabolic demand, but what's interesting is that in addition to the substrate breakdown as a side effect, some energy is endogenously produced during this early phase. There appears to be a little bit of energy coming as a respite, if you like, during this acute phase. It'll become evident that as a result, during the acute phase, with the neuroendocrine cascade resulting in insulin insensitivity, there's also an anabolic, so-called anabolic resistance. If you have anabolic resistance and you have some nutrients endogenously being produced by the breakdown, one might want to be careful about prescribing the energy goal, protein goal, in this acute phase. At some stage, the shift towards an anabolic phase for a nutritionally driven crowd, that's what we'll call it, will allow you to then proceed to a higher, or a relatively higher goal. However, if during the acute phase you become overzealous in your prescription, there is risk of overfeeding, and therefore, the timing of the shift is essential, and while we firmly believe this happens, we have absolutely no idea of when it happens, so there may be a switch happening in some patients on day two, day one, day three, and some on day eight, so it's essentially a moving target, and hence the individualized prescription, and hopefully in the future, some biomarker-driven insight into this switch would be very useful for us. Until then, we use predominantly weight-based equations, and we won't go into this. It's now been 30 years since we've shown with indirect calorimetry that these can be often wrong. Having said that, we don't have any recourse, because indirect calorimetry may not be available or not applicable, and therefore, we continue to use estimation equations, and some of the commonly recommended by guidelines are, Penn State seems to be popular in the adult literature, Dr. Patel and Dr. Evans can guide us if there are new equations coming down the pipeline. The Schofield and the WHO for Pediatrics still remains our go-to, and what we've seen as a result of this awareness of endogenous breakdown and the awareness of the risk of overfeeding, we've gone from these weight-based adult calculations of 25 to 30 to more like 12 to 25 kilocalories per kg per day in that acute phase, so an overall dialing down of our estimation and therefore prescription of energy. The VCO2 and VO2-based equations are something to watch for, not a lot of evidence yet, but the concept is on the metabolic window that can be opened by things like indirect calorimetry. So let's focus on indirect calorimetry. It is coming back with technological advances as once again being extremely emphasized as the only true close to accurate estimation or measurement of energy expenditure. So here's carbon-based nutrients, carbohydrate, protein, fat, they're all just combinations of carbon, hydrogen, and oxygen. And in order to generate energy at the cellular level, these get oxidized, and they release heat, essential for survival, and they release CO2 and H2O as byproducts. If I could measure heat at a global level, minute to minute, I may be able to estimate the metabolic activity at the cellular level. You might be able to do it in you and me, but not in a critically ill patient, where we resort to indirect measures, and not at the cellular level, but at the gross bulk level at the ventilator interface, or at the interface at the breathing canopy, where you can measure minute to minute oxygen consumption and CO2 production as an indirect insight into metabolic activity. And therefore, you can use these equations to try to convert those gas exchange measurements into actual energy requirement. And this comes close to reality in most cases, and where available, it's now recommended universally by all guidelines even more emphatically to be used. However, as we know, in most cases, these energy goals are not driven by indirect calorimetry because of resources, availability, or patients not able to give you accurate indirect calorimetry. So being mindful of these concepts, and to avoid overfeeding, the guidelines now recommend, especially if you estimate the goal, to try to aim for 2 thirds of the goal. I use 2 thirds. It's been shown on our observational studies, but also in many of the adult trials, somewhere between 60 to 70 percent, so 2 third of the goal in the first week. So once again, a slight calibration, a little dialing down of enthusiasm in pumping nutrients in the acute phase. These should be individualized, and if you have a magic window to open up into the switch into the anabolism, maybe you can go from one phase to another. But in most cases, the goal is to prevent overfeeding. Now, having said that, the protein dose is a big head scratcher. And I will summarize tons of data in these guidelines by saying we do not know what protein dose is associated with improved clinical outcomes. So that does not mean the guidelines don't give us recommendations. So here's what the Aspen and Society of Critical Care Medicine guidelines for adults and pediatrics still think that in most patients, particularly some, there may be a net loss of lean muscle mass, negative protein balance. And you can prevent that by giving, to some extent, 1.2. You may start at 0.8 and then go gradually to 1.2 or 1.5, and in some cases, like burns even higher in the first week. However, this is not proven to be beneficial for clinical outcomes yet in clinical trials. And what's happened more recently is we've begun to understand the negative connotations of overzealous amino acid administration, especially through PM. So having said that, there are a lot of trials currently, well, enough trials going on in adult and pediatrics, particularly two trials in pediatrics. So watch this space, and there might be some clarification of what the real dose is. A quick plug for our trial, which starts enrolling this month. It's a two-center trial with Watson Children's and Johns Hopkins. And we are looking at not just protein dose, high versus low, but also the dosing of an exercise along with protein to try and get a complementary effect from the two. We look at muscle markers, but also strength and functional outcomes. Interesting stuff coming down the pipeline for protein. Once you've determined the prescription, the route of feeding still remains enteral nutrition. And Dr. Irving showed you some of the pathophysiologic rationale. Recent trials in adults, and I'll let some of our adult colleagues go into that in more detail. But for high-risk patients, as Dr. Patel will allude to, there is some caution with overzealous enteral nutrition. Yes, enteral nutrition is good, but the goal is not to overdo it. And the NUTRIREA-2 trial, which is, I would recommend you read it, where an aggressive strategy of ramping up within 24 hours in sick adults was met with actually more undesirable outcomes. And as a result, we've learned that enteral route, as long as you're not overfeeding, as long as you're going either trophic to begin with, but then stepwise increase towards two-thirds of the goal within the first week. And that seems to be rational. And as Dr. Irving noted, most trials in adults and observational data and pediatrics still suggest 24 to 48 to 72 hours. As we speak right now, my colleague, Ravi Kimani, is probably showing his nutrition slide for the Palik-2, and he will say within 72 hours and try to get to goal. And he will say maybe 1.2 to 1.5 grams of protein. So it sounds like we still believe in early enteral nutrition. And in most patients, when tolerated, it is actually the go-to strategy. The new guidelines have now emphasized the role of stepwise algorithms, where you get guidance as opposed to coming back every day and reinventing, should we increase? These are nurse-driven bedside guidances that allow you to stepwise increase, but also to assess and then remedy any intolerance. So these are great papers, and you can have your own guideline, which leaves you with some bedside guidance. Having said that, and you'll hear more about gastric residual volume from Dr. Evans, interesting shift. We in pediatrics used to measure GRE, so do adults. You will hear subsequently there's not much enthusiasm for both measuring gastric residual volume, but certainly for using it as the sole marker of stopping nutrition because it's a big sign of intolerance. Maybe not so. We have a lot of data from our center in the pathophysiology of this, and as Dr. Evans will show you in the adults as well. Once you choose enteral, we still stick with gastric, still safe. If you use these stepwise bedside guidelines, which are pragmatic, you will avoid aspiration. You may use post-pyloric, and 20% of patients in worldwide PICUs do use post-pyloric feeding to try to decrease aspiration risk and intolerance, but gastric is still predominant. As long as it's gradually increased, it is well tolerated. Not much data on continuous versus intermittent, two trials, one large worldwide data from our group, and overall it appears that right now you may choose one or the other. What's exciting and coming down the pipeline is, do these modes of feeding, continuous versus intermittent, actually influence the way you synthesize and assimilate protein? Exciting research ongoing. Early EN is safe. You will hear more about this in special patients with Dr. Patel, but a caution from the neutrivia too, in terms of patients with septic shock, especially if you are escalating vasoactives. There is no need for overzealous feeding in these patients, and you can wait safely. No role for early PN if trophic feeding is going on, and you are focused on enteral nutrition. Having said that, in patients who are either not fed for the first few days, or just on low volume, the role of micronutrients to prevent deficiencies is emphasized. Most trials did provide IV micronutrients because the enteral formula, which has enough micronutrients, is not being given in adequate doses. Furthermore, if the trophic feeding or the low volume feeds continue, now you begin to worry a little bit, and there may be a role to try to prevent these deficits on an extended period, particularly in high risk patients, and this is not desirable. You heard the pathophysiology from Dr. Irving. So the role of supplemental PN. This is an exciting area, and a lot of controversy, adult trials, nothing much in pediatrics except for our international observational studies, but if EN delivery is either negligible or very low volume, there is now recommendation to consider supplemental PN, especially in high risk patients. The timing of starting supplemental PN remains controversial, so if you read the EPANIC and the EPANIC trials, in patients the way we interpret are not at high risk, we would wait for seven days. There is no rush. But if you have high risk patients with existing malnutrition, most centers, both adult and pediatrics would argue, and certainly in adults with some trial data, somewhere between four to seven days in the ICU, people do start supplemental PN, and we can debate this and how you interpret individual studies, but it's exciting. One thing we've learned in the last 10 years from the various adult trials and pediatric observational data is that PN is safe. PN should be available to be safely used in patients where it is truly necessary, as we pointed out. It may be used as a supplemental PN at the right time, whatever that is, and you have play there, and if using good aseptic conditions, it is not unreasonable. And finally, if you're using a PN strategy which is prudent, feel free to come off PN once your enteral nutrition starts ramping up again. We would stop PN once we get to 50%. We wouldn't wait for two-thirds, because we know it will get there by the next day. So you can have some pragmatic PN stopping strategy. So this is how we interpret the current data. Finally, a few things in the pipeline. We in the United States, unfortunately, watched our European colleagues with great fascination and frustration, as for decades they had access to different kinds of emulsions, lipid emulsions. We were stuck with soybean, and we thought, theoretically, the soybean oil had unfavorable inflammatory properties, and the concept of the immunomodulation favorable, and the anti-inflammatory effect of some of these fish oil-based, or mixed with MCAT and fish oil and olive oil, we would have loved to try that. So it's only been a few years since we in the U.S. have access to these. So this is research in progress. And if you read guidelines appropriately, they would tell you, at this point, we don't have evidence for one or the other, so they leave it to you. You may use mixed oil or fish oil or soybean oil in your practice. Having said that, a lot of accumulating experience. So if we come back next year, we may already begin to move the dial one way or the other. And we should not presume anything until some of this high-quality evidence comes in. Standard polymeric EN formula, still your go-to. Don't get excited by complex formulations. These formula have enough micronutrient trace elements. As long as you're giving more than trophic volumes, as I mentioned earlier, you may have to supplement to prevent deficiency if all you're doing is very low volume of these formulas. Disease-specific formulas, not much evidence. There was excitement for renal, hepatic, pulmonary, but the guidelines do not recommend. And finally, immunonutrition. I remember phases of this talk over the last decade where there was so much excitement. And that still remains, because the concept of therapy is massively enhanced when you say, I have some nutrients which don't provide just nutrition, but actually modulate. And unfortunately, right now, the guidelines have summarized that there is no evidence for routine use. TBI, severe burns, some trauma patients, ongoing studies. Still some enthusiasm. But we are not using arginine for septic shock as we did 15 years ago. And glutamine, it's only available in an enteral formulation, is still not recommended for routine use. The last thing I'll tell you is the metabolic resuscitation. Very exciting area. Septic shock, MADS, SIRS, still bothers us. Mitochondrial dysfunction in these settings worsen outcomes. So the concept of providing some mitochondria-targeted therapies, thiamine, selenium, zinc, vitamin C, vitamin E, in high doses, not to prevent deficiency, but actually in high doses, was very exciting. And it still remains. And particularly what got exciting with certain reports from individual centers was the combination therapy. One such therapy is known as HAT therapy. We just wrote editorial on that summarizing the recent pediatric evidence. But if you look at the adult and pediatric evidence, the HAT therapy, hydrocortisone, ascorbic acid, and thiamine, currently there is no accumulated evidence of benefit from that. And we are not doing that. And similarly, high-dose antioxidants, in the absence of deficiency. So there are centers where you measure them. And in high-risk patients, there may be a role to replenish. But in general, these high-dose antioxidants for their metabolic resuscitation effects are not routinely recommended. So I'll summarize here. We've moved the needle. We have calibrated some. We have risen to the newfound tag of therapy. And we are doing a gut check. That was my one allowed. But we do need a gut check from time to time. So let's wait and see what the evidence shows. Individualizes the name of the game. Stop believing in one size fits all and these cards that say any patient that comes will be fed like this. Indirect calorimetry. It's back. The technology is now more accessible. So hopefully in the next five years, we may see trials of indirect calorimetry-targeted driven therapy for energy. Protein dose, look out. We might provide you with some data from our center and Johns Hopkins soon. Until then, gastric EN with a judicious early start, a careful trophic initiation, and go up gradually to two-thirds of the goal in the first week. Be careful. No overzealous and excessive feeding in the very early stage. I showed you the rationale for not trying to do that, but also studies. And advance with some guidelines at the bedside. Don't presume that every day someone magically would have advanced stepwise, check every two, three hours, and advance or not or come back based on those stepwise guidelines is what is recommended. You'll hear more how we have kind of de-emphasized the gastric residual volume. PN is safe. Don't let anybody tell you otherwise. There are centers that are using PN, but you wield it with a lot of respect. It should not be overzealous as in the intervention arms in the PANIC and PIPANIC trials. Supplemental PN in high-risk patients, okay to start at four days, four, five, six, seven days. But in a sense, a more nuanced and a respectful approach to using PN. And finally, we will not use routinely some of these magic formulas, but there may still be patient populations where more data is forthcoming and we will be happy to revise these guidelines. And finally, micronutrients. Entral products do have them. If you are advancing as you are expected, no need to. But if you are not, if your patient is fasting, micronutrients to prevent deficiency, those mega doses may not have a routine application. I'm going to stop here. All I will say is that the big challenge for us is the implementation of some of these guidelines at the bedside. And that's a new emphasis in our field in various, you heard the ABCDF bundle, similarly in nutrition. I thank you for this opportunity.

evidence-based guidelines

nutrition therapy

hierarchy of nutrition studies

individualizing factors

enteral nutrition

micronutrients