So thank you very much for giving me the opportunity to talk about protein and to address the question whether protein is the most important substrate in critically ill patients. I have no commercial conflict of interest. I'm a PI on a PI-initiated replenish trial that I'm going to mention briefly. So protein is affected during critical illness. I'll touch on this and I'll talk about how much protein we are giving our patients currently in our ICUs and what would be the optimal dose in general critically ill patients and in special conditions. And I'll touch on certain aspects of protein dosing and exercise and protein timing. So during critical illness, as my colleagues have mentioned, there is significant proteolysis induced by activation of the neuroendocrine pathway with higher norepinephrine, epinephrine, ACTH, TSH, and growth hormone. By the inflammatory response, this will lead to proteolysis mainly in the muscles. And as a result, free amino acids are released in the circulation and used in the liver to generate acute phase proteins to also be utilized for gluconeogenesis and to be used also to generate immunoglobulins. So it is an important part of the response to critical illness, but the price for this is loss of protein and muscles. And this negative nitrogen balance that results from critical illness could be substantial. In one study, it's estimated that a critically ill patient by day 7 lose about 13% of muscle mass and maybe 18% by day 10, especially in those who are in multi-organ failure. And the result of the negative nitrogen balance could be significant. There are significant associations with immunosuppression, poor wound healing, with ICU-acquired weakness, with increased mortality and delayed recovery. So it's certainly a natural thing to think that we should give our patient exogenous protein to make amino acids available so this would mitigate the negative nitrogen catabolic state. And this is supported by observational data that showed that outcomes are better in those patients who are receiving higher amount of protein. And on this basis, current clinical practice guidelines recommend that we give our patients who are in the ICU doses that are higher than what healthy individuals should get. So the WHO recommends for healthy individuals to give 0.7 to 0.8 gram per kg of protein. And for ICU patients, we recommend something in the range of 1.2 to 2.5 gram per kg per day. So significantly higher. So are we sure that this is what we should be doing for our patients? Not very much. In fact, the data supporting higher amount of protein are limited at present. And there are several observational studies showed the contrary, that either neutral association with outcomes or even some suggestion of harm. And it's believed that giving too much protein, especially in the early phase of acute illness, can cause harm by inhibiting the autophagy and increasing urine production. So how much we are giving our patients now in the ICUs? If you go to most ICUs, this is a survey that looked at patients across 200 sites. And what we are giving our patients generally, who are staying in the ICU for 4 days or more, we give probably about 51 gram of protein, that's 60% of prescribed. Certainly much lower than what the guidelines would say. For those patients who stay 12 days or longer, which is significant stay in the ICU, you'd expect we give a lot of protein, patients would get around 57 grams per day. Also this is parallel with that reduced amount of calories as well. So generally, we don't give a lot of protein. So what's the optimal dose? We don't know very much. There are several small randomized controlled trials. This is a systematic review of 19 RCTs. The total number of patients, 1,700 only, so most of the studies are actually small. And the pooled mean protein received in the higher protein group was 1.3. And in the lower protein is 0.9. So not a huge separation between the two groups. And the higher protein is not that high. So small difference between the two groups. And the difference in mortality was not significant in this meta-analysis. However, in five small studies, there was a reduction in muscle mass, reduction in the loss of muscle in patients who were receiving higher amount protein. There are some studies showing that higher protein may not be a great idea. This is a secondary analysis of the EPANIC trial. And the EPANIC trial is a clinical trial that randomized patients to early parenteral nutrition versus late parenteral nutrition and showed that patients who received early parenteral nutrition, which means higher protein and more calories, have delayed recovery. In this secondary analysis, the investigators tried to find out whether this delayed recovery is related to energy, higher energy, or it's related to higher protein. And what they found that it is related to or it's associated with the amount of protein and amino acids rather than to the energy or glucose dose that was given. This is another sub-study from the EPANIC trial where CT scans done on a small group of patients who received early parenteral nutrition versus late parenteral nutrition. And those who received early parenteral nutrition, which means more calories and more protein, did not have difference in the skeletal muscle mass, but they had more fat in the muscles. So giving more protein, more calories early, did not result in change or in the reduction in the muscle mass loss. This is a secondary analysis from our PERMIT trial, a PERMIT trial randomized patient to permissive underfeeding versus standard feeding. This is a secondary analysis where we looked at the association of protein dose and outcome. And to make a long story short, there was no significant association between the protein dose and mortality. And when we stratified patients by nutritional status, high nitric score or low nitric score, again there was no difference. But it's what I found interesting in this study that in patients who have received higher amount of protein, there was slight increase in the nitrogen balance. There was substantial increase in the excretion of urinary urea nitrogen. So as if when you give a lot of protein, maybe you retain a little bit of it and have anabolism, but a lot of it is lost in the urine. So this busy slide is not meant to go through every line, but it's meant to give two important points. This is summary of the clinical practice guidelines from Aspen, SSCM, and Aspen about the amount of protein in different patient categories. And what I wanted to highlight here, two issues. The quality of evidence, and my colleagues have emphasized this, all the recommendations were based on very low evidence or consensus. So we don't have a strong evidence for any of these recommendations. And it doesn't come as a surprise that the guidelines themselves are different. So the general ICU patient in Aspen give you a range between 1.2 to 2 grams. So there's actually considerable variation in the recommendation. The Aspen recommend 1.3 gram per kg per day. So I think this all a reflection of the little amount of evidence that we have for the amount of protein. So how about using nitrogen balance measurement to guide protein dose? We don't have a lot of studies, but the EAT-ICU trial, a small trial that randomized patients who are mechanically ventilated to the early goal-directed nutrition, where the nutrition was guided by indirect calorimetry and the 24-hour urinary nitrogen measurement versus standard of care based on the guidelines, Aspen guidelines. The study found that patients in early goal-directed nutrition received significantly higher amount of protein, about 1.5 gram per kg versus 0.5 gram per kg per day. And they received more energy as well. But the primary outcome, which is the physical component summary of SF36 at six months was not different, and mortality was not different. Protein dose in special situations, I'm going to touch on two or three conditions. One is the obese patients. This is an old study, but it's an interesting one, where it showed that obese patients during critical illness compared to lean patients rely more on catabolism of protein and carbohydrates, relatively speaking, compared to lipids. So as a result, obese patients, relatively speaking, lose more muscle mass during critical illness than lean individuals. And many patients who are obese, they start off with sacropenia and mitochondrial dysfunction and adipose infiltration of the muscles before critical illness. And when critical illness happen, the accelerated proteolysis and skeletal muscle wasting make things worse. And because of this, current guidelines recommend that we give obese patients relatively higher amount of protein during critical illness. So SSCM and Aspen recommend two grams per kg per day of the ideal body weight. The Aspen recommend 1.3 gram per kg of adjusted body weight. In patients with high nutritional risk, without going in the definition of what's high nutritional risk, that would be a different topic, but this is an observational study, looked at patients, the association of protein dose in patients with high nitric score and low nitric score, and it found that in those who are high nutritional risk defined by the high nitric score, there was association of greater amount of protein with lower mortality, but this was not seen in patients with low risk patients. So that's an interesting, but that's observational data again. But in renal and hepatic insufficiency, that's another interesting area for study. And I think it's important to recognize that during critical illness in patients with acute kidney injury, there's significant protein loss and altered amino acid hemostasis induced by multiple factors. The critical illness, the acute kidney injury, renal replacement therapy, all will contribute to the protein loss. Similarly, in patients with liver disease, there's actually significant protein loss as well. So current clinical practice guidelines recommend that essentially you continue with the same amount of protein that you would give to other patients, and suggest that we should not restrict the protein to prevent dialysis or to prevent patients from going to hepatic encephalopathy. So that's a common issue that we face in practice. Ongoing trials, I think probably in a year or two, we'll learn more about the protein dose in critically ill patients with the effort trial run by the Canadian Critical Care Trial Group. The target protein cluster randomized control trial by the ANSIX Group. The replenish, which is our trial, is ongoing for higher versus lower amount protein. In our trial, we're taking into account also of the timing. So the higher amount protein starts on day five of critical illness. Protein timing is another important topic. So the argument for giving high amount of protein early on in critical illness from day one is that we want to prevent muscle wasting. Protein is easily absorbed, etc. But there are drawbacks of giving high amount of protein early. There's increased generation of urea. There's inhibition of autophagy. There's really limited data to show that you're actually preventing muscle loss. So we don't know, but we need data for this. Finally, exercise combined with the higher amount of protein is one of the important areas for research. This is one clinical trial that has been published in mechanically ventilated patients. Higher amount of protein with early exercise versus control group showed that there was significant improvement in the physical component summary score at three and six months, and there was reduction in mortality. It's only one trial, but there are other trials ongoing. Hopefully, some of them will be released soon. And I think we're going to learn more about this in the coming months or years. So in conclusion, critical illness is associated with proteolysis and negative nitrogen balance. Current guidelines recommend that we give higher amount of protein than healthy individuals. Unfortunately, we're not doing that consistently. The amount of protein in critically ill patients remains largely unclear and is considered high priority for research. There are more data that are needed regarding the dose, regarding timing, regarding the type of protein, which I did not address, regarding the mode of administration intermittent versus continuous, and combination with other interventions such as exercise. And thank you very much. Thank you.

protein

critically ill patients

proteolysis

muscle loss

nitrogen balance