Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. This webcast features two articles that appear in the July 2022 issue of Critical Care Medicine. This webcast is being recorded and the recording will be available to registrants on demand within five business days. Log in to mysccm.org and navigate to the My Learning tab. My name is Thomas Zagmani and I'm a professor of intensive care at Cardiff University in the United Kingdom. I will be moderating today's webcast. Thanks for joining us. Just a few housekeeping items before we get started. There will be a Q&A session at the conclusion of both presentations. To submit questions throughout the presentation, type into the question box located on your control panel. If you have a comment to share during the presentations, you may use the question box for that as well. And finally, everyone joining us for today's webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete this. Your feedback is greatly appreciated. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I would like to introduce today's presenters. Ryan Haynes is training in intensive care medicine in London and is a PhD candidate at the William Harvey Research Institute, Queen Mary University in London. His research explores the impact of critical illness on longer-term outcomes with a focus on acute kidney injury and persistent critical illness. Dr Deborah Riberia-Campos is a physiotherapist specialised in cardiorespiratory rehabilitation. In 2021, she earned her PhD in sciences, working with early mobilisation and neuromuscular electrical stimulation, with her final article being recently published in Critical Care Medicine. Also in 2021, she collaborated with the research team of the Rehabilitation Sciences Department at Leuven, Belgium, where she worked with weaning from mechanical ventilation and differences in diagnostic accuracy of severe respiratory muscle assessments to predict weaning outcomes. At the moment, she is an assistant professor at the Federal University of Triangulo Mineiro, Minas Gerais, Brazil. Thank you both for joining us today. I will now turn the presentation over to Dr Haynes. Hello. Yeah, thank you, Thomas. And thank you, Critical Care Medicine, for the opportunity to talk today. Yes, so my name is Ryan. I'm going to talk about our paper, which is Catabolism in Critical Illness. And it's a reanalysis of the reducing deaths due to oxidative stress Redox S trial. So I have no relevant disclosures for this presentation. So I suppose to begin with my story and how I got to working on this in my PhD. So where I work at the Royal London Hospital, it's in a busy central part of London, and we're a major trauma centre. And what I saw when I was working there as a trainee is there's a distinct cohort of patients that have maybe had a car accident or falling off from their construction sites. They come into intensive care, and although they survive that 24, 48 hours of their initial injuries, they then spend a very long period in the intensive care. And it's something that me, Dr. Proud, Dr. Puficiri, who I work with, became very interested in. Having looked through the literature, as is often the case in intensive care, Dr. Jackie Waschner kind of had been looking at this concept and gave a really good kind of epidemiological approach. And if I just read out his quote here, he defined this concept of persistent critical illness as kind of when a patient's reason for being in ICU is now more related to their ongoing critical illness than their original reason for admission to the ICU. And essentially, he's describing a patient, I think, as critical care clinicians, we all recognise. It's someone who's been in our intensive care for maybe seven, eight, nine, ten days was the mark that he used. And what they came in with becomes less and less relevant. And instead, you're faced with this kind of unique kind of clinical issue, which is a patient who's acquired some of these phenotypes of persistent critical illness. So we took this concept further and we looked in our major trauma population. And first things first, we looked at muscle wasting because I think it's been well recognised that patients who spend a long time in intensive care lose muscle. And we looked at CT scans in these patients and we saw that there was a reduction in muscle volume when the psoas muscle, as you can see in slide C, and then in panel D, there's an increase in the cross-sectional area of muscle in the abdomen. The fortunate thing here was these trauma patients had lots of CT scans so we could have a look at their muscle changes over time. At the same time, we were interested in two biochemical markers that we all measure frequently in our intensive care patients. One is urea and one is creatinine. And there's two things that we noticed in these patients. We see an increase in urea the more time you spend in intensive care. Also, you see a decrease in creatinine. So after that trauma patient comes in, after, for instance, their rhabdomyolysis and their acute kidney injury, and an increase in urea, you then tend to see the creatinine fall and we think that's related to a loss in muscle. Now, we combine those two markers in the urea-creatinine ratio, as has been done decades ago. And we found that urea-creatinine ratio, or high urea-creatinine ratio, was strongly associated with an increase in intensive care stay. And actually, those that were discharged from the ICU before day 10 and discharged alive had a trajectory that was much lower and decreasing. Now, as I said, that was in a major trauma population in London, in one centre, and was very much looking at associations. So we wanted to take this story further, which led us to Darren Halen's group, and we were very fortunate to be able to collaborate with them on this project. They gave us access to a very interesting data set from a randomised control trial that they performed back in 2013. And that was called the REDOX-S study. I'll just say a quick summary of that trial. It was a randomised control trial of glutamine and other antioxidants in critically ill patients. What they found was that those patients randomised the glutamine, one, had an increase in their urea, and two, that increase in, well, the extra glutamine they got led to a worse outcome, which was kind of a surprise finding for that study, and really questioned some of the literature moving forward for nutritional interventions in this cohort of patients. So I suppose what people have been asking since that study was published is why was the glutamine harmful? And as I've already said in some of the postdoc analysis that were done before R1, the suggestion was that there was a high urea in these patients. Now, we'd already seen that high urea in our trauma patients in people who'd been in the ICU for a long time. So we wondered if we could test that hypothesis again in this cohort of patients. And just to recap, the REDOX-S trial was a RCT multi-centre and included patients with kind of very different types of multi-organ failure. So a mixed bag of patients. So how did we do that in our current study? So we, although causal is almost a dirty word in observational research, we took what we thought was a causal approach to give our best estimate of what a potential causal effect could be associating urea crackling ratio, which is a surrogate of catabolism and mortality. And we introduced confounders into our modelling using a direct acyclic graph, which I presented here, which hopefully is a way of us managing some of the complex confounders we see in ICU patients without introducing too many biases. We then set out to use a kind of a triangulation of methods, and I've sold on that word for Professor George Davies-Smith in Bristol, who's applied this kind of approach to genomics. And the idea is that you're using different models to address the same question. I suppose different to a sensitivity analysis where maybe you're just changing a small element to your analysis. This is taking a whole different approach to the data and seeing if you get the same relationship. So we really wanted to try and test that relationship between urea crackling ratio over time and mortality in this randomised controlled trial cohort. So I suppose the main model that we used and the one that we felt gave the best inference was what we called a joint model. And it's a joint model because it combines two forms of very commonly used modelling techniques. So we had to model urea and creatinine over time. And to do that, we used a longitudinal linear mixed effects model, which is a very robust way of handling trajectories of biomarkers. At the same time, we incorporated that with a Cox model, so a time to event model. By combining the two, we can be a bit more robust in our estimates to look at the relationship between a change in urea crackling ratio and mortality. And as this plot shows, an increase in urea crackling ratio led to a increase in 30 day mortality in our study. And that was across the whole cohort of patients in the Redox study. Our second kind of bag of tricks was to look at something called a mediation analysis. So here we wanted to really harness the glutamine randomisation element of the original Redox S trial. Here, our hypothesis was, right, OK, we know glutamine cause harm, but how much of that harm is directed through the urea crackling ratio change? And actually, if you see from this study, glutamine, the direct effect of glutamine on 30 day mortality was non-significant. So with a confidence interval of 0.62 to 1.3 for the hazard ratio. Actually, the harm seemed to come through a change in urea crackling ratio, which showed a significant increase in the hazard ratio for those effects. And lastly, we used a marginal structural model again to answer the same question. Is urea crackling ratio associated with death? In the light of the previous two models, we were only able to adjust for our confounders at baseline. Now, the marginal structural model allows us to adjust for time varying confounders. And that's really important in intensive care patients. We know that illness severity, for instance, changes over time. Someone can go from a very severe illness to a very quick improvement. Other patients can go up and down. We were able to adjust for that change in illness severity over time by using this form of modelling approach. And in summary, all three models show very similar things. They show the significant association between urea crackling ratio and harm, despite these different approaches that we've used and different confounding we've tried to address with each one. So what are the clinical implications about this? I think the first thing to say about our findings is we've really tried to map what we think is kind of the time course of catabolism. Of readily available biomarkers that we use on a regular basis, potentially urea crackling ratio combined seem like the best we have to monitor a catabolic process in intensive care, which is, I think, very important. And going back to what Jackie Washington said, we know what these patients are, but we haven't quite dug down into their phenotype. We think urea crackling ratio might give us a little bit of a lens to look at them through. A few other things that we think are relevant clinically, and we mentioned in our discussion of our paper, we think this is further evidence of the harm of severe uremia. Now, at the bottom, you'll see a reference to Steven Gowdry's study looking at the Akiki 2 trial. So that group randomized patients to early versus late renal replacement therapy. And the difference was actually late could be beneficial for these patients. However, they did another study looking at late, late renal replacement therapy. And in those patients, they started to see some of the harm. And they noted very severe levels of uremia. And I think it's starting to add to the evidence that severe, persistent uremia might be harmful in our critical care patients. And that brings on to how the Adki group are starting to look, or asking us to look as critical care nephrologists at the supply-demand relationship and the kidney. If we want to move forward with our delivery of renal replacement therapy, we might have to start thinking about tailoring some of our treatments. In our patient who's been in the ICU for 10 days, who has a recurrence of their sepsis, for instance, is very catabolic, and urea is rising, that may be someone who you wouldn't stop renal replacement therapy on because their supply demand for the kidney is going to be out of sync. And also, it's someone who, if it wasn't on renal replacement therapy, you might say you would lower your threshold for that patient than going on renal replacement therapy. This is obviously hypothesis generating and needs to be thought of in a more randomized sense, but we think is kind of consistent with some of the new evidence that's coming out now. What got Zudin, who's one of the senior authors on this paper, really interested, and also Darren as well, is this kind of question of, well, how can we intervene? What can we do? And this kind of question of timing, which really comes into play in the nutritional research land. So, nutritional support in the acute phase of critical illness is relatively a very debated topic. This review from Van den Berge's group from the England Journal of Medicine says the recommendation for clinical nutritional practice in the ICU in future research should maybe allow hypochloric enteral feeding in the acute phase of critical illness up to seven days in previously well-nourished patients. Now, that's not really based on much evidence. As the glutamine trial shows, some of these interventions that we give to these patients who are very catabolic can be very effective in the acute phase of critical illness. And those who are very catabolic can be very harmful. Could urea-creatinine ratio be used as a surrogate in these interventional trials? If my patient has, for instance, some extra feeding in their persistent critical illness phase and the urea-creatinine ratio starts to rise, should maybe we pull back and say, oh no, we'll wait, they're still catabolic, we're unable to use those nutrients. Again, this is hypothesis generating, mainly because urea and creatinine are readily available and readily measured in an almost pragmatic sense for an interventional trial. Perfect. That's my allotted time. Thank you for listening. I'll hand things over now to Dr Campos for her presentation. Thank you. Thank you very much, Dr. Rains, and thank you very much for the Critical Care Society. Today, I will be presenting my last paper recently published in the Critical Care Medicine. The title of my paper is Early Neuromuscular Electrostimulation in Addition to Early Mobilization Improves Functional Status and Decreases Hospitalization Days of Critically Ill Patients. It's important to mention that I received support for my article from the Coordination for the Improvement of Higher Education Personnel. It's an institution in Brazil, and the remaining authors have not disclosed that they do not have any conflicts of interest. And to understand my work, first, we have to understand the consequences of prolonged immobilization. So, some of these consequences, they are logical, because if you don't activate your muscles, some of these patients, they will have ICU-acquired weakness, and also, they will be more susceptible to have deep vein thrombosis. But these patients, they also have pulmonary consequences, like longer mechanical ventilation duration and waning failure, and also nosocomial pneumonia. These patients also have cognitive impairments, delirium, and all of this can cause a longer ICU and hospital length of stays, and also higher mortality. So, to deal with these problems, we already have a robust literature on early mobilizations that show that the early mobilizations have influence in some of these outcomes. However, we know that we still have barriers and limitations. For example, some of the patients, they are with sedation, they do not have an adequate level of consciousness, like, for example, neurologic patients, patients that had stroke, trauma brain injury, and some of the patients, they are not comparative. And because of this, we cannot have active muscles contractions, and we know that muscle wasting is more significant in the first week of critical illness. So, we have to find strategies to deal with it before a patient lost the muscle mass. And one of these strategies is the neuromuscular electrical stimulation. And we have some articles that shows that this therapy reduces the loss of muscle mass, preserves or increase muscle strength, attenuates ICU acquired weakness, and shortens the duration of weaning, and decreases mechanical ventilation duration, and shortens ICU and hospital length of stay. However, we still have few studies, including critically ill patients, and these studies have small sample sizes, and they also have different kinds of results. So, we would like to know that when we have a positive result, when we have the increasing or preservation of muscle strength, can it result in better functional status? Because clinically, it's important to have a preservation of muscle strength, but clinically, we also need the patient to be functional. So, we designed a randomized controlled trial, where we included consecutive patients in one year and a half, where we screened within the first 48 hours of ICU admission. We had two groups, the control group, where we did the early mobilization, and the intervention group, where we did the additional application of the neuromuscular electrical stimulation. We had a computer-generated list with an allocation ratio of one to one, and we stratified the patients by age, and we did a randomization and data management with the RedCap platform. Our early mobilization protocol is available as a supplement of digital content. We have six phases, where we attend the patient for 20 to 60 minutes, depending on what the patient could be able to do. Always, the priority was to do out-of-bed activities. For example, sometimes, the patient was not totally conscious, but even though, we use a lift to position this patient out of bed in the armchair, for example. And regarding our neuromuscular electrical stimulation protocol, we apply it on the quadriceps and tibialis anterior, with a frequency of 80 hertz, a pulse duration of 400 microseconds. With five seconds on, 10 seconds off, with a rising time of one second, and we did it for one hour, five days a week, beginning the first two days of ICU admission. This is very important, because you want to preserve the muscle mass. The intensity of the stimulus was increased until visible or palpable muscle contraction, and the maximum intensity was 120 milliamperes. It's very important this, because most of the devices, the intensity goes until 60, and our device, the intensity was until 60, but we changed it. We set it back to the technician, so we send it back, so we could have a higher intensity. And this was very important to have adequate muscle contraction. So here, I have an example of muscle contraction. As you can see, we have very simple electrodes, and we place them with adhesive tape. We have five seconds of contraction, and as you can see, we don't see fibrillation of the muscle. We have to see it maintaining for the five seconds. So sometimes, we need to increase the intensity in order to get it. So it's five seconds on, and then 10 seconds off. So our outcomes, as you can imagine, our primary outcome, because of our main question, we use a functional status score for the ICU, that's a functional status scale. And the secondary outcomes, we use the MRC scale to see the muscle strength, and also the physical function tests in the ICU, because we thought it was important to use more than one functional status scale, because they check different items. We also analyze the ICU and the hospital-legal stay, barter index, quality of life, mortality, and delirium. Our time points were first day awake, ICU discharge, and hospital discharge. We did a sample size calculation, also considering a minimal change of seven points in our main scale, the FSS-ICU, where we have, in the end, 21 patients. And here, it's important to mention that it's 21 patients that were cooperative, that we could apply this scale. So here we have the flowchart of the study, and as you can see, we screened for 151 patients, in which we randomized 139. So we had 69 patients in the control group, and 70 patients in the interventional group. We lost some patients because of deaths, and some patients could not complete the protocol. So in the end, we had 40 patients that completed the protocol, and 34 patients, 40 patients in the control group, and 34 patients that completed the protocol in the interventional group. Some of the patients were with inability to perform the FSS-ICU scale, most of them because they didn't have adequate level of consciousness. So in the end, we had 26 patients in the control group, and 21 patients in the group that we did the additional use of the neuromuscular electrical stimulation. Here we have the baseline characteristics of the patients who completed the protocols, and as you can see, we didn't have any significant difference between the groups regarding to age, sex, and also some comorbidity indexes, like the SABS-3, SOFA, Charleston Comorbidity Index, Body Mass Index, Barthel Index, and also we have similar diagnosis between the groups. Also, we had the opportunity to answer a letter to the editor, where we did a multivariate analysis, and we also did not find any correlations between our characteristics, our baseline characteristics, and our outcomes. Our primary outcome was the FSS-ICU score at the ICU discharge. As you can see, we have a significant better result in the group where we did the additional application of the neuromuscular electrical stimulation, so we have already here a difference of 10 points between the groups, and also we saw the same results in the first day awake and the hospital discharge. And when we look at the MRC-SAM score results, we also find the same results. The patients in the interventional group, they had better results since the first day awake. They also did in the ICU discharge and hospital discharge. And when we look at the results from the PFIT, the other functional scale that we use, we also have corroborating results, where we see that the interventional groups since the first day awake have better results, and also at hospital discharge, the patients, they achieve the ceiling effect of the scale, because the maximum is 12, and the other group, the control group, we did not see the results. We also checked the number of days until reaching some motor milestones. So here, especially, we look at the patients when they were sitting on the edge of the bed, sitting on the armchair, standing up, and days until walking. And we also find better results, significant results, in the patients that had the additional use of the neuromuscular electrical stimulation. So it's important to mention that these patients were under the same early mobilization protocol, but they had a fast recovery because they were standing up first. Regarding the other outcomes, we also see that when we look at the hospital length of stay, the patients that did the additional use of the neuromuscular electrical stimulation stay nine days less than the other patients in the other group. And also, they have a lower frequency of ICU-acquired weakness. But it's important to remember here that the study was not designed to see these outcomes. They are secondary outcomes. And also, the frequency of the ICU-acquired weakness is also important to understand that some of the patients could not be evaluated because they were not conscious. So here, we are saying about patients that could be evaluated. So our conclusions, the additional application of the early neuromuscular electrical stimulation to an early mobilization protocol not only promoted better muscle strength, as we were expecting, but also better functional status outcomes. And this is very important clinically. And this happened in the first day awake and at ICU and hospital discharges. The group, the interventional group, also took fewer days to stand up, had shorter hospital loss and lower frequency of ICU-acquired weakness in the patients that were able to perform the MRC sum score. And it's important that for future research, we need bigger samples because we calculated our sample to see especially the functional status. So when we want to look at other outcomes, we need bigger samples. Also, we need to find the long-term outcomes. We have a PhD student that is working with the follow-up of these patients. She's doing the follow-up until six months after ICU discharge. We started to analyze the data and soon we will give the results. We also need to define a patient population that would benefit better for this stimulation. We know that some studies that exclude the neurologic patients, they didn't have positive results. And studies like ours that maintain the neurologic patients like stroke patients or trauma brain patients, we saw positive results. But of course, this is just a hypothesis. And we think this because normally this kind of Normally, this kind of patients, they need to stay sedated for more time because of neurologic conditions. So it's just a hypothesis. But of course, we need to define a patient population and we need future research. So I would like to thank all the multi-professional staff from the ICU. Our article, our work would not be possible without a multi-professional work. Also, I'd like to thank the physical therapist Tatiana Carnevale and Jacqueline Nopes. Tatiana Carnevale is the physical therapist that is doing the follow-up of this study. And I would like to say a special thanks to Professor Rick Gosling, that is always supporting me in all my activities, including this presentation, and Professor Marcos Borges, that were my promoter in my PhD. Thank you very much. And now I will turn it over to Dr. Tomas again, so you will go to answering questions. Thank you very much for the wonderful presentations. And I would like to start with the the Q&A session. The first question is going to go to Ryan. And I would like to know, or we would like to know, that with the cut-off, do you have a cut-off value for severe uremia that you were talking about, which could be useful either in future research studies or at the bedside? So yeah, that's kind of the, I suppose that's one of the golden questions. I think to look at the relationship, so the answer is no. To look at the relationship, how we did in our study, which was trying to prove the relationship, I think we, all costs avoided any kind of cut-off value, because it's kind of more statistically friendly and lets us make better inferences and kind of reduce information loss. But as you've kind of suggested there, as a clinician, is there a cut-off? I suspect there probably isn't. And I think it would be something that is more dynamic than a single value. And it might be patient specific, which, yeah, is something that would need to be considered if we're going to bring this forward into, for instance, an intervention. So yeah, to answer your question, not quite there with a cut-off yet. Thank you. Deborah, there was a question from the audience asking about the difference in mortality between the two groups. Was there any significant difference? No, we didn't find any significant difference regarding mortality. Thank you very much. And follow on that again, Deborah. How was this intervention received by the patients and the relatives? Were they concerned? Obviously, the patients who were randomised, they were probably not very much aware of what is going on, but how it was perceived by visitors? Yeah, at first, some of the family, they were not very into it. They were worried because when I say something electrical, they say, oh, but it's like an electric shock. You're going to do this with my relative. So some of them were worried. But I showed them videos, I showed them photos, and I also explained to them that we would be looking at the skin of the patient to see any changes. Also, most of the patients were sedated, so they would not feel pain at first. And if they start waking up and they start to feel pain or something, I told the family that we could interrupt the session, that we could interrupt the study, as we always have to say when we are talking to the family. So at the beginning, I had some difficulties, but during the study, I was learning the process. During the process, I was learning how to talk to the family and explain everything. So it was becoming easier as I was learning how to explain it better. Thank you. Ryan, you mentioned that this harm from the glutamine is looking like to be driven by the urea creatinine ratio. What's the proposed mechanism there? Do you have a proposed mechanism? Yes, that's really interesting. I mean, we don't have any kind of mechanistic samples from the study. It was done in 2013, but we have some theories. So I think in these patients that were given essentially an exogenous load of amino acid, which is what the glutamine did, and kind of feeds directly into some of the metabolic cycles. I think one of the mechanisms that we stress in the paper is ammonia genesis and an increase in ammonia, basically a stress of the urea cycle. We know in critical illness, there's subclinical liver injury. We know that muscles lose volume as well. All of these organs help process ammonia, as does the kidney. So people with acute kidney injury have reduced ammonia processing abilities. So if you give someone an increase of an exogenous amino acid, I think it's pretty biologically plausible that you're going to stress the urea cycle, which may not be working at its best and create lots of ammonia. So I suppose moving forward to getting some tissue ammonia samples would be great to try and link these hypotheses together, because I think there is a pretty clear signal that ammonia is bad for you. There's a paper in CCM actually a few years ago that we referenced that looks at hyperammonia in patients who haven't got liver failure, so not in people who have got issues with their liver. And it seems to be quite prevalent in the critical care population. So I think that's possibly where this mechanism comes from. Thank you very much. Deborah, when I was looking at the results section of the paper and the presentation, it struck me that you included relatively young and acutely unvalved patients. Do you think that this mechanism would have the same beneficial effect in older patients who might not have that good muscle mass, because they have been suffering from other chronic diseases? Yes, sure. I think it would be very helpful for older patients. We saw this clinically in older patients too. What I noticed is that sometimes it's difficult when the patient has edema, because the edema makes it harder for the neuromuscular electrical stimulation to work, because sometimes we put a high intensity and we don't see a muscle contraction. So I think that the bigger problem is edema. So if the patient is older, but we can put the electrodes and we can see the muscle contraction, we think this will be more helpful. But of course, to know this, to know, I also said this in the presentation, that we need more researchers to understand what's the best patient population, what's the patient population that would benefit better. But from my experience and from what I saw in the patients, I also think that would be very helpful in older patients. Thank you very much. Thank you. Ryan, your findings are, you know, they are very interesting. And I was thinking, do they apply to the routine ICU patient in the UK who has got a length of stay of about two days on average? Or is it really applicable to that 15% who does develop the persistent 15% who does develop the persistent critical illness? And then I've got a follow up question on that. I think, yeah, I mean, I suppose the real answer to that from these data is we don't know, and I don't want to infer those relationships in those more short stay patients. The short stay patients haven't got a requirement for organs for beyond 48 hours, so probably not. I think I know that's the most common admission and you're talking about only 15%. But as Jackie Washington says, it's that 15% is a lot of our work. That's a lot of our nursing works, a lot of our resources on intensive care. So I know that wasn't your point, but they are definitely a 15% that's worth paying attention to. But yeah, I think looking at the acute phase, I'd be guessing, I think at the moment, it's difficult to say what those metabolic processes would be for someone who's going to be back on the ward in 48 hours. It's a very different cohort, isn't it? Yes, no, I agree. And I know that the 15% generates about 70-80% of the work. We have seen it in our data, just locally looking at a couple of ICUs. So I fully agree that these patients are more taxing on staff resources than the routine patients. Now, if the mechanism is really applicable to those who develop the persistent critical illness, and we postulate that the early intervention with full feeding might be harmful in the short stay patients, how can we square this round hole? Is there anything that you are aware of which could help us to distinguish between the two groups early on so we can intervene early, but we don't harm the ones who don't need it? I mean, it's difficult, isn't it? I think, I suppose, going back to our results, we found that, I know the group that we selected were, you know, in ICU for more than seven days, but you're seeing that rise quite early. And there was a big rise in urea, even day one, day two for people randomised to glutamine. It really ramped up the process. So if I've interpreted your question right, I think it's going to be that delta, so to speak, that change in whether it be urea or urea ratio, the change in that mark that might help us distinguish what trajectory people are going to land onto. And it might even come to the point where you say we're going to stress someone. I suppose your analogy might be like a stress echo, for instance, but you say, right, we're going to stress the metabolism and see, and see if it responds. If there isn't a response, then you say, right, we'll stop the feed. But actually, if there is a signal that there's some anabolic processes going on, and the treat could be absorbed, then maybe you would say, okay, we'll carry on. Maybe that might be an approach. But yeah, that's a tricky question. No, thank you very much. That's really interesting. And it would be nice to see this probably in a bigger cohort. As you say, the delta is, it seems to be that it might be more useful than absolute values, like in many other biomarker work as well. Deborah, I've got one sort of last question for you. And that's, I have, I must admit, I missed it on the slides. But did you have any difference any difference between thromboembolic complications, especially DVTs between the groups? Because you could, in theory, you could, you could think that moving the muscle with electrical stimulus might help with the blood pump and might reduce this complication. Yeah, indeed, this is a very interesting data. We were planning to look at it when we started the project. We also received this question at the letter to the editor that we answered. We also received the same question. However, during the data collection, we noticed that we, this data, this data, we didn't have a protocol to get this data. So the results were not reliable. And also because our sample is not very big. And the percentage of patients with thrombos is like, I think it's 5%. I don't remember the exact number. And our sample was already low. We didn't find adequate to analyse this data because it was not reliable. So unfortunately, we don't have this data now. But I also think it would be an important information. And we also have other articles that approach this regarding the neuromuscular electrical stimulation. Thank you very much. And thank you for the very nice presentations. Again, I think the audience and myself have learned a lot today. Thank you very much for the invitation. And this concludes our Q&A session. So thank you to our presenters and the audience for attending. And again, everyone who joined us for today's webcast will receive the follow-up email, which will include an evaluation. And we would be very grateful if you could share your thoughts about our webcast in that. And on a final note, please join us for our next Journal Club, Critical Care Medicine, on Thursday, August the 25th. And this concludes our presentation today. Thank you and goodbye.

Critical Care Medicine

catabolism

urea creatinine ratio

mortality

neuromuscular electrical stimulation

functional status

muscle strength

ICU-acquired weakness