Transcript

ARISE Fluids · CRITKNOW

Ramesh: Right. Bharath Kumar: Hello everyone, welcome back to another episode of Crit No. this is Bharat Kumar, and I'm joined by my co-host Ramesh Venkat Raman. Before we start off with today's episode, again, as always, if you enjoyed what you've been what we've been doing, please comment, like, subscribe, and share and spread the word. Thank you so much for all of the feedback that you've received until now. in today's podcast episode, we are going to focus on another trial that relates that is related to resuscitation. And in some ways, this will extend the conversation that we started with our first episode, the Andromeda Shock trial. so another trial that we're gonna talk about today with is focused on resuscitation strategies and specifically fluids. I'm referring to the recently published RICE fluids trial that compared a strategy of restrictive fluids with early baso pressor versus a slightly more liberal or liberal-ish approach to fluids. and a delayed start of vasopressors. So this is a trial that we're gonna talk about today. And I'll request Ramesh to kick us off. Ramesh: Thanks Bharat, nice looking t-shirt there. So we'll just get started with this. I think this is a very important trial, very relevant to what I I think all of us would be doing on a day-to-day basis. So without taking too much time, just going over to a quick brief summary of what has happened so far. I think we first had the single center early goal directed therapy, which actually showed significant improvements in outcome. Bharath Kumar: Thank you. Ramesh: And at those points of time, I think we were doing wild type fluid assessment. We didn't know enough about how to go about doing it. So the separation in the EGDT group was 3.5 liters versus five liters in the first six hours or within the first short period. So that was a lot of fluids given within a short time, and about thirty percent of them required vasopressors in the first six hours based on the protocol. The subsequent three EGDT multi-centered trials across three different continents, the process, RISE, and Promise, also did some kind of a goal-directed therapy, but it there was about a decade separation between the single-centered trial and the multi-center trials. And I think our fluid resuscitation methods changed. So, on average, most of them in the process trial got about 2.8 to 3.3 liters. In RISE trial, somewhere around two liters. And promise again somewhere close to around two liters. So I think we had all learned to restrict fluids a little bit, and the vasopressor rate was slightly higher, somewhere between 50 to 60 percent across these three trials. So then the question is as we were recognizing the importance of the fluid overload, and that what we think that helps at the front end probably hurts us in the back end when the patient is trying to get better from shock. I think we were Going towards a restrictive fluid resuscitative strategy. The first trial that actually looked at it and worth mentioning is the classic trial that was done in 2022. And they basically did it in, I have a cheat sheet here, about 31 European centers, and they basically randomized patients into a restrictive strategy or a conservat or a liberal strategy after the initial ER resuscitation. I think that is an important point that we need to make here. And on an average, the two groups got about 3 liters of fluid, 3.2 in one group and 3 liters in the other group prior to randomization. So this is the baseline fluid that people got. On top of it, on day five, I think people got either 1.8 or 2.7 liters, and significant amounts of difference between the two groups in terms of the total fluid received. However, there was only an 800 ml difference in the cumulative fluid at the end of five days between the two groups. A large amount of the fluids was given prior to randomization. This did not show that their primary outcome was a 90-day mortality, and this their study did not show any significant differences at 90 days between the two groups. And the next study that is worth mentioning happened in 2023, the Clovers trial, which is very relevant to the study that we are doing here. They not only looked at conservative and liberal fluid strategy, they also wanted to know whether the conservative fluid strategy in combination with early vasopresses. So, one of the rationals for that, as you know, Bharat, is just when you start norepinephrine, you're going to squeeze the veins and therefore you're going to recruit some volume into the central circulation, and that itself functions as a boost to the overall preload, and maybe we can reduce the total amount of fluid. We were given. So this trial actually compared two strategies: the one with liberal fluid, the other with conservative fluid with the early onset of vasopressor. Again, this study was initiated in the intensive care unit after the initial resuscitation was done in the emergency room. And they had a cutoff of I think excluding people who received more than three liters were excluded from the study, but most of them received anywhere from one to three liters at baseline. So most of the resuscitation. Was already done in the emergency room, and then subsequent 24 hours, they randomized them into a conservative strategy where they had very strict criteria of who would get fluid boluses and why, in in combination with early waste suppressors with norepinephrine predominantly to keep a map of around 65, versus a liberal fluid strategy. They originally wanted to basically enroll about 2300 patients, but the interim analysis they found that. There was no difference between the two groups after enrolling about 780 patients in both the groups, and they basically stopped the study, you know, after that for futility. And about 42% of the patients required sorry, 59% in the conservative arm and 37% in the liberal arm needed basopresses. So what was clear among all these three studies is that conservative versus liberal probably didn't matter. And two early vasopressors means that more patients need vasopressors, and therefore more patients need central lines and more patients need ICU admissions compared to the liberal fluid group where the vasopressor rates were lower. However, the problem often happens that if most of the fluid is already given in the emergency room, I think we are now looking at patients who have already received a certain amount of fluid, then the additional volume probably doesn't matter. So I think the current study, the RIS fluid studies from Anzix group, basically goes one step further and recruits patients in the emergency room. So the patients are allowed to get up to a liter, which is pragmatic. I think somebody comes with a hypotension, they get a liter of fluid. But anybody who gets more than two liters of fluid were excluded from the study. And they looked at the same question. No, if I enroll patients there and then I give a very strict fluid criteria versus a liberal fluid criteria, am I going to see differences? And the conservative group were allowed to start vasopresses very early. So that brings us to this RIS fluid trial over a period of time in terms of how the literature has has evolved. So I think it's a fascinating journey that we keep learning sequentially at every step to try to fine-tune how we resuscitate patients. We are still nowhere close to perfection. Perfection is a myth, as Roger Federer recently said. So I think that continues to haunt us in critical care too. So I think from that pine point of view, I think this trial is very crucial. It answers a very relevant question, Bharat. So I I think it's time to just delve into the trial with that kind of a background and see where we are at this point of time and maybe look into the details of the study. Bharath Kumar: Yeah, absolutely. No, thank you for that excellent summary. And I think you you alluded to it, the fact that in general the amount of fluid we've been giving has also obviously come down you know over time. so yeah, I'll get into the pico of of RISE. so as you said, this trial is very close in terms of the research question to Clovers. so They are asking whether an you know a strategy of restrictive fluids with early vasopressors is superior to a slightly more liberal fluid strategy with a delayed start of vasopressors. They included adult patients with clinically suspected infection, a systolic blood pressure less than 90 or a MAP less than 65. and they were enrolled in the year, as you said, they should have received an antimicrobial and should have a lactate more than two. So trying to get that septic shock kind of a population. And again, as you pointed out here, they catch them early in the ER and they also exclude those that have received more than two or more litters. So they're trying to really you know get into the early phase of resuscitation, unlike the previous trials. they randomize patients in a one is to one ratio, stratified by site and by using permuted blocks to earn the interventional strategy, which is, as I said, restrictive fluids and early vasopressors. So in this arm, as soon as you're randomized, the fluids would be stopped, any fluids that are going on, vasopressors would be started, and you are allowed to give rescue fluid boluses as 250 ml alicords as needed, but there were specific indications for when it could be given. Now, in the control arm, you will be allowed to give, you'll be allowed to be more liberal in your fluid strategy. You can give a one-liter bolus to start off with as soon as randomization happens if required, and more fluids in finite ml alicords as needed. Ramesh: Mm-hmm. Bharath Kumar: and the idea is to delay the vasopressors if possible. In both arms, clinicians were obviously given the you know freedom to override the protocol and either start vasopressors early or give more fluids if needed, and also to have both running if needed. In the liberal arm, it's also important to note that any vasopressors already going on were not, you know, it was not mandatory to stop them. so clinicians could continue them if needed. and so that's sort of what They did, and the protocol itself was followed for a minimum of six hours and up to 24 hours. and the consent model, you know, given how how quickly they had to enroll, was that they would have waiver and then the patients or families would later either opt in to or you know, or opt out or continue in the trial. So that's the model which they you know had informed consenting was you know in that in that model or approach. The primary outcome here, and I'm gonna spend a little bit of time on the outcomes. The primary outcome here is days alive and out of hospital at day 90. Now, this is an outcome that we have encountered in some other trials as well. So essentially, it's a composite outcome that is combining survival with also being out of hospital. so it's patient-centered because survival alone is not enough. You also want to be free of organ support, you don't want to be in an acute care setting, you want to be home ideally, right? So As a patient, that's your goal. So this outcome is trying to get at all of those aspects. and and the way it's analyzed is that if you survive, then you obviously count the number of days, you know, until day 90 that you're out of the hospital. And and they're obviously factoring in readmissions as well. So anytime out of the hospital. But if you don't survive, you already get a score of zero, right? So it's not that. this is to ensure that for example if somebody survives sixty days and then dies, they can't be given thirty days of, you know, being out of hospital, right? If they've not survived, they get a score of zero. If they survive then the number of days is counted. Ramesh: So somebody got discharged just for clarifying for the audience. So somebody gets discharged, they live till 88th day and then they die. They still would get a zero. So irrespective of how long they lived outside the hospital. So you have to be alive first and then at 90 days, how many days were you outside the ICU? Right. So it becomes a very stringent criteria and a very relevant one, obviously. Bharath Kumar: Yeah. Correct, correct. Correct. Correct. Yeah. Yeah. So that's the primary outcome. and as I said, it's a it's a peripatient-centered outcome. There are a number of secondary outcomes that they focus on, which includes obviously the landmark mortality, 28 day, 90 day mortality, and so on. But there are also a number of time to event outcomes in this particular trial. And I thought it'd be nice to, you know, maybe a brief segue into what time to event outcomes are, because here they look at time to vasopressor cessation, time to discharge, survival time, and so on. Now, time to event outcomes again, we have encountered this in in several critical care trials. the the key difference is when you're thinking about a set time point like twenty-eight days or ninety days and looking at mortality, it only gives you the exact no the number of people that died by that time point, right? It does not tell you much about what happened to them in between when they died or when they had a particular outcome. So it does not does not tell you the experience from you know randomization until that time point. So this time to event outcomes, one mitigate that. The second thing is if you had an outcome, for example, as length of stay, and if you die on day one, you obviously have a very short length of stay, but you know, it doesn't matter, right? Like the patient died. So that problem is called as a competing outcome where death is a competing outcome for an outcome, you know, for an outcome such as length of stay, for example. It could also be something like time to intubation. Or time to escalation of therapy or whatever. If you don't even have the opportunity to have that outcome by dying, then you know that's a competing event. And traditional outcomes again don't compensate for that kind of a problem. So again, time to event outcomes account for that law. It could be death, it could also be discharge, it could be loss to follow up. So it accounts for these kinds of events that happen in the interim by using a concept called censoring. So that's how you know that's why time to event outcomes are important and useful. from a clinical perspective. And when you look at very quickly, when you look at how we analyze time to event outcomes, I'll just spend a minute on that. We typically look at them using what again Cynicians are going to be familiar, which is the Kaplan Mayer plots. Now, a Kaplan Mayer plot will have the experience or the that could be a survival experience, whatever the outcome experience of the patient by the intervention arm and by the treatment arm. And visually you'll first look at the Kaplan Mayer to see is there a difference between the two curves, right? Between the two groups. The next thing we would do is we would postulate a null hypothesis that says that there is no difference, and you would test that as a hypothesis. And we would do that by using again, people might be familiar with the term called a log rank test, which will actually give you a p-value for that test you know between the two arms. And the last thing we would do with the Kaplan mayor is that we would tell or we would try to estimate the instantaneous risk of having that event by estimating a hazard ratio, which you know is an effect estimate like a risk ratio or an odds ratio. But it's sort of telling you the instantaneous risk throughout that period of having that particular outcome. Although traditionally there's been called survival or time to you know survival outcomes, it could be as I said, anything. It could be time to vasopressor cessation or initiation, it could be time to ventilation cessation and so on. So I thought it'd be nice to talk a little bit about you know, this concept of time to event outcomes. Ramesh: We know that's great, but because we see capital miers all the time. And I I you know, I I think I I I wouldn't say that I'm hundred percent comfortable interpreting no all the things that you said right now. So again, I'm gonna ask you a question both for myself and for the sake of audience. So can two groups have the similar mortality rate but a different hazard ratios? Because the rate of death would be different in one group the other, right? That's what you're trying to get at with these kinds of time to event, right? Because the total Bharath Kumar: Yeah, yeah, yeah, yeah. Absolutely. Yeah. So yeah. Ramesh: Death at the time of ninety days may be easy, but one group is probably dying much faster than the other, right? So it's still possible, correct? Bharath Kumar: Yeah. Yeah. And the longer we follow up, obviously, you know, mortality is going to slowly keep increasing. Whereas what we might be interested is in the experience in that period, right? The time to yeah. Ramesh: So I I think, I mean, I I remember doing some animal models where time to death becomes the because e every rat you inject mototoxin dice, right? So so ultimately there's no mortality difference between the two groups. But how fast they die, I think is what we we look at. And I think that's what acad ratio captures better than than just the crude mortality rate, right? So that was very well articulated. So I think now that we have gone through the method methodology, I think it is just some time to just look at the results of the study, but so I thought I'll just go Bharath Kumar: Yeah, yeah, yeah. Ramesh: Through the table one. So about 500 patients in each arm were enrolled between the two groups, much, much lower than the previous studies that are done, especially the classic trial, which had a lot more patients. And remind you that the claw was got stopped somewhere around 780 patients in both arms. So the study is actually smaller than both those studies for reference. The median age is 68, which is quite okay. 58% male population again, okay. But what struck me about the study is how less sick these patients were. The Apache score was 18, which is mediocre, right? Somewhere in the middle, it is neither too high nor too low. And then there are other things. For example, the Charleston's comorbidity index is one. That's very, very like they're all otherwise reasonably healthy with not too many comorbidities coming in with some kind of sepsis. The median lactate was 3.3, not terribly high. Just over the two mark. So again, not something that a little bit of volume can take take care of. The median volume given prior to randomization was 1.5 liters. So I I think that's and I think they included people with the first one liter, but not more than two liters. So I think they got exactly what they wanted. But the other two things that are very important is at baseline, half percentage of the patients were ventilated, right? I mean, they're all fine, essentially. Maybe a little bit flu, fever, and a little bit sympathetic drive causing the lactate. And only about 11% and 8% in both the groups were on vasopressor. So, overall, when I look at table one, I always think and say what kind of patient population am I dealing with? And this is this the patient that I would deal with in my ICU. And I would probably say that I deal with a lot more sicker patients in my ICU than that, than what this study represented. And this also is reflective when it comes to outcomes that we will talk about. But they were true to their randomization. At one hour, the conservative arm received only 185 ml more, and the liberal arm actually received about a liter. So almost a good difference in the first hour. As the time goes by, the separation gets smaller and smaller and maybe less meaningful, right? At six hours, it is 500 ml in the conservative arm and 1.5 liters in the liberal arm. Under 24 hours, it is 1.1 liters in the conservative arm and 2.2 liters in the liberal arm, which is basically telling you that they got 1.5 liters at baseline. And even the liberal got arm got only about another 2.2 liters, which is only 3.5 to 4 liters. Clearly shows again what you and me discussed, but that over a period of time the amount of fluid we all give is probably come down. And and that pretty much is what happened. Time to initiation of vasopressor was like 0.4 hours. If I remember right, somewhere like 20 odd minutes in the vasopressor arm, which is the conservative fluid with vasopressor arm, they were very quick to start vasopressors. In the fluid arm, it's it's it's about 1.4 hours. So an hour later they started vasopressors, which I don't feel is clinically very important. An equal number of patients basically got vasopressors through peripheral peripheral lines, they didn't need a central line. And we have plenty of data now to support the fact that vasopressors through peripheral line is reasonably safe. But the caveat here is they are all Australian ICUs, they are probably staffed better than the Indian ICUs that and Indian emergency rooms that we have. Their adverse events rate with peripheral vasoconstrictor is almost negligible. We may have a little bit more, so we need to be a little bit more cautious if you're going to adapt it in our ICUs. But but broadly, I think peripheral line vasopressors are perfectly fine for this kind of population. And the number of days alive and out of hospital, which is the primary outcome, was 76 days exactly in both the groups. Mind you that when they actually did the power analysis, they powered it for 60 days in the in in one of the arms and then no reduction from that. But here clinically looks like most patients actually did really well, which means they stayed in the ICU for only stayed in the hospital only for 14 days. And their power analysis was for a reduction in seven days. I I thought that was kind of No, considering this numbers, it was kind of over over ambitious because to decrease it from 14 days to seven days is going to be very difficult with any kind of intervention. And especially the fact that this intervention stopped between six to twenty four hours. And there is a lot of things that happen to an ICU patient between 24 hours and hospital discharge that can no impact the survival of that particular patient. And therefore I feel that no, we shouldn't be too harsh about the outcome that they have shown because We probably caught them very, very proximal that we probably know is going to be very difficult with this kind of numbers for us to show any outcome differences. The overall 28-day mortality is 12% in one group and 10%, which is very, very small. The most most of the world's septic shock mortality is still around 25 to 35 percent, I would say, in probably no resource limited settings, maybe even close to 40%. 2022 classic trial showed a mortality of around 42%. Right, but Clover's trial pretty much represented similar patients with similar acuity, and they also had only about a 15% mortality. So it is not that our survival has improved. I just want to know reiterate the point that this patient population was probably not as sick as the rest that we have used to. And at the end of the trial, only 15% needed ventilator. So from half a person, only 15%. Majority of them didn't need vase process. And only about Two-thirds of the patients in the fluid arm needed ICU admission compared to 76% in the vasopressor and considerative fluid arm. So good one-fourth to one-third of the patients didn't even come to the ICU. So they probably went to a kind of an observation unit or a step-down unit, and they were just subsequently discharged. So one take-home message for me, Barat, out of this, is this is not the bread and butter septic shock that I am thinking in my mind when I Take care of a patient in the ICU, and that is something that has to go into how I in in interpret the trial at this point of time. And about 39 and 37 percent in both groups needed central lines. So that's the other thing that has been consistent. Somewhere around 35 to 40 percent of the patients, anyway, need central lines for vasopresses across all the trials. So if I summarize all of that together, whether it is classic clovers or the RIS fluid trial, it is. Reasonably consistent that giving more and more fluid versus less and less fluid probably doesn't have a difference beyond a certain threshold of fluid. I think that threshold of fluid right now is somewhere around one and a half to two liters. Beyond that, I think may not have additional benefit to giving fluids. Just starting early vasopressor to minimize fluids may work in terms of decreasing the fluid, but really doesn't change the outcomes in terms of what we need to be looking at for the patients. If you start baser pressors early, you probably need more central line and more ICU. So that's something that we need to be k careful about. I think all these messages are very consistent across the three trials that we talked about, classic clovers and the R Ice fluid. I think all of them are important messages. Bharath Kumar: Yeah. So absolutely. J just to, you know, get back to the results. So the there is a ten percent higher, you know, ICU admission rate in the in the restrictive arm, right? Like so obviously the use of vasopressors perhaps necessary, but overall not everybody anyway ends up going to the ICU. that's that's a key message that I think came out. And again, higher vasopressor usage, but about like eighteen or nineteen percent in the vasopressor arm. And and I think also a slight the in the vasopressor arm the vasopressor cessation was also a bit earlier as compared to the i that's correct. Ramesh: It's interesting, they get started early and they get terminated early. So but not very significant, just less than an hour or so, something like that. I think initiation and and and stoppage time I can't remember, but I think initiation there's only an hour. Bharath Kumar: Right, right. Yeah, yeah, yeah, yeah. And the separation between the arms e as you were pointing out, it's it's very good in the first hour, but obviously with time at six hours, for example, it's only about a liter, right? between the two arms. And the median fluid is about one and a half liters pre-randomization itself. Yeah. Ramesh: So this is expected, right, Bharat. I mean, if you go back to the original Andromeda trial, the the first Andromeda trial, at two hours, only twenty-five percent of the patients in that trial were fluid responsive. So as time goes by, I think all people become less and less fluid responsive and it doesn't make sense to just keep pouring fluid into them. Bharath Kumar: Mm. I mean I I had a few thoughts in terms of the you know the strengths and the limitations. the results you have summarized you know very comprehensively. so I thought this is you know a large, well conducted RCT that's methodologically very rigorous. Analysis you know was all was all very appropriate. I thought their key strength was the fact that. Ramesh: Sure. Bharath Kumar: They were addressing the question that Clovers could not, I guess, right? If you start early enough, does it does it make a difference, right? From the ER. Clover still had a window of four hours, it was still in the ICU, and the limit was I think three liters before you would exclude. So I guess it's probably very difficult to catch the patient earlier than this. and they've done wonderfully well to do that. I also want to go back to your point that These are less sicker patients, but also probably a reflection of the fact that there is early recognition, early referral, right? All of that. Whereas in our context, presentation it's tends to be later and they also probably show up sicker, right? So I think that's again a key message that that we should keep in mind. a few limitations in our concerns. As I s I think the first one is I said the fluid, obviously the the separation isn't great after the first hour. Ramesh: At the end of twenty four hours it's just a liter. Bharath Kumar: Exactly. not very sick patients. You I think you you mentioned that. and again we've said this generally I think we are at least in in units that are tertiary care with you know intensivists and and qualified ER clinicians, the amount of fluid we give is generally gone down over time, which I think is is is a trend in in itself. I noticed that there was I'm not sure what the significance of this is, there's a three percent you know less patients in the vasopressor arm get source control. the time to source control the same. Maybe just the fact that they either didn't need it or, you know, it it it's probably too small a difference to to to sort of think too much about. But that is something that I saw. The other Ramesh: Most of the patients in the study had respiratory infections followed by urinary infections. G GI was actually the gastro-intestinal abdominal sepsis was quite low compared to the classic trial where abdominal sepsis was more. So maybe the scope for source control in a respiratory infection population may have been also much lower. Bharath Kumar: Infections, yeah, yeah, yeah. Yeah, yeah, yeah. Possibly. Yes, absolutely. The other point is obviously, you know, what is the risk of the liberal arm? And there is you know numerically more pulmonary edema, but it was actually a very in in some ways a very subjective assessment, right? so wasn't that the case, yeah. Ramesh: Yeah, yeah, yeah. It's a subjective assessment. There was no objective measure of pulmonary edema. I think one group had like five percent pulmonary edema based on whatever definition they used. Other group had close to half a percent, point six or something like that. So that there was a higher evidence of pulmonary edema, but no difference in time to needing ventilation or the percentage of ventilation or coming off the ventilator. So whatever pulmonary edema was probably very subtle, maybe near NIV, but not clinically significant for me to. Bharath Kumar: Is Yeah. Exactly, exactly. Yeah. Correct. Significant and the clinicians were unblinded, right? So obviously, you know, they're gonna so that I think that was that was part of the issue. I guess a couple of other points. you brought this up as well. The intervention itself is being delivered up to only 24 hours. you know, do we expect this to make a difference to a longer term outcome at 90 days? That's that's a question. And then there are some limitations of the outcome itself, the days alive and out of hospital. this has been seen in previous trials too, Ramesh, where there is actually two spikes of this outcome, right? A lot of people, I mean, the people die, so there is a spike at zero, right? A lot of people get zero, or they get the best value, which is the 77 or 78 or whatever. There are two spikes, and this does create some analytical challenges. So, this is a limitation, one of the limitations of this DAOH outcome. The other limitation is that once you go home, Ramesh: So it's it's actually very interesting this point. I never thought about it the way you said, right? I mean, most people are going to peak at zero or most people are going to do really well. Even though you you think of it as a continuous variable, it's not technical technically continuous, right? I mean you're not going to have a every single of those variables going on. So that's an interesting point. I didn't think about that. Bharath Kumar: Well pick yeah. It's not really a continuous variable, right? So yeah. Going, yeah. I and we'll see that in you know results as well, right? So the other point that you know is a limitation of this kind of outcome is that so once you go home, it sort of treats you equally, right? If you stay at home, it doesn't really take into account where you functionally okay, what is your quality of life, etc. So that's one another challenge of you know these correct. We don't even know, yeah, exactly. They stayed out of hospital. they do, I think, have a sensitive analysis where they look at days alive and at home. Ramesh: Mm-hmm. You don't even know if they went home, right? You just went out of the home. Bharath Kumar: where the data was available. but the primary outcome itself is off hospital. So so it does have those sort of limitations. It's still a good outcome, but it has those kind of challenges that I think clinicians need to understand. So those are some of my thoughts on the strengths and limitations. anything else that you thought Ramesh: I I think I think you're right on Bharat. I think the first point I want to make is comment this group for doing this trial. It is extremely hard to catch someone after the first liter of fluid before they get the second liter of fluid, right? I mean it's going to be very, very difficult to do a study like this in multiple centers and recruit patients and standardize them to a fixed protocol. I think kudos to the Anzix group for doing it. So I think one that's number one. Patients not being sick is not their fault, right? I mean, they just have to pick the criteria and So happens that this happens. The only other point that I thought I'll add to whatever you said, all your points are valid is that the clinicians were kind of unblinded, and generally the the authors make a statement saying the clinicians were generally unaware of assignments. Generally unaware is not true blinding. So they may have still known how much fluid they got. And my discharge decision could be. Could be Bharath Kumar: Yeah. Ramesh: subjective, right? I can discharge somebody two days earlier, two days later. So that could be a potential bias in the number of days outside the hospital, if especially the clinicians have been non-blinded. So that's the only other limitation, maybe I would I would probably throw in to see. But overall, I think it's a fabulous study. It was very necessary. It makes me feel comfortable that my take would be that if somebody has received One and a half liters of fluid in the emergency room. It probably doesn't matter whether I give more and more fluids or I start vasopresses and give fluids only for a specific indication in small aliquots, which is 250 ml, and see what happens. It probably doesn't matter. Either of those strategies are acceptable. The way I look at it as a clinician is if I think somebody cannot handle the fluid, they have a tight aortic stenosis, their ejection fraction is very low, they are. They have another end stage lung disease from something else that has happened that will tip them over, then probably I would customize them to minimal fluids and vasopressors earlier on. On the other hand, I get a reasonably young patient who can probably tolerate a liter extra liter of fluid. Then I don't think I need to rush to start vasopressors. And maybe, like you said, I can avoid vasopressors and ICU admission in 10% of the patients if I push the fluid a little bit. So I think I'm going to be. Bharath Kumar: Yeah. Ramesh: Looking at the patient and say which category would this patient be better off, rather than trying to say one is better than the other. And I I feel reasonably comfortable, at least based on the existing evidence so far, that either of the strategies is reasonably acceptable. First of all, I don't do major harm in either of those strategies. And and probably they we can get away with using either of the strategies, and probably it is just coming down to. Bharath Kumar: Yeah, exactly. Ramesh: Whether you think you're going to put a central line and take him to the ICU or probably give a little bit more fluid and see if I can keep him off the ICU and see if I can get him better. Assuming you do all the other things right, right? You still have to give antibiotics, you still have to do source control and and all of that. So I I think that's the way I look at it, Bharat. What do you think? Bharath Kumar: Absolutely. Source control, yeah. Yeah. No, no, absolutely. Agree on all of those points. I think as you said, it's reassuring that, you know, the strategy of lesser fluids and also starting mesopressors was obviously not causing any harm. and we perhaps, as you again said, have to tailor it to the to the patient in front of us. but it's and it also I think underscores the message that in general the amount of fluid we are giving is lesser. So I guess the potential to demonstrate a major difference itself is is small. so no, nothing else to add. Again, I think as you said, congratulations to the investigators, wonderful trial, and thanks to everyone that's joined to listen the to this episode. we will stop there. Again, a reminder to you know to like, comment, subscribe and share. Thank you so much. Ramesh: Thank you. See you all next time. Bharath Kumar: Yeah.