Dr. Adrienne G. Randolph - Acute Respiratory Distress Syndrome

faculty from the Department of Manassizia here as well and welcome. I thank you to Dr. Adrian Randolph, who is our speaker today. She's someone that we know most of us know well from our work in the 7th South MSICU. And she'll be talking to us about acute respiratory stress syndrome. And she's been here since 1997 and is full presser in pediatric sand in Esthesia. And she is an internationally known expert in ARDS and sepsis in pediatric sand. It really helped create the policy network for pediatric acute lung injury sepsis investigators. Network is really a great example for any disease process where we're trying to put together information from multiple centers and really get good data on how to address issues in pediatric. So it's my pleasure to introduce some Dr. Randolph and I look forward to hearing what you have to say. So thank you. Thank you. I'm glad that everybody wants to hear about ARDS because there's a lot of new updates on it. And it's important that everybody sort of aware of all the new information that's recently been published, especially in children. And so I'll try to review that. I don't have any relevant financial disclosures, but I'm going to talk about ARDS first starting where when it was first reported. Talk about what the triggers are epidemiology mechanisms. Then talk a lot about management because a lot of you work in the medical surgical ICU, managing patients and. It's important to understand and also in the operating room where a lot of the ARDS can be initiated if depending on how you're managing the patient in the operating room. As I'll talk a lot about management and then evolving diagnostic criteria, especially in children. So I just want to point out and there's a handout for the talk that this handout here that this nature reviews disease primers has this entire ARDS primer that we just published. And it has a lot of the stuff that I'm talking about if you want further information. They also did an interesting one on the softial atreasia. So this these nature reviews disease primers are really great reviews of the entire topic up to date and that was just published. So the refer first report of ARDS was a reported in 12 patients, including two children, one or a child age 11 and a 19 year old. Where they reported that there was acute onset of the kidney, hypoxemia, loss of lung complaints after a variety of triggers. And that this was profound refractory hypoxemia. It didn't respond to any of the usual and ordinary methods of respiratory therapy. Even then they thought that there was something that had to do with the alveolar surface active agent being triggered or impeded and that people they knew right away that people is one of the first things that might help this syndrome and this was the ash, big low and petty first report in the Lancet. So then they first called it ARDS adult respiratory distress syndrome because they thought this is similar to what happens in these neonates with surfactant deficiency, RDS. But then they realized later on that it wasn't all due. It was a different type of syndrome and also to allow inclusion of children and exclude these chronic lung disease processes that also could appear similar. So they changed it to acute respiratory so the A became acute. And one of the first scores was the Murray Lung injury score that they tried to categorize how severe the lung injury. And if anybody who had a total score of 2.5 was considered at ARDS, the other author on this was Michael Matthew, who was the lead author on that nature abuse disease primer and one of the major people in the field of ARDS over many years. And has been involved in all the definitions. So the problem with this score was that they tried to score how many infiltrates you had hypoxemia, the higher your peep that you needed and the worst year lung compliance. But it didn't predict outcome. And it also didn't exclude non cardiogenic pulmonary demon, which is a key issue with ARDS is you have to make sure that the pulmonary demon isn't due to heart failure. So then this the first real definition was acute lung injury and ARDS. And the whole process was called acute lung injury, the whole syndrome. And this more severe form was ARDS. So this was the definition for a long time. And the one most of you probably remember from 1994 to 2012 acute onset severe hypoxia. And it was acute lung injury considered if it was between 300 and 200 and ARDS if your PF ratio, your ratio PA02 over your F out to being delivered is less than 200. This was the first time they put in no evidence of left heart failure. So this wasn't cardiogenic pulmonary demon. And that the and it was really important in the definition that this was a diffuse process in the lung. It wasn't just a single sided process. So you had to have infiltrates on both sides of the lung bilateral lung disease. So this is just a picture of a patient with a child actually with ARDS showing this diffuse pulmonary infiltrates and diffuse disease process. So there's many triggers of ARDS and there's they categorize it usually into direct triggers that they started in the lung versus indirect it started elsewhere in the body and now you have ARDS in lung. And so pneumonia is overwhelming the most common trigger for ARDS and it's mostly viral and bacterial pneumonia. But aspiration is also a very common trigger. And sometimes that aspiration becomes infected and becomes a pneumonia on top of aspiration. Pulmonary contusion is another common cause of ARDS. And then indirect lung injury sepsis is very, very common cause of ARDS that the patient started out with a bloodstream infection or infection from other. Eurosepsis and then develops ARDS. Non other overwhelming trauma to the body can cause ARDS. Sometimes that trauma, especially with broken bones, et cetera. Oh, this should be actually indirect pulmonary embolism can cause ARDS. Major burdens, pancreatitis, as you all know. And then there is trolley transfusion associated ARDS. Now that's gone way down after they got rid of using using some certain types of blood products from female donors and screening for antibodies in the blood products. So for for FFP and platelets and things that often triggered trolley more commonly than pack cells. We no longer use female donors routinely. So there is very little trolley anymore. But if somebody has massively transfused ARDS for trolley and then repurpersion repurposing pulmonary edema when you're repurposing the lung is also a less common but very important cause. And then in frequent causes are listed below, including high altitude pulmonary demon or a genocidema. So there's a lot of different pathogens because infection still the most common trigger for ARDS. But they are different pathogens in different settings. You don't need to really read this. This is in that review, but community acquired has different pathogens. Of course, the hospital acquired and then young children are going to be more likely to have ARDS triggered by viruses. Outside of pandemics when ARDS triggers, that's what you get in all the ICUs when in an influenza pandemic is influenza related ARDS. And then different pathogens depending on underlying host factors, especially immune suppression where you get both common and rare pathogens that affect immune compromised patients. So the epidemiology of ARDS, the biggest study in adults is the Lungsafe study from 2014. And it showed that it in adult ICU patients, 10% of them meet criteria for ARDS using that American European consensus definition. It was identified in 40% of ventilated patients and the associated mortality was pretty high, lower with less severe hypoxia, highest in the more severe hypoxia, between 38 to 46%. When patients are in randomized trials in the ARDS net, which is a network, clinical research network that folks is just on ARDS, which is now called the pedal network that tries to prevent ARDS. Those patients have a much lower mortality because they screen out a lot of patients with comorbid conditions that will have the highest mortality, especially those with heart failure and other underlying heart disease, coronary arid disease, and things that might make them die of other causes. And one thing that they really identified in that big study is that clinician recognition of ARDS was very low. The policy network did a similar study internationally at 145 pqs and found that 2.3% of all pq admits had ARDS and the overall mortality in this study was 17%. Now it was higher in the under-resourced less resource countries and it was highest in immune compromised patients and near drown in certain subcategories of patients and it was lowest in the pneumonia patients, but even then it was close to 6 to 7%. So it still was fairly high. And then pediatric trauma, there's multiple studies here that are recent, but the incidence is low, but the associated mortality is fairly high if a patient in trauma with trauma, child with trauma develops ARDS. It is a, it does really increase the mortality rate. So now I'm just going to go over and this figure is in that nature reviews disease primer. This is a normal alveolus. What you can see here is that the space is empty because ARDS is supposed to come in and transmit gas across these alveolar type 1 cells and go into the blood stream. But in this, in the blood stream here, but the, and these are alveolar type 2 cells here that makes our factant and everything is supposed in this are factant helps it so that the alveolus doesn't collapse. And everything has all these type junctions that keep fluid from coming in and what you see here is some healthy out resident alveolar macrophages and then the epithelial cells lining the alveolar type 2 cells. And the endothelial cells lining the whole capillary and the fluid very slowly comes across here and they get rid of fluid and the whole things empty. Now in the injured alveolus, what happens is this whole alveolus is filled up with this protinatious fluid that's full of cytokines and this is the process, the pathophysiology of ARDS. And cells are there that shouldn't be there. These neutrophils, all of a sudden are called to the lung and they come in through the capillaries and they fill this space as well, giving off all of these proteases, neutrophilic stress, all of these different things, platelets come in here, red blood cells come in here, the protein content of this fluid is high and it's full of these cytokines that are very inflammatory. So then what happens is all these type junctions break open and they can't keep the fluid out. And the surfact that this is usually made normally by these type 2 cells is now not working normally and it can't even get in there because there's so much fluid in there that the whole thing is collapsing, it's not working. You can't exchange gas across these cells and these type 1 cells sometimes become so injured that they even if you got the fluid out, they aren't going to work correctly. So and then sometimes if it is a infectious process, there's also bacteria and viruses in there that these neutrophils are in there trying to kill and when they kill a bacteria virus, all kinds of other contents are spewed out of the cell and sometimes it injures the cell and energizing pneumonia can develop in certain areas. And you get epithelial cell death and then these endothelial cells are very damaged. So this is just a picture showing something that for many years the pathologic diagnosis of ARDS is still is pathologic diagnosis of ARDS is diffuse, alveolar damage. Part of that is these highland membranes, these pink things that come up across that are now showing this very damaged lung. When we sometimes review some of the patients who died in the ICU, who've been on very high mechanical ventilator settings, we see these highland membranes. Lately, these diffuse alveolar damage, although it's seen in the most severe cases on autopsy, it's actually not necessary to have diffuse highland membranes to have the diagnosis of ARDS clinically or even thought to be pathologically anymore. Although it's an indicator that severe, severe damage occurred, you can see these basement membranes are also on these electromycrusca be very disrupted as far as the endothelial cells up at the allele cells. So this is just now what happens though, there's two phases of ARDS. There's this whole exudata phase, the whole alveolar is filled up with a protendacious toxic brew of fluid that's damaging the alveolar's further. And then as that clears up and the patient, and that's usually the first seven days of it, as that clears up and the patient's getting better, hopefully, what happens is a fibro-proliferative phase. So all these fibrandeposition or scar tissue comes in. And that's when some of the trials people did that somewhat controversial, but it's unclear, for sure, especially in children whether it works. But after seven days, giving steroids to try to treat or prevent that fibro-proliferative phase and medurian others have been, had protocols that they've developed for that is trying to treat the fibro-proliferative phase. But this is showing that these are green fluorescent cells, this is mouse that lung that was damaged with lipopolysaccharide to make an ARDS model. And basically, and the purple fluorescent are these type 1 cells. And there's a hypothesis now that these alveolar type 1 and type 2 cells transfer different sheet into each other to help repair the lung. So that the alveolar type 1 cells are damaged, those are the gas exchange cells, and then replaced by these alveolar type 2 cells that then become alveolar type 1 cells. So the process of repair is now being better understood a little bit as to how do you regenerate these lung cells that are so important for gas exchange and also some factor production. So then when you have this repaired alveolar list, you know, you still are going to have, you now have to restore all that fluid and ion clearance. All of this is cleared out and finally all these, there's patches to all these membrane pores, and there's this transdifferentiation that I just showed you. And finally, reprival evrration of all those alveolar type 2 cells to remake this effect that is necessary for the alveolar to collapse. So now one of the things that's really important to understand is that in, you know, the lung injury happens usually for one of those other triggers that I showed you on that list. If there's not a trigger present, be suspicious that this process is likely not ARDS because it's, it's really thought that it's mostly associated with those triggers. If somebody comes in with other reasons with profound hypoxia, it could be they have underlying chronic lung disease, anything could tip them over. So be, be suspicious if you don't see one of those triggers, but then it's how we manage these patients that can make things worse and add to the problem, and especially mechanical ventilator management. So the normal lung has normal compliance and resistant. You can set the title volume 8 to 10 cc per kilo use whatever type of ventilation you desire, and you're going to have low peak respiratory pressure. Every time you increase pressure, you get increased volume, and you're you put in a little bit of peak to prevent out of lectasis, and you a small amount of ventilator rate will achieve normal capnia. But air in air, yes, this isn't necessarily true. So I showed all those alveolar damage, and it's a very heterogeneous process. Some of the lungs going to see the ventilation and some of the lung is not going to see the ventilation. And as you try to open up these areas, especially the dependent areas, this is a picture here showing that there's this very, very consolidated deep in that lung area here, where, you know, the more you give higher pressure and volumes, the more you're traumatizing this other lung here that is, especially if you're using low peak strategies to make that open and close, open and close, where you're probably not opening this dependent lung area that is causing half of the most of the problem. So it's a very heterogeneous disease. And what happens is this ventilator induced lung injury, where you get all kinds of trauma, you get adelecto trauma, you repeatedly opening that these areas, these alveolar are really big and then collapsing them, opening, collapsing them. Barotrama, which before we the era of lung predictive ventilation, we had lots and lots of early people would often who've worked who were, you know, working in the ICU in the 90s and early 2000s, we had, we put in tons of chest tubes every day, we were putting in chest tubes. We often patients had three or four chest tubes with constant air leak when we used really, really high, high ventilator settings when we were aiming to use 10 to 12 per kilo, title volumes, volume trauma, where you have this lung over distinction from too big of title volumes. And then this bio trauma, where you're basically all that toxic group of all these inflammatory mediators is now going out, licking into the bloodstream and causing some of the systemic and other invulmation shock sometimes as well as more inflammation in the lung. So lung protective ventilation, you know, was a strategy that people started really believing in and is to prevent all of this trauma and preventing respiratory pressures of over 32 centimeters of water use low ton of lives, four to six per kilo lower than what we normally read that, which is somewhat six to seven per kilo. To prevent trauma to these areas of the lungs that are inflamed and optimize peak to prevent that collapse and expansion and keep them open at in expiration. There was a big pivotal trial, New England Journal of Medicine 2000 on the lower title volumes. This was the first positive trial ever in ARDS. It was a mortality trial showing that that was a lot of damage. But with lower title volume, you actually decrease mortality and increase the number of days without the later use by using this permissive hypercaptnea approach with the low title volume. They are protocol. They published on their website and this was the ARDS net trying to get people to use it. But unfortunately, you know, uptake of this protocol, it is a complicated protocol and doing permissive hypercaptnea can be a little bit scary because your pH on the patient can be 7.25 to 7.3. The CO2 can be in the 70s. The patient can get unstable. It takes a lot of training and having respiratory therapists and understanding why it's important to do this correctly. But at ARDS net sites who have done this over many decades, their mortality slowly, slowly dropped for ARDS and down into the 20% tiles. They have this plateau pressure goal of less than 30 in this protocol. And your pH goal is lower and you can, if your pH is really low, it has things to do. And what happens is the patient develops this really significant metabolic alkalosis to buffer themselves. But if your kidneys aren't working, this protocol often won't work. And often patients who have ARDS and from sepsis sometimes develop a kidney injury. And as you guys know, who manages faces on dialysis, it can be really hard to buffer somebody above a bicarb of in the high 20s if you're on dialysis, no matter how much bicarb you give. So sometimes it's achievable and sometimes it's not achievable to do this permissive hypercaptnea. So now I'm just going to show some slides that John Arnold shared with me from Gary Neiman who he did this limited thoracotomy on these pig lungs. And it just shows the importance of peep. And I hope this works. It's this lung injury followed by recruitment. This is five centimeters feet. This is like a little scope outside of the lung showing, you know, what's happening with these alveoli. This is video with the in view of microscope of subplural alveoli ventilated with the lower peep setting of five centimeters of water following tween and notaky lavage and recruitment maneuver. And we see dramatic repetitive recruitment and de recruitment of alveoli with title ventilation. Okay. So that was five centimeters of peep and you can see that alveoli getting really big and then going down. That's called, you know, you don't want that to happen because you're sharing the alveoli over and over, especially as you go up up on the pressures trying to open up that dependent lung, but you're actually opening up the healthier lung. The alveoli that are able to open will open. And so then you're damaging them further and exacerbate the problem. This is video with the in view of microscope of subplural alveoli ventilated with the higher peep of 10 centimeters of water following tween and a trake lavage and recruitment maneuver. And we see the alveoli are stabilized with a higher peep setting, changing size very little with title ventilation, much like that seen in the normal healthy lung. So that's just showing that peep is really the number one strategy for ARDS to maintain these alveoli in an open state, not to prevent all of that secondary ventilator induced lung injury that occurs as soon as you recognize ARDS. And also now there's studies in the operating room that some of the ARDS that's triggered occurs in the operating room. How we manage them in the operating room. There's now and at our center, we have better ventilators on the anesthesia machines, but the anesthesia ventilators used to be pretty primitive. As far as what they could do, we have basically a full ventilator on the anesthesia machine that John Arnold and respiratory care developed to. And so some of these very high risk patients, especially those with massive fluid shifts, those that you're doing pulmonary interventions are collapsing the long re expanding plus big fluid using lung protective ventilation strategies can be important and understanding when when the patient's getting in trouble to. Intervene early. So this is the second one of the second trials. Okay, so we talked about the title volume. So that was the higher lower title volume. So four to six per kilos. The goal if you have severe ARDS. But now what about the peep should you be using high peep strategy or low peep strategy high peep strategies really high we're talking. You know, in ones that are 14 to 20 of peep, which we didn't use in children for a long time, but now now we do use we go up as needed to whatever we need on the peep. So so that on the lower peep group, there were 8.3 centimeters in the high peep group 13.2. But either protocol actually had the same outcome. So they didn't prove that the high peep versus low peep. They had these different algorithms. This was the low peep algorithm. Tight trading with the 502. This was the higher peep algorithm. You went up to on the peak quicker and you've got to higher levels of peak quicker. So one thing that's controversial about this area of research on peep is that different trials. There's these different trials that have been going on. There's five different trials that some of them said yes, you need to hire peep. Some of them said no, yes, no, and then sort of a mixed output, you know, effect. And so why is that? Where are we getting all these different results in these different clinical trials. So one thing that's really important to understand is there's different pressures on the Avioles. And so, you know, one thing that might be important is to understand what is the plural pressure pressure. So the chest wall itself is actually having pressure on the on the outside of the lung, a counteracting pressure. And if somebody's morbidly obese with like almost a, you know, 100 pound weight on their chest, that can institute a lot of pressure. And you actually need to use higher ventilator settings in morbidly obese patients to overcome this external pressure. If somebody has other reasons for severe restriction, it could be that you can't you have to counteract that. The other thing that's coming up from the bottom is the abdominal pressure. So somebody who has a massively, you know, inflated, you know, huge abdomen for some reason sometimes it's organs in some of our oncology patients, the liver is enormous and then on top of that, they may have the sighties. You need to counteract that pressure. You may need more peep. So the abdominal pressure, you can actually measure the bladder pressure to estimate it. But the plural pressure, what is been used to measure it is this isophagial phenomenon, this isophagial probe, which in adults, some people are very into measuring this. And we've tried to do this some here. It's a little bit more challenging in children because they don't make them down to the small size of babies that are as safe because they're a little bit too big. But when they did do Danny Talmar, who's over at the BI, they did this, it'sophagial pressure guided, I think lung injury management, trying to estimate the plural pressure to really get at the trans alveolar pressure and titrating peep baby. And titrating peep based on that and they showed that it actually did improve your oxygenation and your lung compliance. This other thing that is a bit still controversial is recruitment maneuvers. So recruitment is you try to reopen those unsabeled airless alveolar oil, why you where you go up on the pressure, transiently you hold it at a really high pressure. And hopefully, as well as those dependent lung areas slowly, slowly will open up. And because you're not doing this ad electo trauma, let me just open it up really big and go down open it up really big and go down. You're just opening it up and holding it. Hopefully all these little area, depending on who will open up. And so this sort of shows what they're trying to do. And these are the time in seconds, two seconds. This is 40 seconds. And that the micro, the gross is the gray opening of the lung and then the micro is in the black. And it takes a while for all these different areas to really open up even though of the of the whole lung, which is why you have to do a sustained inflation maneuver. So people then tried to, you know, start implementing this as you set your peep is doing a recruitment maneuver and then putting the patient on, especially that's what we do often when we put patients on high frequency oscillator ventilation. And people tried to do randomized trials to show whether or not you needed a recruitment maneuver, but it really hasn't been shown that recruitment maneuvers really improve your outcome. And you have to be careful who you do it in because if the lung disease is super heterogeneous, especially if somebody hasn't necrotized pneumonia, you can cause baritrama in those areas that are very susceptible to really high pressures. So you just have to be really thoughtful about what is the patient's lung disease and is this somebody that's safe to do a recruitment over. So then the other big area that is very, you know, that there was a lot of hope for is, OK, in the regular mechanical and mechanical, it's the title volume, you know, you have this peep at it somewhere around 10 and then you set that is the TORI pressure above people. You're 30 over 10 and you're going up and down up and down at some rate in the 20s or whatever your rate, depending on the size of the patient. But what if you could actually just continuously develop deliver low title volumes with a laminar airflow and not do that to the lung and sustain amino repressure. So this is the theory behind the or the mechanism of high frequency oscillatory ventilation where you oscillate around this mean airway pressure. And overall your inspiratory pressure is you're able to maintain a higher mean airway pressure without getting these toxic levels of high inspiratory pressure. So John Arnold from our institution did one of the first high for example, the TORI ventilation randomized trials published in 1994. And he used this aggressive volume recruitment strategy for high frequency. It was very novel at the time. People weren't really using high frequency at that time. And one of the issues on this trial was that you were able it was a crossover study. So, you know, you were able to cross over into the other arm. If you needed to bail out because a lot of these centers used high frequency as a rescue therapy. And high frequency overall improved oxygenation. It wasn't a huge trial, but there was no differences in duration and mechanical ventilation, nearly for 30 day mortality. But it might have prevented worse lung damage because at 30 days fewer patients required oxygen. So that is really important because in that era, we didn't look at long term outcomes. We just looked at survival and all of our trials were underpowered for survival, especially in children. The adults they were not necessarily underpowered for survival, but there was other things causing death in these patients that some days it was hard to see a mortality effect. Now we're focused on these long term outcomes. So if you go back to this trial, this would have been a very important outcome that you probably caused less lung damage if you have less oxygen at 30 days. But the problem is that all these trials have had mixed outcomes and none of the adult trials were really significantly positive that they switched over the high frequency oscillatory ventilation. It's hard because you can do multiple things with the high frequency oscillate later depending on where you set the hertz. If you set it really low, you might as well be doing conventional ventilation because the higher the hertz, the higher the rate, and the higher the oscillation with the lower the inspiratory pressure. So unless that's really specified really clearly and the control alarm is specified that you're using a protocol, you can't really interpret these trials. And in some of the adult trials, because they didn't want to paralyze the patients, because of the risk of critical illness, myopathy, they had these patients on a lot of purple fall to keep them pretty much anesthetized. And then they used the high frequency, but they weren't paralyzed. And so it can be hard to manage adult patients and really big patients without paralysis, where younger patients sometimes you don't need to paralyze them and you can oscillate them. So so far it hasn't been taken up in widespread use in adults, although it is in children, it's used as a rescue therapy. And in fact, there's going to be a new oscillatory high frequency oscillator trial through the policing network that's starting to enroll very soon. Neuromuscular blockade, the risk is prolonged paralysis. And often these patients, the artists get steroids for different reasons and critical illness, myopathy and that can really prolong mechanical ventilation, ventilator duration. So it's thought that as much as possible to avoid paralysis, when I missed a slide here. So this is the trial of Neuromuscular blockers, however, and it actually shows improved survival ventilator free days with paralysis using Neuromuscular blockade. So if somebody has severe air DS, it's thought that it probably is, if you're not able to actually ventilate them, best to then paralyze them. Don't avoid it to the point where you end up that the patient dies from avoiding the paralysis. And some of that is because the ventilator is a synchrony when the patient is trying to breathe and you're on these really high pressures and you're not able to really control what's going into the lung. And that can cause a lot of trauma to the lung. Is this a layer of the synchrony? So that's why it's thought that the paralysis is very important. So I'm just going to go back one slide. This is the prone positioning trial. So remember, I showed you those dependent lungs areas of lung. So there was a prone positioning trial and adults that looked very promising. The policing network and this came out of our center when Martha Curley was here and John Arnold, one of the senior author is the senior author on this along with Michael Mouthey. They did a randomized trial of 102 children across seven centers of prone positioning 20 hours a day. A lot of the patients were from our center and it was in part a nurse driven protocol that because they had to flip the patient and then flip them back for and have them prone as much as possible. And basically it was software futility because they didn't see any differences in this trial. However, there's now been more positive adult trials about prone positioning and it's thought almost to be standard of care in the adult world. If you have profound hypoxia that you should flip the patient because of those dependent areas of lung. If you can, some of the surgical patients with open out abdominal surgery, it said there's reasons not to flip the patient. But otherwise you should try to flip the patient if possible. So now they're enrolling in this prone and oscillate factorial RCT prospect is called so it's actually a factorial design of high for isolation versus prone positioning through the policing network, a randomized control trial. And there's the website for more information. So the next thing I want to talk about is fluids because this is incredibly important in ARDS because it's now the arts net switch to the pedal network. The pedal network is all about preventing ARDS and it's got sites in the ED and ICU trying to prevent ARDS starting in the emergency department of how you manage the patient and the biggest, biggest thing is fluids is how that you know, especially with steps is recitation, which it used to be that everybody, you know, really recommended more fluid more fluid more fluid now. We're really careful, especially to watch the if the patient's developing pulmonary DMA because that's known that that's one way if you want to exacerbate ARDS is to over give too much fluid that's not necessary to the patient. So, you know, in this cardiogenic pulmonary DMA, the DMA fluid is protein poor. This is the there's a whole article on pulmonary DMA, the English Journal of Medicine that's a good review where it is this is this protein rich edema fluid in the noncardiogenic pulmonary DMA. And, you know, that is you have increased hydrostatic pressure in the cardiogenic pulmonary DMA pushing the fluid in, but in the noncardiogenic this hydrostatic pressure is normal. This is the only other major positive randomized trial in ARDS is liberal versus restrictive fluid and looking at the liberal fluid strategy where they gave a lot of fluid that they thought really more mimicked what we were doing in real usual practice at the time. Although that was criticized that you were overdoing it on the liberal side later on versus the restrictive at day seven, you were positive seven leaders in the adults versus minus 136 ml in the restrictive. You got more ventilator free days these alive and free of mechanical ventilation, which is important because they're mortality by 2006 in the ARDS net had dropped down to the 20 24% or so. I mean, you can really do mortality trials anymore, but this protocol is called the fact algorithm because they're also randomizing to do you need a pulmonary catheter that was a factorial design. It was really complicated and nobody could really use this and it was very hard to do this protocol with the fluid restriction. We worked with ARDS net. This is Stacy Valentine when she was a fellow here and then junior faculty to get all their data and compare the amount of fluid per kilo per day because they didn't report it in per kilo per day and in kids we have to use per kilo per day. They gave us all their data and we compared the fact conservative arm fluid. By day two, you're actually negative. You start initially recessed at the patient, but then you cut it off. In fact, they have KVO, which means to keep open. They don't give maintenance fluid. And then this is the liberal arm. They're positive, positive multiple days. And then we're comparing the pediatric cohort, which we took from five centers. And in the children, because everybody argued, oh, we don't use that much fluid in children, but we do. And in fact, the infants under a year were the highest. And why is that? Because all the antibiotics and everything else has to be diluted. And just giving them bacon, my son, when you say I'm going to give them a bacon, my son, you just gave them this huge amount of volume. And so unless you're watching what you're doing and saying total fluids at maintenance, you're going to give maintenance fluids on top of that. All this other stuff and sometimes be at two times maintenance fluid. So it's really important to watch your fluids. Other therapies that have been tested include in health nitric oxide, it improves your oxygenation, but, but it hasn't really been proven to affect outcomes in any trial. I don't want to go over all that. That was a very hot area early on. But and people still use it as a rescue if you're trying to get a patient on neckmonia need to improve oxygenation. It still does work well for that. And the policing network did three trials. This was our hot area was surfactant. So we thought, you know, you have surfactant dysfunction, gives surfactant to this injured lung and you could improve outcomes. And the first trial does Wilson did. This was one of the first policy trials was publishing jamma on Cal factant. And that is is a calf lung surfactant high end protein B. And so then it was weekly positive and then we did this loosen act that which is recombinance or effect and I did that with Neil Thomas in kids under two thinking viral induced lung injury. We had a lot of patients involved from here. We put it down the endotracheal to we have all protocol how you move the patient around to try to swish it around. We have to then rapidly decrease the later settings because you can cause them with our season these areas that you now put surfactant in that now open up. But we showed improved oxygenation but no will major it was a pilot feasibility trial. It was unlikely that we're going to show improvement and outcome. And some of that was because we also enrolled in South America in Chile. So we could do our you know viral season on both you know around the year and people ventilated a bit differently and kids were sicker in the US. But so surfactant will improve your oxygenation but it's unlikely probably to improve our outcome because the second Cal factant trial was overall negative. And then ECMO, John Arnold, Jim Fackler and others designed, tried to design a randomized trial of ECMO early in the 90s. But then what happened is the mortality in ARDS as we got better at ventilating these patients dropped and it wasn't feasible to do a mortality trial. And you can't really justify putting patients on ECMO for anything but a mortality trial. So they basically now ECMO uses a rescue therapy for patients with ARDS dot have reversible cause that you can improve there that you can get them through and then let the lung kill. An important note is that now there's evolving diagnostic criteria. We now have two new diagnostic criteria for kids. And that in 2012 the adult criteria changed a bit. We have this pediatric. It was the policing network did the pediatric acute lung and reconstruction since this conference to redefine this pediatric ARDS is now called parts. And then the Montro conference defined it for neonates and it tried to exclude surfactant deficiency premature lung disease. It hasn't been evaluated the party observational study did do a multi center evaluation of this. One of the problems with ARDS diagnosis is that even ARDS experts in the arts net are not don't have good agreement on what is the bilateral infiltrates. So it was only about 50 to 60 percent agreement on these chest X-rays, which is the key core of bilateral infiltrates. So this is cardiogenic pulmonary Dima. This is ARDS. You can see that the hearts a little bit more globular but like curly B lens and all these other things they're not really varies accurate in saying the weather distinguishing between the two. So it's really hard to say on the chest X-ray bilateral infiltrates are present. So that is now this new Berlin criteria, which is modified a bit from the American European criteria. The real only modification is that they gave a timing is within seven days of inciting trigger for and this is the same for the complete definition and the Montro definition because acute was never defined. So acute now is to find a seven days and the same as the old definition restaurant failure not fully explained by cardiac failure overload and how do you exclude that they recommend more echocardiograms now in neonates you actually have to have an echocardiogram to exclude a pda. But the difference between the peak definition and the Berlin criteria and the Montro criteria, they're still wanting bilateral disease and in the peak criteria now unilateral infiltrates are acceptable because they say we can't tell the bilateral infiltrates. It's just to inaccurate. Well, it may be too inaccurate, but ARDS is still supposed to be a disease diffuse disease process. So unfortunately now in the mild disease, you're now including patients who have unilateral pneumonia who don't really meet the criteria for puzzle physiologically what I was showing you that happened in the lung being full of fluid and all the things that happen with the RDS. But those patients are at risk for a RDS and it's been shown that many of them go on to have ARDS so long protective ventilation is important in that patient population. And the big difference in the Berlin criteria is that they have mild moderate and severe there's no ALI anymore Berlin criteria that came in in 2012 published in jama is I mean the whole thing of course is acute lung injury, but it's now all ARDS mild ARDS moderate and severe depending on your oxygenation. Same thing in children except we in the public definition they're using oxygenation index or if you don't have an arterial line oxygen saturation index, which is your mean air repressure tantrum to 102 times 100 over divided by your PAO2 because it incorporates how much support they're on where the PF ratio does not. And the mantra definition used the same criteria as the public definition and was recently published in Lancet Respiratory Medicine. So finally it's important to really understand so now in the pediatric definition they're saying that it's important to understand the host and that even patients for example are diaphragms who were ventilating those patients could have ARDS. That could be making their lungs sicker. We previously didn't have definitions of ARDS for patients with the chronic lung disease or underlying lung processes, but now the the public definition is trying to include patients, including patients with hypoplastic left heart syndrome who are cyanotic by saying that it's a change from previous. So this was their baseline and now they came in with this profound hypoxia that is not attributed to their heart condition that it's true that hypoplastic left heart syndrome patients can get ARDS can deal diaphragmatic, and they're currently in patients are at high risk for ARDS because you're really over-distending their health their side of the lung while you're trying to ventilate them as they're recovering. So they're at high risk for developing ARDS but it's really hard to diagnose it in them. And although they included them in the definition, there really is zero data on that population of patients including pathophysiology. Certain populations of patients that steroids may help, especially those with viral induced lung injury, and certain populations that you should keep them dry as a bone like BPD patients, you know really be careful of fluid overload. And then there's all these different biomarkers that have been shown that these are now potential biomarkers that may help give us sub-dena types of ARDS, including surfactant protein D that leaks into the lungs. These are in the CIRA although they're generated often from the lung. Club cell protein, some of them are epithelial biomarkers, endothelial biomarkers. Different inflammatory biomarkers, IL-8 is a serum biomarker that tracks really well with lung recovery and has been a very good predictive biomarker early on of ARDS outcome. And then coagulation of fibroanalysis biomarkers and so there's all these different things that can help us to stratify patients into different categories of ARDS. And there's a whole literature on that more on that is reviewed in that in that nature reviews disease primer and if anybody there's also other review articles in that area. So overall, you know severe parts is now called parts is associated with high morbidity and mortality in children and it's important to recognize it early because you might be able to prevent it from getting worse. You might even be able to prevent it from happening all together by how you manage patients with fluids when they come into the ICU, don't get them more fluid than they need. If they're inflamed and sick and they have a pneumonia, they should have an order that says total fluid limited maintenance give them boluses as needed to if you need to resuscitate them. But otherwise don't don't just write maintenance IV fluids and then all this other crystal oil and other things on top of it. Do also make sure that you turn off the inciting source if somebody has an ongoing infection, for example, in their abdomen and they have ongoing ARDS that is likely that that is an inciting source just like it's you know, you know, sepsis induced ARDS that if you do source control, you're going to turn off the sepsis, you're going to turn off the ARDS. And without source control, you're going to have an ongoing process. So somebody who has continually inflamed ARDS think that you know, look hard to make sure that you're not missing source control. And then focus, you know, future directions are to substratify these patients into different subvenet types, don't clump them all together into ARDS, figure out what works for who, what treatments and therapies should you be doing in these different subcategories of ARDS like sepsis induced indirect lung injury ARDS. And viral induced influenza induced ARDS. So I just want to thank all the policing network collaborators and also now the pick flu network is the network that I'm running that we focus specifically on influenza and influence induced ARDS. And then this is Michael Matthew and Carolyn Calthie who are ARDS experts who've done a lot of the work on biomarkers trials, definitely Michael Matthew on definitions. He's really been instrumental in helping the policing network with all of the ARDS studies, including pro positioning and the new prospect trial. And all the different fellows in collaborating experts, many of them here and through the policing network who helped with all the different studies in ARDS. Thank you. Well, you're doing I first like to thank you for bringing to us this very important topic and very comprehensive review. It's certainly something that we struggle with our mutual patients quite quite frequently. I have a couple questions and I'm sure there'll be more from the audience. So you talked about the paralysis and high frequency ventilation. So is the issue if you don't have paralysis that you have just all. Regidity or is it that the patients are fighting the fighting the ventilator so to speak. I think I think it's a little bit of both, but it's mostly that if the patient is trying to breathe and you're trying to oscillate them and it's not synchronizing, it's going to potentially cause trauma with this to synchrony. And the bigger the patient, the stronger they are at at impeding the ventilator support, which is why sometimes in the infants, we don't need to paralyze them and it could be just infants don't have a rigid chest wall. They aren't just strong with their respiratory muscles to fight the ventilator, but in adults, it's really hard and many of those adult trials tried to not they did not paralyze. So it's hard to know they were negative studies. They didn't necessarily show harm, but some of them did show longer time on the ventilator. You know, it didn't show increase mortality, but how you set up your protocol to can prolong your ventilation, how you design your protocol in the high frequency because when do you come off. You know, so we test patients on conventional will take them off test them on conventional to see if the compliance is improved because the problem with high frequency. You can't tell if the compliance is improved, so that's another issue with high frequency, but it's mostly the patient trying to breathe. So, and then the second question with the subsistence, and the ARDS and you talked about trying to restrict the fluid volumes as much as possible, but obviously if you restrict the fluids, then you have to give more pressers. So, so what are the accepted metrics now for how much fluid do you give a two-year-old that comes in with with sepsis and respiratory failure as far as what volume do you give them versus increasing the pressers further? So, they're in children. It's still a work in progress. There is a randomized trial of early basal pressers. I mean, you still should resuscitate them some. It's not like don't give no fluid, but this 60 per kilo in an hour. That is on the outs because we're probably fluid overloading a lot of patients, especially with this broad definition of sepsis that somebody with bronchialitis could have sepsis. So, because it's softer criteria, especially in children, of just perfusion. But if somebody's really in septic shock, you need to resuscitate them, but you also need to early on do an echo. Look at the cardiac function. They may need some type of anotropic support for their heart. There's a lot of toxins mediated by bacteria that cause myocardial dysfunction. And you need to figure out what's going on. Is this distributive shock? Is the patient super vasodilated? You can pump as much fluid as you want. But if you don't tighten them up with some type of vasopressor, you're going to probably give them an excessive amount of fluid and then institute the vasopressors later and have too much fluid. So, earlier institution of vasopressors, but it's not no fluid. How much fluid and in who is still controversial? It has to be individualized. But this 60 per kilo to 100 per kilo. And many patients got 100 per kilo resuscitation. Some patients need it. They may come in really dehydrated. But in general, you have to be more thoughtful about it. And after the first 30 per kilo, you need to really think what is, you know, you really understand the process. Is this vasodilation? Is it a pump problem? If it's a problem, you're going to treat it differently. Additional questions for Dr. Wrenoff. Dr. Fauza. Very nice review. The hemoglobin dissociation curve can be manipulated pharmacologically. For example, the induction of fetal hemoglobin to treat sickle cell disease. And one could envision pharmacologically increase in the affinity of hemoglobin to oxygen as a means to weather the storm during the RDS. Has any worked me down that area? Not necessarily on that people early on did do, you know, high hemoglobin, you know, and excessive transfusion. And we used to transfer these patients up in the 90s and into really high hemoglobin thinking that we were helping their oxygen delivery. But that turned out to be not helpful. So we no longer do this excessively high hemoglobin transfusion, but we haven't used as far as I know there may be, there may be people who are working on that in animal models, but there's never been a trial of it in humans. Additional questions. So everyone's fine with one. So with the current evidence in with the child with ARDS, let's say a seven year old. What, at what point do you go to high frequency ventilation versus conventional ventilation? Or is it not enough evidence to really determine which? So I would say that there really isn't good evidence to determine that years ago, we used to bail out at like a peak of 12 and go to high frequency thinking we're being lung protective. Now we tend to go up on the peak and we're better at using the lung protective ventilation and the ventilators have gotten better too in their how they deliver the ventilation. So they're a little bit less damaging. We don't really have a set criteria, but there's and there's some patients who may benefit more than others, especially those with diffuse lung disease from like a viral induced process or sepsis induced lung disease might be another where somebody with, you know, some other forms of lung disease may not. So just nobody knows exactly who is the best candidate. When you do go up on the high frequency, usually the other thing that you do is you go up by five on the main airway pressure when you transition them on. So that's why people now think that probably we're under using peat we could be more aggressive with the peep and we don't need to transition them over there to the high frequency. So we have to think about how can you ventilate the patient because if your ventilation is really bad, you're probably going to have to use a low hurts, you're may not do better at high frequency. Your oscillation at a low hurts around that mean of 30 is going to be, you know, maybe even 55 you may be worse off on high frequency. Think about what's going on the patient and would they potentially benefit some places still do early high frequency, but it's sort of not as many. And we do it a little bit later and we're not using it as frequently as we used to. Thank you for bringing all this information of us today. Thank you.