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Multiprofessional Critical Care Review: Pediatric ...
Acute Lung Injury
Acute Lung Injury
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So thank you all, my name is Robby Kamani, and today I'm going to talk about pediatric acute lung injury and ARDS. I have no disclosures that are really relevant for this talk. So here's what the board wants you to know about ARDS, know the epidemiology and risk factors, pathogenesis of lung dysfunction, how to diagnose it, the pathophysiologic mechanisms, the principles of medical management, principles of an open lung strategy, general principles of ventilator management, and then the potential implications of a fluid management strategy. One of the most important things to remember as we're talking about ARDS is that there is an S in this. This is a clinical syndrome that's characterized by diffuse inflammation in the lung. This will result in hypoxemia from either injury that occurs at the alveolar epithelial surface, i.e. somewhere here, or the endothelial surface, somewhere over here. And unfortunately, there's no definitive diagnostic test like a biomarker that's going to be present in all cases. As a result, our definitions have all been clinical, starting with the original descriptions by Aushbach in 1967 with 12 patients with acute respiratory distress with cyanosis that was refractory to oxygen, decreased respiratory system compliance, and diffused pulmonary infiltrates. And you'll notice that these symptoms are still present in what we think about with ARDS today. It was originally called the adult respiratory distress syndrome to really differentiate it from the process that occurred in neonates, but eventually was changed to acute to account for the fact that children could have it too. So as we're thinking about defining ARDS, it's important to remember the hallmark symptoms of the pathophysiology of the disease. This is hypoxemia, which we think is most reflective of intrapulmonary shunt, poor respiratory system compliance, and loss of end expiratory lung volume or functional residual capacity, that the process is diffuse, albeit non-homogeneous. There is significant endothelial injury, as well as alveolar epithelial injury that results in alveolar and interstitial edema, as well as increases in alveolar dead space. So after Oshbach's original description, the first real attempt to define ARDS came with John Murray's lung injury score in 1988. There were four components, the chest X-ray, hypoxemia score, PEEP, and respiratory system compliance. And all of these were tied to a pathophysiologic concept, the chest X-ray to differentiate diffuse versus low-bar disease, the PF ratio to characterize the severity of hypoxemia deficit. The PEEP score was about how much of a reduction there was in end expiratory lung volume, and then, of course, a direct measure of respiratory system compliance. There, in fact, has been a pediatric modification of this score, which is similar with respect to the chest X-ray and the hypoxemia, slightly lower ranges for PEEP, and, of course, compliance is normalized here to weight. Now, the lung injury score, while really comprehensive, did not gain a lot of wide-scale acceptance perhaps because it was a little too cumbersome to use in clinical practice. So there became the American-European consensus definition in 1994 of ALI versus ARDS, acute onset of disease with PF ratio less than 300 for ALI and less than 200 for ARDS. This was regardless of the amount of PEEP. Bilateral infiltrates were required on chest X-ray. We had to exclude other causes like left atrial hypertension with a wedge pressure. And there was no formal ARDS risk factor that was required in the definition. Now, this definition was used for 20 years, but there were many limitations. There was no definition of what was meant by acute. This ALI versus ARDS categorization was a bit confusing in that ARDS was a subset, then, of ALI. The effect of PEEP or ventilator management in general on oxygenation was not accounted for with this definition. There's poor inter-observer variability or poor inter-observer reliability, more specifically with the chest X-ray, particularly on the idea of bilateral infiltrates. Of course, wedge pressures were increasingly less measured, especially with the advent of echocardiography. And, again, no formal risk factor was required. And as we think about applying this to pediatrics, there are some additional limitations specifically related to the use of arterial blood gases in that those are not standard on all children that we take care of on mechanical ventilation. And, of course, we almost never use the pulmonary artery catheter. So the Berlin definition of ARDS was subsequently created in 2012, which overcame some of the limitations of the AECC definition. Timing was specified to be within a week. Chest imaging still required bilateral opacities, but there were some common training films that were provided to try to reduce some of the variability in the diagnosis. Respiratory failure not fully explained by cardiac failure or fluid overload. So the PA catheter requirement was removed. And in the circumstance where a clear risk factor was not known, then an echocardiogram, for example, was recommended. And then ALI versus ARDS was eliminated, and it was all ARDS, mild, moderate, and severe based upon the PF ratio. With a minimum PEEP requirement of 5 in the mild to moderate group. And initially, they considered a PEEP level of 10 in the severe group, but ultimately in the final publication, in fact, they went back to a PEEP of 5. Now until 2015, as a pediatric community, we simply used adult definitions for ARDS. And that was until PALICC was convened to create a pediatric-specific definition for ARDS, as well as recommendations for clinical practice management of pediatric patients with ARDS. Now, the PALICC definition has many similarities to the Berlin definition, specifically with respect to timing and origin of edema, as well as this gradation of severity in terms of ARDS. But there are some notable differences. Specifically, we have pediatric-based definitions. So we have age incorporated into the definition to exclude patients with perinatal-related lung disease. The most striking difference probably relates to the chest imaging criteria here, findings of a new infiltrate consistent with acute pulmonary parenchymal disease, i.e., the removal of bilateral infiltrates from the requirement from the definition. We have PARDS for those on non-invasive ventilation, which is full face mask, CPAP, or BiPAP with a PF ratio less than 300 or an SF ratio less than 264. And then for those on invasive ventilation, we have switched to the use of the oxygenation index for mild, moderate, or severe ARDS. And if an oxygenation index is not available because there's no PaO2, then you can substitute the SpO2 in that equation for the oxygen saturation index here with criteria, again, for mild, moderate, and severe. We also have some special considerations for those with cyanotic heart disease and chronic lung disease. In addition, we established criteria for patients at risk for ARDS. And the real hope with this was to identify patients that are at high risk of progression to ARDS through which prevention strategies may be helpful. The similarities with the ARDS definition with respect to age, timing, origin of edema, and chest imaging, the difference simply relates to the degree of oxygenation impairment. So now we'll switch gears away from the definition and talk a bit about epidemiology. So with the new definition of ARDS, it was really unclear if there would be any change in the number of patients that were diagnosed with ARDS and what the impact potentially would be on the epidemiology. And so we conducted the PARDI study in 145 international ICUs screening over 23,000 ICU patients, about half of which were on mechanical ventilation, and identified 744 new cases of PARDS. So this gives about a 3% rate of ARDS that occurs amongst ICU patients, or 6% of those on mechanical ventilation. And overall mortality was 17% for all the patients enrolled. As we look down into this flow chart and we further characterize the patients that were enrolled, 28 of them were on home ventilation. And then it's about an equal split of one quarter each in NIV-related PARDS, mild, moderate, and severe PARDS. And interestingly, the mortality rate is quite similar when you look at initial PARDS severity for those on NIV, mild, and moderate PARDS, with a very large increase in mortality that occurs for those with severe PARDS, with mortality rates over 30%. The biggest risk factor for PARDS was pneumonia or a lower respiratory tract infection. And this is consistent with descriptions of PARDS really going back for the last 20 years or so, with sepsis being the second most common cause, and in fact, sepsis being more associated with non-survival. And in fact, as we look at the risk factors for mortality in pediatric ARDS, certainly the degree of oxygenation impairment is a relevant phenomenon here, characterized by the PF ratio. But perhaps the more important factors are things like if the patient is immune compromised or if they have other organ dysfunction on the day of PARDS diagnosis. Certainly there is a relationship between the initial oxygenation index amongst those that are invasively ventilated and the risk of mortality, with this large increase in mortality risk that occurs around the oxygenation index of 15 or 16, which is what also corresponds to that severe categorization. And consistent with what we've been observing over time, there has been a trend for lower mortality with pediatric ARDS from initial descriptions back in the 90s to the updated PALIC, to the PALIC recommendations that came out in 2012. And if we were to put the party study on here with an overall mortality rate of about 17%, we'll see that this trajectory appears to be following this course. Now, one of the most important changes with the PALIC definition was the use of pulse oximetry-based criteria. And this is the oxygen saturation index for the oxygenation index, or the SpO2 to FiO2 ratio for the PF ratio. And this simply substitutes the SpO2 and the PaO2 in that equation, as long as the SpO2 is less than or equal to 97%. And we've previously shown, as well as others, that these OSI and OI, one over the SF and one over the PF, in fact, have a very strong linear relationship with one another. And this is important because, as we see when we look closely at the party study, most of the patients that are diagnosed with ARDS are diagnosed with pulse oximetry-based criteria. And the pulse oximetry-based criteria allows us to diagnose ARDS sooner than we would if we required the arterial blood gas. So here is, at PARDS diagnosis, what we see is only about a third of the patients met full Berlin criteria at the time they met PALIC criteria, i.e. they had a PF ratio less than 300 with bilateral infiltrates. Now, this group had the highest mortality, over 25%, but that's because there's a bit of a selection bias for who gets arterial lines. Those that have an arterial line typically have multiple organ dysfunction and hemodynamic instability, and those are the higher-risk patients. There's a very large chunk that still have bilateral infiltrates on chest imaging but do not have the arterial line in place but still would meet criteria if an SpO2 to FiO2 ratio was used, for example, with Berlin. And then there's a small portion that have unilateral infiltrates on chest imaging. Now, by three days, the overlap gets bigger, i.e. more developed bilateral infiltrates and we place more arterial lines, and there's only a very small portion that are left within the three-day time frame that persist with, for example, only unilateral infiltrates. In this next section, we'll concentrate on pathology and pathophysiology. So there's really a nice review in the PALIC papers that describes the pathobiology of acute respiratory distress syndrome and how there are really implicated pathways related the epithelial-endothelial permeability barrier, the permeability with pulmonary edema and pathology in ARDS, alveolar epithelial dysfunction, endothelial dysfunction, inflammation, surfactant dysfunction, thrombosis, and fibrinolysis, as well as the processes that are involved in resolution. It's important to remember that the hallmark symptoms of the pathophysiology that we see at the bedside, hypoxemia, poor compliance, loss of lung volume, diffuse process with endothelial injury, alveolar and interstitial edema, and increases in dead space, all have pathophysiologic starting points that are important on the molecular level. This is a very classic schematic of the pathobiologic perturbations that we see with ARDS. Remember, the injury can occur either at the alveolar epithelial surface here or at the endothelial surface. There is disruption of the basement membrane, for example, here that results in activation of the alveolar macrophages that are present. The activation of the alveolar macrophage results in release of pro-inflammatory cytokines with neutrophils that come from the bloodstream that now will come into the alveolar space. The release of all of these intermediary markers can result in inactivation of surfactant, as well as destruction of the normal cells that are there, the type 1 and the type 2 pneumocytes. This may result then in deposition of these hyaline membranes across the alveolar epithelial surface. And as a result, now you've got an alveoli that's full of edema, as well as that doesn't have the structural integrity that you would expect because the typical cells that are present there have been replaced by these denuded basement membranes with lots of hyaline membrane. Again, the injury could occur on the opposite side as well, triggered at the endothelium with the same sort of mechanisms occurring, but going from this side inward rather from this side outward. And in fact, that's one of the key hallmarks in ARDS is that there's significant endothelial dysfunction, as well as dysfunction in coagulation. Now edema, particularly in the alveoli, but also in the interstitium is very common in ARDS. And it's important, however, to differentiate this edema from the edema that we may see from other causes, such as cardiogenic pulmonary edema. One of the key components is the fluid in the alveoli is very different. In cardiogenic pulmonary edema, this is protein-poor edema fluid, whereas in the alveoli, this is very protein-rich because this is full of inflammatory cells and poor surfactant as a consequence. And the mechanisms of edema with cardiogenic pulmonary edema are primarily from increases in hydrostatic pressure, which leads to increased fluid filtration across the endothelial layer, leading to a fluid-filled interstitium and alveolar fluid that is primarily occurring through bulk flow as the mechanism. In contrast with ARDS, we have normal hydrostatic pressure. And the reason for the edema that may be coming into the interstitium is predominantly from increased permeability and increased on the epithelial surface. Now classically, we think ARDS has a few phases. The first phase is the acute or exudative phase. This typically occurs after a clinical trigger with rapid onset of edema, effusions, and patchy infiltrates that we may see on chest imaging, either x-ray or CT. Classically, the most dependent areas of the lung are the ones that are most affected with relative sparing of other areas and lots of heterogeneity in the lung units that are affected. If we look at what's happening on the microscopic level, this is what's characterized by diffuse alveolar damage, i.e. the presence of these hyaline membranes, for example, and an infiltrate of neutrophils and macrophages in the alveolar spaces with disruption of the epithelium. Now, some patients have relatively rapid improvement in their ARDS, while other patients may persist with significant disease. And it's likely that the type 2 pneumocyte has a really important role in this process. Certainly, the type 2 pneumocyte creates surfactant, which is a role that I think we are all well aware of, but it also has other functions. It can differentiate actually into type 1 pneumocytes that will help restore the basement membrane. It also has a very important role in fluid and water transport out of the alveoli with the sodium potassium ATPase pump, as well as helping differentiate into the type 1 cells for aquaporins for alveolar fluid clearance. Now, if patients are really unable to clear this fluid, then the consequence may be the development of fibrosis. So, in particular, if the type 1 pneumocytes have been significantly destroyed and fibrin has been deposited along the alveolar epithelial surface, we start to see a phase of fibrosing alveolitis, which is characterized by persistent hypoxemia, increases in dead space, and worsening compliance. This is where we may also start to see development of significant pulmonary hypertension. If we do further imaging, diffuse interstitial opacities and bullae are often seen on CT scan, as well as chronic inflammation and clear evidence of fibrosis. So, let's now switch gears and start to talk about ventilation of patients with ARDS, and in particular, how we can be lung protective with our ventilation. There have been an evolution in our thinking about the importance of lung protective ventilation and the concepts here, starting with initial recognition of the importance of barotrauma from experiments in the 70s to volutrauma, with really landmark animal experiments of chest binding in mice that demonstrated its importance in the 80s. The biotrauma and adalectrauma hypotheses that emerged in the 90s and in more recent years are concepts of burgotrauma. This relates to stress, strain, and mechanical power. And the first real clinical evidence came from Keith Hickling's group in adults, which observed that if a strategy with permissive hypercapnia and low volume and pressure limitation was used in adult patients with ARDS, that these patients actually had significantly lower mortality, 26% mortality, compared to what would have been predicted at that time with the Apache score. And none of the patients went on to develop a pneumothorax, which, of course, pneumothoraces were very common when Hickling first published the study. Now, since those initial clinical observations, we really have learned a lot more about the pathobiology of how ventilator-induced lung injury may, in fact, lead to worse outcome in patients with ARDS through multiple mechanisms related to increased apoptosis that leads eventually to multiple organ dysfunction and is in that final common pathway of death. Now, what we may see at the bedside are the physiologic abnormalities of increases in dead space, decreases in compliance, and further impairment in gas exchange that occur as a consequence of ventilator-induced lung injury and not just the initial injury itself. So the key concept that emerged initially is trying to ventilate patients in a safe zone, that as we think about this quasi-static pressure-volume curve where we have pressure on this axis and volume on this axis, that here is that theoretical curve of the lung that as we inflate the ARDS lung, it takes a long time, a lot of pressure before we can get an increase in volume. Then we reach this lower inflection point and to the upper inflection point at which the relationship between pressure and volume is relatively linear. And when we exceed the upper inflection point again, we have a point of where compliance drops as we are starting to over-distend the lung. Now, this is based on the quasi-static pressure-volume curve. So this leads to a question that is important to think about as we're studying ventilator management here in ARDS. Which of these two lung units has the longer time constant? So remember, the time constant is the time it takes for a lung alveolar unit, i.e. the alveoli and the airway next to it, to either inflate or deflate to two-thirds of its original size. So in this example, lung unit B has a much shorter time constant than lung unit A. This might be counterintuitive to you, but remember that it's to the capacity that it is going to fill to, not to a normal capacity. So as air comes in here, this lung unit, lung unit B, will fill relatively quickly. And those lung units that have significant impairment in compliance are ones that fill more quickly. You remember the time constant is the resistance times the compliance. So low-compliant unit, much more quick to inflate to its capacity. So what will happen is, if I have a very prolonged inspiratory period, I'm going to have a very prolonged inspiratory time here. This unit may inflate to its capacity, and then there will be preferential inflation of this lung unit that is more healthy, that has the more normal compliance. And this is a really important concept as we think about the risk of over-distention of the lung, or strain on the lung, from volume trauma. Now, there is very clear clinical data about the importance of over-distention and volume trauma that, of course, emerges from the adult ARDS literature with the ARDS network landmark clinical trial comparing 6 versus 12 mLs per kilo, clearly demonstrating that those patients managed with 6 mLs per kilo had improved survival over those with 12 mLs per kilo. But what is a really important concept that is sometimes ignored in that paper is that this benefit is different based upon the compliance of the lung. That those patients that had relatively preserved compliance, relatively normal compliance of the lung, there was no clear difference between low tidal volume versus high tidal volume ventilation with respect to mortality. But that the benefit of low tidal volume ventilation really is clear for those with more impaired respiratory system compliance. And this illustrates the concept of lung strain, which I'll talk about in a second. But before I go there, it's important to remember, of course, that ventilator-induced lung injury in adults may be a little bit different than ventilator-induced lung injury in children. And we don't have the same level of controlled trial data in children. And there is certainly some animal data that suggests that perhaps pediatric animals may be less subject to the risks of high tidal volume ventilation as compared to adult animals. And as we look to observational data in pediatrics, what we see is that many studies, including this one that we published in 2009, show that the relationship between tidal volume and mortality may, in fact, be that as patients that achieve the higher tidal volume, here are the ones, in fact, with the lower mortality. But this comes back to the concept of lung strain. And as we look at, especially if we use a pressure-limited mode of ventilation, then what we see is that those patients that have the most severe injury to their lung, here stratified by the baseline lung injury score, are the ones that are achieving the lowest tidal volume. And those children that have the least injured lung are the ones that are achieving the highest tidal volume. So perhaps the relationship that we're seeing in pediatric observational studies is simply a reflection of the severity of lung injury. But it also ties back to this concept of lung strain. So lung strain is the tidal volume over functional residual capacity. The strain on any structure is the change in size of that structure in relation to its original size. So if we take an example of a patient that has ARDS, a normal patient, let's start with first, that's being ventilated with a tidal volume of 10 mLs per kilo, that has a functional residual capacity that's normal, let's say 20 to 25 mLs per kilo, the lung strain is 0.5. If that patient now develops ARDS, where the FRC is what's reduced, or end-expiratory lung volume is significantly reduced, and we keep the same tidal volume, now the strain on that structure has doubled. So what do we do? We lower the tidal volume further. If we lower the tidal volume to keep it more proportional to what the size of the lung is, now the strain on that structure is again back in that physiologic range. And so that's what underscores the recommendations that came out of the Pellet Group for this. The tidal volume should be 3 to 6 mLs per kilo for patients with a very poor respiratory system compliance, and it could be higher, i.e. 5 to 8 mLs per kilo for those with more preserved respiratory system compliance, i.e. we should not just use the same tidal volume for all patients. We need to be more conservative with our tidal volume choice for those with the more severe lung injury. And there has been some recent data that's come out of one of the sub-analyses of the PARTY study that suggests that this phenomenon might be right. Now what do we do in actual practice? In actual practice, the tidal volume based upon delta pressure, so here the delta pressure is, you know, the peak inspiratory pressure minus the PEEP, and again this is now a surrogate here for lung compliance, that the tidal volume doesn't vary as a function of delta pressure, i.e. we are not changing the tidal volume based upon the compliance of the lung. We're using 7 to 8 mLs per kilo in almost all of our ARDS patients. What the Pellet recommendation would be, would be that for this group of patients with more mild disease and more normal compliance, that's appropriate, but that we should be down in the 3 to 6 range here for those with more severe disease with higher delta pressures, and in fact we are very rarely there. And what we found in this PARTY study is after controlling for a number of confounding factors that that pattern was in fact associated with the nearly threefold higher risk of mortality. So the tidal volume is lung strain. As we start to think about the other side of this coin in pressure, this is where we start to think about lung stress as the risk of barotrauma. And in fact it's quite difficult to sometimes separate the volume and pressure issues. If we look at the ARDSNet trial for example, that of course used 6 versus 12 mLs per kilo, it wasn't just a difference in the tidal volume, it was also a difference in the peak inspiratory or the plateau pressure rate between those groups. If you use a lower volume, you will inherently achieve a lower pressure for the same compliance. And in reanalysis of a number of adult trials related to both PEEP and tidal volume management, what Dr. Amato has highlighted in this meta regression is that perhaps the most important variable in terms of the risk of mortality is the driving pressure. The driving pressure is the plateau pressure minus the PEEP, and after controlling for a number of other factors there is this almost near linear relationship here with driving pressure and risk of death in adult patients with ARDS. Now we must remember that the driving pressure contains both lung and chest wall components, right? The driving pressure is the plateau pressure minus the PEEP. That pressure has both a component that is used to move the lung but simultaneously may also move the chest wall out of the way. If we are most concerned about the risk of barotrauma or the risk of stress to the lung, then we should be thinking about the transpulmonary pressure. The transpulmonary pressure, like any transmural pressure, is the pressure inside minus the pressure outside. So here the pressure inside is the alveolar pressure, the pressure outside is the pleural pressure. So in this circumstance, if I've got a patient with a very stiff thick chest wall that's got an elevated pleural pressure of 25 centimeters of water, even if I generate an alveolar pressure, i.e. a plateau pressure of 30 centimeters of water, the total transpulmonary pressure is relatively low at 5 centimeters of water. In contrast, if that patient has a very compliant chest wall where the pleural pressure is low, let's say only 5 centimeters of water, now that transpulmonary pressure would be quite high, i.e. 25 centimeters of water. And this is why a high airway or alveolar pressure doesn't always cause harm. And let's think of an example of a trumpet player who's playing a note that generates a very high alveolar pressure of 150 centimeters of water, but that is from a very concomitantly high increase in the pleural pressure as well, keeping that transpulmonary pressure in a very low and safe range. And so hence the recommendations to try to prevent stress of the lung is to try to minimize that transpulmonary pressure. And we don't measure that in routine practice since we don't use esophageal catheters, for example, as a surrogate for pleural pressure. So here we should limit, we think about just simply limiting the plateau pressure to 28 centimeters of water for those with normal chest wall compliance, and for those with more impaired chest wall compliance where more of that pressure may be transmitted to move the chest wall out of the way, we can allow for a slightly higher plateau pressure of up to 32 centimeters of water. But really it's the transpulmonary pressure at end inspiration or perhaps even the transpulmonary driving pressure which are the most relevant metrics for the risk of lung stress, i.e. barotrauma related injury. Now there is another risk of ventilator-induced lung injury that's not about over distention of the lung, but it's about ventilation at low lung volume and adelectroma. And what we see is that the ARDS lung is very inhomogeneous. So even at the end of inspiration, you may have lung units that still are completely collapsed. Ventilator variable that we can control to help prevent adelectroma is PEEP. And PEEP seems to matter in adult RCTs for ARDS with likely benefit from higher PEEP strategies. But what we see in these adult clinical trials is that there's this important heterogeneity in treatment effect. That is that there are some patients that are very clear PEEP responders and there may be other patients that in fact are harmed by high PEEP or recruitment strategies. Some of the reasons for heterogeneity may be captured in things like the PF ratio. Those with the more compromised PF ratio are the ones that perhaps will benefit more from the higher PEEP strategy. Or those that have a hyper inflamed phenotype. This phenotype is based on a bunch of biological markers for example. They're the ones that seem to benefit more from the high PEEP strategy. And in fact there's a suggestion that if the patients are not in that phenotype, they may in fact be harmed from a very high PEEP strategy. Now we don't have this trial data in pediatrics. And as we think about high versus low PEEP strategies, what are they talking about in those adult studies? Many times they're referring to the high PEEP versus low PEEP FiO2 table in the ARDS network. Where what you see in green here would be the low PEEP FiO2 table and in red is the high PEEP FiO2 table. So for example on the low PEEP table would be a PEEP of 14 with an FiO2 of 0.7. In the high PEEP table this would be a PEEP of 20 with an FiO2 of 0.7. Now what do you see in gray is what we do in actual practice. This is observational data from pediatrics and what you see is that we tend to limit our PEEP to about 10 or so even in relatively severe amounts with severe amounts of hypoxemia or high FiO2. And many times we fall well below what would even be recommended by this ARDSNet low PEEP FiO2 table. And we have shown that that practice of managing patients below even the low PEEP FiO2 table may be associated with harm in all patients and even stratified by all degrees of initial PF ratio. This is observational data, it's not trial data, so then it's of course important to control for other factors. And so and multivariable adjustment for a number of other factors that might be associated with these findings we still see that PEEP below what would be recommended by the ARDSNet protocol in children is associated with a nearly twofold higher risk of mortality. Now the relationship between lung stress and lung strain is in fact also related to ventilation at low lung volume. So if we think about the lung stress strain relationship here we have strain on this axis, which is remember the tidal volume over functional residual capacity, we have stress on this axis which is the transpulmonary pressure, and of course they're related based upon the elastance of the lung. That's what really is determining the slope of this line. So if I have a circumstance over here where I've got a very let's say poorly recruited lung, I may be at a very dangerous point on this stress strain relationship that at that given transpulmonary pressure for example I'm at a very high amount of strain. But if we're able to recruit the lung then we shift the slope of this elastance curve and I might be at a more safe point of lung strain for example for a given transpulmonary pressure. This concept of recruitment is tied to the notion of hysteresis of the lung. Hysteresis implies asymmetry of the lung status based upon the whether you're on the inflation or deflation limb of the lung. So here is a situation of normal hysteresis for example, whereas we see that there is a slight difference in terms of the volume that's achieved for a given pressure based upon whether I'm inflating the lung here or deflating the lung here. Hysteresis will be increased right when there is a larger difference between those two that as I'm inflating the lung it takes a lot more pressure to achieve a low volume compared to that same pressure would achieve a much higher volume after I've already recruited the lung. And inflammation, surfactant deactivation, and airspace collapse are what really favors the development of hysteresis. All of these things that we see in the acute phase of ARDS. And so the principles of our management are to try to ventilate patients in fact on the deflation limb here of the pressure volume curve because as you can see the the slope of this line is improved but also that I achieve a higher tidal volume for a given pressure. And this is the theory behind doing recruitment maneuvers and in fact there have been some some big trials in adult ARDS with recruitment maneuvers with titration of PEEP or the ART trial was the most recent example of this where there was a stepwise recruitment maneuver starting first with a delta P of 15 patient was on a PEEP of 25 the PEEP was increased to 30 and 35 subsequent decremental PEEP titration to find the point of best compliance once that was found the patient was taken back up to 50 over 35 to again re-recruit the lung and then they were maintained in that point where PEEP was deemed to be optimal based upon respiratory system compliance. Now unfortunately the ART study demonstrated that sometimes physiologic principles don't translate into benefit for patients especially if they're associated with harm and in fact they found that that approach was harmful that patients that were simply managed with the low PEEP FiO2 table did better and as we look at the reasons for this it's likely explained here higher rates of pneumothoraces in those with the lung recruitment group as well as more hemodynamic compromise with the recruitment strategy as compared to the empiric low PEEP FiO2 table. What that point highlights is that if you attempt to recruit a lung that is not recruitable especially if you use relatively aggressive recruitment strategies you may cause more harm than good. So then what should we be doing with PEEP in our usual practice? Well certainly we probably should be using more than what we're using in in our usual practice and it may be that simply using the PEEP FiO2 table the low PEEP FiO2 table as a starting point might be a good way to start but as is clear from the ART trial if you use an excessive amount of PEEP for patients or you use recruitment maneuvers in patients that don't have recruitable lung you may be causing more harm than good. So hence a physiologic based approach to individualized PEEP titration is really what we need. So in the last few slides we'll hear just talk about other therapies. Fluid management is a specific area on the board outline. Now we don't have randomized trial data in pediatrics but several observational studies have demonstrated a clear association between higher cumulative fluid balance and higher mortality and fewer ventilator free days in pediatric patients with with ARDS and of course there was an adult RCT examining a restrictive versus liberal fluid strategy which did show a clear improvement in ventilator free days for those that were managed with the more restrictive fluid management strategy. This adult trial was the FACT trial fluid and catheter trial where actually a PA catheter was used for many of these patients or or a CBP measurement was used to gauge a target for the central venous pressure or the or the wedge pressure with fluid administration versus use of diuretic therapy or inotropes or vasopressors. And the FACT trial did show that there was no significant improvement in mortality but there was a pretty significant improvement in ventilator free days as well as an improvement in oxygenation with a conservative as compared to a liberal strategy. Now the study was critiqued a little bit in that maybe the liberal group was too liberal like we were artificially put they were artificially pushing up the amount of fluid that these patients were administered but it regardless it demonstrates the importance of that physiologic concept that a conservative fluid management strategy certainly can result in improvement in ventilator free days. The pediatric data is largely based on observational cohorts but most of those observational cohorts are relatively consistent really showing that we in our usual practice are often either as liberal or more liberal than the FACT liberal group and that that these practices generally there's a clear association with higher mortality or longer duration of ventilation for those managed with the higher cumulative fluid balance with pediatric ARDS. This is additional analysis of an observational cohort which shows the same thing that cumulative fluid balance in pediatric patients is associated with higher risk of mortality even after controlling for other factors. And here's another secondary analysis here of a randomized control trial with surfactant which also demonstrated that there is a clear association between higher fluid balance and higher mortality in pediatric ARDS. This has led to pallic recommendations that pediatric patients with ARDS should receive total fluid simply to maintain adequate intervascular volume and optimal oxygen delivery and that there should be a goal to maintain in intervascular volume while aiming to prevent a positive fluid balance. So the last thing I'm going to talk about is prone positioning and certainly there are many adult trials which have demonstrated potential benefits of prone positioning but what's important is that the real benefits of prone positioning have become clearer in the era of lung protective ventilation which implies that a lack of doing lung protective ventilation may negate any potential benefit that's gained with prone positioning. And of course the most recent adult randomized trial was the PROCEVA trial which was published in in 2013 in the New England Journal which demonstrated in adult patients with relatively severe ARDS. This was defined as a PF ratio less than 150. There was a clear survival benefit for those in the prone positioning group as compared to in the supine group. Now there are many physiologic rationale for the use of prone positioning in ARDS some of which might be slightly different in pediatrics. Certainly we know that there are changes in regional distribution of ventilation and perfusion which may change BQ matching. Now this might not translate to improvement in outcomes and it may just result in short-term improvements in oxygenation for example. But it also improves the cephalocaudal as well as dorsal ventral distribution of air by shifting the weight of the harder mediastinal structures onto the sternum when prone which may normalize differences in pleural pressure that are regional and net result might be alveolar recruitment. It may also reduce inequalities in regional time constants which may reduce the heterogeneity of the lung and promote more homogeneous distribution of gas and prevent over distention injury. We often gauge response to prone positioning by improvements in oxygenation but maybe that's not the right variable especially as we think about how it ultimately may improve outcomes. It will likely come if it prevents ventilator lung injury or results in alveolar recruitment and what this study that Gatnoni did you know in the early 2000 highlights is that the PaO2 response actually was not really a good predictor of net improvement in mortality but the PCO2 response was i.e. those patients that had an improvement in their PCO2 are the ones that did better. Now these were volume modes of ventilation so an improvement in PCO2 inherently would you know would mean less dead space ventilation i.e. less over distention as an example and that might be what results in less lung injury progression and improved outcomes. Now in pediatrics we certainly had a randomized trial Martha Curley published this trial in 2005 which really did not show any significant differences in terms of clinical outcomes between pediatric patients that were managed prone versus supine. This was 20 hours a day of proning for seven days during the acute illness. This was a median of moderate ARDS with OIs of 14 to 18 or PF ratios of 150 or so and ultimately the study was stopped early for futility because of lack of any evidence of benefit and an overall pretty low mortality rate of 8%. Now it's difficult to translate our adult findings with a very clear benefit to pediatrics especially in the face of a negative pediatric RCT but there may be some really important things to think about like disease severity certainly it appears that the benefit is most in those with more severe disease. There are certainly impacts of chest wall compliance that's one of the ways in which we think prone positioning might be most beneficial and so age is an important variable in that equation. In the pediatric study the rescue was to go to high frequency oscillatory ventilation in both groups and as was highlighted by the meta analysis in adults prone positioning must be coupled with very good lung protective ventilation and so if the strategy used on high frequency for example was not was not the same it may be that the potential any potential benefits for prone positioning were not seen and we certainly saw that many patients had an improvement in oxygenation in the pediatric study but they did not report the pco2 response we don't again know that these oxygenation benefits of what the mechanisms of them were and how that then potentially may translate into improvements in outcome. So are the recommendations for prone positioning are certainly that it should not be used as routine therapy but it could be an option in cases of relatively severe disease and certainly more study is needed and in fact there's a large pediatric international RCT that's ongoing right now. So again here is a board outline for ARDS and we did we did cover all of the topics here. So now I'll go through some questions so please try to answer these questions for yourself and I'll go through the answers then. Question one most common risk factor for pediatric ARDS is sepsis, lower respiratory tract infection, aspiration, trauma, or pancreatitis. Okay so the answer here is lower respiratory tract infection that was clear from the party study but has previously been shown in multiple other studies as well sepsis is next most common and then the rest have a relatively lower frequency. Risk factors for mortality in pediatric ARDS include all the following except indirect lung injury, lower initial PF ratio, higher alveolar dead space, more non-pulmonary organ dysfunction, or adolescent age group. Okay so the answer the answer here is five adolescent age group. Certainly indirect lung injury has been implicated in multiple studies ie patients with sepsis for example higher risk of mortality. Oxygenation markers like the PF ratio as well as dead space markers both have shown strong independent associations with outcome and then non-pulmonary organ dysfunction and immune compromised status are probably the two most important risk factors for mortality. So this here is a real process of elimination. As far as age goes the the data is quite inconsistent about whether there is any particular age group that actually has higher risk of mortality within the pediatric age spectrum. Third question all of the following have been implicated in the pathophysiology of ARDS except activated alveolar macrophages, ICAM-1 on vascular endothelial cells, elaboration of oxygen and nitrogen free radicals from neutrophils, four alveolar fibrin deposition from stimulation of tissue factor, and then five decreased surfactant production by type 1 pneumocytes. So this one the correct answer or the the incorrect answer ie what has not been implicated is number five. Remember that it's the type 2 pneumocytes that are responsible for surfactant production not the type 1 pneumocyte. So although decreased surfactant production is important it's really it's the wrong cell here. So the rest is by process of elimination here of identification. The others are all true. Which of the following statements about hysteresis is true? It's more pronounced after alveolar recruitment. Two, on the deflation limb higher lung volumes are maintained for the same airway pressure. Three, it is seen as beaking on the pressure volume curve and represents area of overdistension. Or four, it's measured when patients are spontaneously breathing during using the dynamic pressure volume curve. So the correct answer here is number two on the deflation limb higher lung volumes are maintained for the same airway pressure. That is the definition of hysteresis here. You've got a difference in volume for a given pressure on the inflation limb as compared to on the deflation limb. It becomes less pronounced after you've recruited the lung. Overdistension does not necessarily have to do with hysteresis. You know that is more about the actual pressure or volume that's being applied to the lung. And it is it needs to be measured actually under static conditions using the quasi-static pressure volume curve not a dynamic pressure volume curve. And then the last question, which of the following edge of therapies has been demonstrated to shorten their duration of ventilation in pediatric ARDS? Prone positioning, high frequency, corticosteroids, a conservative fluid management strategy, surfactant, or none of the above. And so the answer here is six, none of the above. This is an important question just in terms of reading the question stem very carefully, has been demonstrated to shorten duration of ventilation. So here you're not looking at anything that has an association. You need really RCT, empirical causation proof, and none of these have had an RCT that has clearly demonstrated benefit. Certainly on the fluid management side there's observational data that supports that there is an association, but it has not been proven in terms of an RCT, so hence has not truly been demonstrated.
Video Summary
In this video, Robby Kamani discusses pediatric acute lung injury and acute respiratory distress syndrome (ARDS). He covers several key concepts related to ARDS, including the epidemiology and risk factors, pathogenesis of lung dysfunction, diagnosis, pathophysiologic mechanisms, medical management principles, open lung strategy, ventilator management principles, and fluid management strategy implications.<br /><br />ARDS is a clinical syndrome characterized by diffuse inflammation in the lung, resulting in hypoxemia and lung dysfunction. There is no definitive diagnostic test for ARDS, so definitions are based on clinical observations. The Berlin definition, used in adults, specifies timing and chest imaging requirements to diagnose ARDS. The PALICC definition, used in pediatrics, includes age-specific criteria and emphasizes the use of oxygenation indices to diagnose ARDS.<br /><br />Lung protective ventilation is key in managing ARDS and involves minimizing lung strain and stress. This includes using low tidal volumes, limiting driving pressures, and applying appropriate levels of PEEP to prevent lung injury. Furthermore, fluid management strategies should aim to maintain optimal oxygen delivery while preventing positive fluid balance.<br /><br />Prone positioning has been shown to improve oxygenation in adult ARDS, but the evidence in pediatrics is limited and inconclusive. Further research is needed to determine the benefits of prone positioning in pediatric ARDS.<br /><br />Overall, this video provides a comprehensive overview of ARDS in pediatrics and highlights key concepts in its diagnosis and management.
Keywords
pediatric acute lung injury
acute respiratory distress syndrome
ARDS
epidemiology
risk factors
pathogenesis
diagnosis
medical management
ventilator management
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