SCCM Pod-532 PCCM: Understanding Quality-of-Life Risks in PARDS Survivors

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Host Elizabeth H. Mack, MD, MS, FCCM, welcomes Elizabeth Y. Killien, MD, MPH, to discuss pediatric acute respiratory distress syndrome (PARDS). Dr. Killien explains the findings from her retrospective study on PARDS severity, emphasizing how factors such as severe hypoxemia can impact health-related quality of life (HRQL) after discharge. (Killien EY, et al. Pediatr Crit Care Med. 2024;25:816-827). Dr. Killien is an attending physician in the pediatric ICU and an assistant professor at Seattle Children’s Hospital, University of Washington School of Medicine, in Seattle, Washington.

Transcript:

Dr. Mack: Hello and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Dr. Elizabeth Mack. Today I’ll be speaking with Dr. Elizabeth Killien, MD, MPH, about the article, “Pediatric Acute Respiratory Distress Syndrome Severity and Health-Related Quality of Life Outcomes: Single-Center Retrospective Cohort, 2011 to 2017,” published in the September 2024 issue of Pediatric Critical Care Medicine. To access the full article, visit pccmjournal.org. Dr. Killien is an attending physician in the pediatric ICU and an assistant professor at Seattle Children’s Hospital, University of Washington School of Medicine in Seattle, Washington. Welcome, Dr. Killien.

Dr. Killien: Thank you so much for having me. I’m looking forward to chatting.

Dr. Mack: Awesome. Before we start, do you have any disclosures to report?

Dr. Killien: I receive NIH funding from NICHD and have a completed consultancy relationship that’s not related to the current work.

Dr. Mack: Perfect. Thanks so much for this fabulous contribution to the literature. Would just love to hear where the idea for this study came from. Is this a continuation of prior work? Have you all collaborated before? Would just love to hear.

Dr. Killien: Yeah, this is a dataset that I first accessed as a pediatric critical care medicine fellow for my fellowship project. It was a dataset that had been collected by a different group in the hospital to assess quality-of-life outcomes among hospitalized patients, both in the general pediatric wards as well as in our ICU. Their dataset included baseline discharge and follow-up quality-of-life data on a number of children, close to 800 pediatric ICU patients.

As a fellow, what was advantageous to me about that dataset is that I could investigate my interest in post-ICU outcomes without having to collect prospective outcomes data, which is very arduous and takes a long time, which is difficult for a fellow project. I was able to merge their dataset of the baseline and outcomes data with EHR data to evaluate outcomes after pediatric sepsis.

That experience using that dataset led me to subsequently work with the team who had collected that data to develop a more comprehensive dataset, an ongoing project to access these existing data and evaluate all sorts of different exposures. This group that coauthored this manuscript has actually collaborated on a number of manuscripts using the same dataset with different exposures, such as pain, delirium, sepsis, and now ARDS.

Dr. Mack: Well, thanks so much for sharing this story. I think that’s very relatable for many of us, thinking back to our fellowship project. Please would you summarize the aims and methods? Really, what were you all attempting to do with this study?

Dr. Killien: The question that we had was, how does the severity of hypoxia in pediatric ARDS, how is that associated with non-mortality or in-hospital outcomes? I was a member of the Pediatric Acute Lung Injury Consensus Conference 2, the 2023 version of that, which was an updated collaboration or consensus conference from the original 2015 PALICC guidelines. As part of that second iteration of the PALICC guidelines, there was a real focus in all of our discussions as part of that group on the delineation of severity of hypoxemia.

In the original 2015 guidelines, pediatric ARDS was defined as mild, moderate, or severe based on the severity of hypoxemia for invasively ventilated patients only. In reviewing the literature between the publication of those guidelines, or the development of those guidelines rather, and the development of the subsequent second iteration of the guidelines, several studies had come out demonstrating that there really was not a large mortality difference between the mild and the moderate categories. Because of that, it didn’t seem like there was very much discrimination between those two groups.

So the decision was made in the new iteration of the guidelines to actually combine the mild and moderate categories into a binary hypoxemia severity categorization compared to a three-level or trichotomous categorization. So one of the questions that I had is, we know that there’s no substantial difference between mild ARDS and moderate ARDS, what was previously termed that, in mortality, but how does that compare to non-mortality outcomes?

There had been some initial literature showing that some of the non-mortality but still inpatient outcomes that had been assessed, such as ventilator duration among survivors, ventilator-free days, perhaps did have some better discrimination with a three-level severity classification. So it’s possible that there may have been some better discrimination for non-mortality outcomes than mortality. So that was one of my motivations in trying to look at this question for the ARDS population specifically, having been, again, a part of those PALICC guidelines.

The second part is something that I have been interested in a long time and is really what motivates a lot of my work now, this idea that mortality is so low among our pediatric ICU population and steadily decreasing still, that using mortality as an end point for most studies, whether it’s clinical trials or even observational data, is a very inefficient end point. It just doesn’t occur very frequently, which is great for the patients but challenging when you’re trying to develop a study looking at differences in risk factors or interventions as they relate to that outcome.

For any type of research, the more common the outcome, the more efficient it will be in terms of the number of patients you need to evaluate differences in exposures and how that relates to the outcome. So I’ve been interested for a while in what non-mortality outcomes are both common enough that they could be used as end points in clinical trials or observational studies but also meaningful to patients and families.

Dr. Mack: Thank you so much for that. I think this is the sort of thing that we all think about if we end up in the ICU or our family ends up in the ICU, not whether we live or die, but really our functional status. So really grateful for you digging down into the next layer.

Dr. Killien: Yeah, and what we know is that previous work has found that when you ask patients and families what they care about, it is quality of life and functional status. It’s not necessarily these in-hospital non-mortality outcomes like ventilator-free days or length of stay. Those are much easier to assess after mortality but they don’t necessarily mean as much to the actual patients and families experiencing those outcomes than longer-term outcomes.

So there’s been certainly increasing interest in evaluating these longer-term non-mortality outcomes. What struck me when we were evaluating the outcomes that we do know about for pediatric ARDS as part of the PALICC guideline development for assessing outcomes after pediatric ARDS is that there’ve actually been very few studies that have evaluated quality of life after ARDS, despite it becoming an increasingly common measure for people to investigate.

There actually were only three studies published so far that looked at health-related quality of life after pediatric ARDS, and none of them evaluated hypoxemia as a risk factor, which is the factor that best discriminates mortality risk. So one of the motivations in this study was to essentially establish whether the risk factors for mortality are also similar for health-related quality-of-life decline. Because if you’re thinking about eventually developing intervention that could improve mortality, which is certainly the goal of most, if not all, of the interventions being developed, you also need to understand whether it could be expected to also contribute to improved quality of life among those who do not die in the ICU but live long enough to have those non-mortality outcomes assessed.

So what we did for this study was we used the existing data that had been already collected with baseline and follow-up quality-of-life data. The follow-up was conducted a median of six weeks after hospital discharge and then used as a retrospective design to go back into the electronic health record and extract oxygenation data and do a manual chart review to specifically look at x-ray data, diagnosis, timing of hypoxemia, and some of these other nuances to the diagnosis of pediatric ARDS that aren’t easily extracted directly from the EHR.

Then we evaluated how patients who were diagnosed with pediatric ARDS based on our definition of it using the PALICC guidelines, how ARDS itself was associated with quality-of-life decline compared to patients who did not have ARDS but were also in the ICU. Then, if you subdivided that cohort by a binary categorization of hypoxemia for the 2023 PALICC-2 guidelines or per the trichotomous severity stratification of mild, moderate, and severe from the original 2015 PALICC guidelines.

Dr. Mack: Thanks so much for that detail and really the history of kind of how this came about and really from a patient and family lens. Give us an overview just briefly of the various scales that you all use. We’d love to hear your thoughts.

Dr. Killien: The Pediatric Quality of Life Inventory and the Functional Status 2R were the two outcome measures that were used. The Pediatric Quality of Life Inventory, or PedsQL, has become the most commonly used health-related quality-of-life measure in pediatric critical care studies. There are a number of quality-of-life measures that are validated for use in this population, but the PedsQL has really emerged as the most commonly used, and that was the measure used for many of our patients in this study.

The Functional Status 2R is a measure that has been adopted to be used as an essentially surrogate quality-of-life measure for patients with severe developmental disabilities. The PedsQL asks a lot of questions about school, running, interacting with peers, interacting with the family, that may not be applicable for many patients with severe cognitive or physical disabilities. So Seattle Children’s, as part of its program to assess outcomes across many inpatient ward and ICU patients, has adopted the Functional Status 2R, FS2R, for patients for whom the PedsQL is not necessarily as applicable.

Families are actually given the choice of which one is more applicable to their child when they complete it, with some guidelines or recommendations based on the contents of each of those. The Functional Status 2R is really more focused on functional status and includes things like smiling, grimacing, feeding, that are potentially more applicable than school function, exercise activity, playing with friends, for some of our patients.

Those were the two outcome measures. The PedsQL is well validated in the pediatric ICU population. The FS2R has been used less frequently, but our group has used it in a way that has actually been incorporated alongside the PedsQL in terms of the scoring for that. So that’s been at least established as an approach, to use the same scoring methodology and the definition of what a change from baseline might be.

One of the potential limitations of this study is that we don’t know what a clinically important change in the FS2R is. Again, it’s just based on prior literature that we’ve adopted the same change in score as the PedsQL, which is four-and-a-half points from the baseline score. The change of four-and-a-half points from baseline was our primary outcome measure as a binary yes-or-no outcome.

We also looked at the continuous score change as a secondary outcome. The other measures were used as covariates in our multivariable modeling. The Pediatric Overall Performance Category, or POPC, is a measure that assesses children’s level of general functional status on a relatively nongranular basis, so from normal to coma on a scale of essentially one to five. It gives a very broad sense without getting into details of the person’s specific functional status in terms of their baseline functional status.

The Pediatric Cerebral Performance Category score is a measure of cognitive function. We used that as a covariate. The other metric that we used as a covariate is the Pediatric Logistic Organ Dysfunction score, or PELOD score; that’s a measure of organ dysfunction. We elected to use the nonrespiratory PELOD score. Essentially, all that means is that the PELOD score is made up of a number of different organ systems, and if you remove the points allotted toward respiratory status, that becomes the nonrespiratory PELOD score. So it’s really a measure of how severe the organ dysfunction is across different organ systems, not the lungs.

This was intended to, when we compare patients with and without ARDS and with different levels of ARDS severity, to try to, as closely as possible, approximate similar conditions in terms of baseline, health status, other nonrespiratory organ dysfunction. We also adjusted for age, diagnosis, length of stay, and time to follow-up, which were all factors that we thought could conceivably be associated with both ARDS and their outcome.

Dr. Mack: Thank you for that review and overview. I’m curious, why classify pediatric ARDS severity both in binary and trichotomous ways?

Dr. Killien: The question that we really have is whether the discrimination seen with different levels of hypoxemia severity is better or worse if you look at it in two categories versus three. Those groupings are drawn directly from the two different iterations of the PALICC guidelines, with the 2015 original PALICC guidelines suggesting a three-level or trichotomous severity stratification and the subsequent iteration, the second PALICC guidelines in 2023, revising that to instead suggest a binary categorization based on lack of discrimination for mortality. Our first question with this study was, is hypoxemia related at all to quality of life?

There have been many studies across different patient populations and disease categories that suggest that there are many factors that are associated with post-discharge quality of life after pediatric critical illness. And illness severity is not consistently one of those factors. So we consistently see that patients with relatively low illness severity may have a risk of quality-of-life decline that is similar to patients with higher severity of illness.

That’s the contribution of environmental, patient, family, etc., factors that really contributes quite a bit to their post-discharge status. So question number one was, what are the risk factors associated with quality of life after pediatric ARDS? We found just in our initial evaluation that severity of hypoxemia was one of those factors that was associated and was in fact the only factor that we assessed that was associated with quality-of-life outcomes. Again, we did not do a detailed analysis of other patient, family, and environmental factors. These were all demographic characteristics and clinical characteristics of the patient.

So, once we had established that there was an association between severity of hypoxemia and quality of life, we wanted to know, are the new guidelines that had just come out at that time appropriate for assessing quality of life? Or is a more granular evaluation with a three-level severity stratification going to give us better discrimination?

Dr. Mack: Anything more that you’d like to tell us about the results and how they have changed your practice in any way, whether that’s earlier rehabilitative efforts or developmentally appropriate supports or anything along those lines?

Dr. Killien: Yeah. What we found is that, before adjusting for any covariates, patients with pediatric ARDS had a much higher prevalence of quality-of-life decline compared to their baseline. Forty-one-and-a-half percent of all of the ARDS patients in our cohort had a clinically important quality-of-life decline compared to 23% of patients with an unplanned ICU admission who did not have ARDS. That, I think, is important, just to acknowledge that the prevalence of quality-of-life decline among patients with ARDS of any severity is extremely common and suggests that that could be, if used in an interventional trial, a very efficient outcome.

The other part is that we did identify an essentially stepwise increase in risk of quality-of-life decline based on the severity of hypoxemia from mild to moderate to severe when evaluated in a trichotomous fashion and from mild-moderate to severe when evaluated in a binary fashion. That is both on overall prevalence and when adjusted for multiple covariates.

Given relatively low sample sizes, we’re not able to say definitively that there is a difference between, for example, mild and moderate for every category. But there is an increase in prevalence, and there certainly seems to be a notable and statistically significant increase in risk for severe compared to the other categories. The other component that I think is very interesting, and this is consistent with other studies, is that we were able to, as a secondary analysis, stratify our groups based on invasive versus noninvasive ventilation.

I had mentioned that the updated PALICC guidelines included severity stratification not just for invasively mechanically ventilated patients but for noninvasively ventilated patients, which was new compared to the original guidelines. So we were able to look at, for the noninvasively ventilated patients, what was their risk of quality-of-life decline based on mild, moderate, and severe hypoxemia. What we found is that the stepwise increase in risk of quality-of-life decline remains true for both invasively and noninvasively ventilated patients and that severe hypoxemia among patients who are noninvasively ventilated was associated with a higher risk of quality-of-life decline than patients who were invasively ventilated with mild or moderate hypoxemia.

So I think one of the really important takeaways there is that patients who are noninvasively ventilated, and again, these are patients who never were invasively ventilated during their entire ICU course, so who remained during their entire ICU course on noninvasive ventilation, have a similar risk of poor quality-of-life outcomes, and this has been seen in other types of outcomes as well, as patients who are invasively ventilated, that our management of patients does not necessarily change their original risk of that poor outcome.

Dr. Mack: Other than curing pediatric ARDS and shouting from the mountaintops the need for health-related quality-of-life outcomes to be an end point in our studies, what’s your next step?

Dr. Killien: The field of outcomes after pediatric critical care has focused for a while now on identifying the prevalence of abnormalities across various domains, and we’re at a point where that’s been pretty well established. There is emerging literature about risk factors for those declines, and this work, I hope, contributes to that. But really, the next step is to actually intervene to change those outcomes, and I think that the first step to doing that is to really think about how our in-hospital outcomes affect not just our likelihood of survival or ventilator-free days or these short-term outcomes, but really our long-term outcomes.

The reason why that’s important is that an intervention that, for example, were to decrease the time on the ventilator but in turn increases the number of days in the ICU, for example, that could conceivably have a result in which the quality of life of patients a month, two months, six months down the road was actually worse for the patients who had spent a longer time in the ICU. We know that exposure to the ICU in and of itself is a risk factor for poor quality of life and functional outcomes, not to mention emotional and family outcomes related to PTSD and reintegration into society. So I think acknowledging that not all of our assumptions about what a good or bad outcome is on the inpatient side necessarily translates to what the patient status will be several months down the road.

The other piece of this is to really acknowledge that many of the risk factors for poor quality of life or other outcomes are not necessarily very modifiable. We looked at, in this study, the severity of hypoxemia four hours after diagnosed severity. That’s not a lot of time to intervene to change that trajectory.

So, thinking about what interventions improve recovery is something that more and more people are starting to focus on. Whether that’s reduction of sedation, earlier physical therapy, post-discharge support with the primary care team, and other specialty services to improve functional, cognitive, etc., recovery is going to be really important. One of the next projects that we’re working on is to build on some of the work that’s been done in identifying these post-discharge outcomes to really figure out, what are the best ways that we can screen for these and then subsequently who’s the right person to manage them, whether it’s the primary care provider, whether it’s post-ICU clinics, whether there’s another model that’s most effective.

Dr. Mack: Well, thank you so much. Lots of food for thought there about how we might pivot going forward. And thanks for all that you’ve done in this field. This concludes another episode of the Society of Critical Care Medicine Podcast. If you’re listening on your favorite podcast app and you like what you heard, consider rating and leaving us a review. For the Society of Critical Care Medicine Podcast, I’m Elizabeth Mack.

Announcer: Elizabeth H. Mack, MD, MS, FCCM, is a professor of pediatrics and chief of pediatric critical care at Medical University of South Carolina Children’s Health in Charleston, South Carolina.

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