Hi, thanks. I am also very thrilled to talk to all of you and see everyone here on the last day. A little bit of this is repetitive, but I do just want to emphasize that this is something we've seen and has been really well described. This is actually Aaron's table here on the left. And this is a table on your left showing improving mortality across the developed and developing world in children with sepsis, especially fast in the developed world, especially depending on how we measure it. And as Dr. Carlton just discussed, we do see a lot of increasing morbidity in these children. We also see, again, that the majority of children who have sepsis in the developed world have some underlying chronic disease. And Dr. Carlton was just speaking about some of the challenges of diagnosing and managing these children, the risks of increasing chronic morbidities in these children. This is a table from the LAP study, which most of us know as a study from 2014 describing point prevalence of pediatric sepsis. And really just highlighting here that about 17% of children in the LAP study with severe sepsis globally had pre-existing neuromuscular disease. And really only half had baseline, quote, good performance. And especially as we get more refined cohort studies, we really see this pretty clearly, that most children who have sepsis do have some pre-existing chronic disease. I want to transition for a moment and talk a little bit about health-related quality of life. I think this was a really innovative thing that Dr. Zimmerman has been working on for years, really describing this as a primary outcome of pediatric critical illness. And many others, including some in this room. I think we all are familiar with the core outcome set. Really, parents, clinicians, and researchers asked about what was important to them in survival after pediatric sepsis or pediatric critical illness. And after mortality, health-related quality of life is the most important outcome for these stakeholders. I think most of us know that this is a multidimensional concept. It's assessed by questionnaires. It focuses on the impact of health status on overall quality of life, including physical, mental, emotional, and social functioning. Importantly, it's personal. It's subjective. It focuses on an individual's assessment of their own quality of life. Obviously, this is problematic in children because the gold standard for health-related quality of life reporting is self-assessment. However, some instruments, including the PSQL, have been validated for proxy reporting. This is more challenging still to assess in children who have pre-existing developmental disability. Again, 15% to 20% of children with severe sepsis in the developed world have a developmental disability or static encephalopathy. Of course, these children require proxy reporting by a caregiver for health-related quality of life. Many of them have communication challenges. Their caregivers may be more used to having children with chronic illness and may have different priorities than caregivers of children without severe developmental delay. And they may, of course, have a different baseline health-related quality of life than other children. PSQL is a commonly used, well-validated tool for assessing health-related quality of life in children. It's validated in all ages and in children with baseline chronic disease of other kinds. But some items in the questionnaire are less appropriate for children with baseline neurologic disease, especially severe static encephalopathy. A few notes about the scale itself. It has an established minimum clinically important difference of four and a half points on a 100-point scale. The other instrument that was used in LAPS is called the Stein-Joseph Functional Status Scale, or FS2R. And in LAPS, parents were free to choose whichever instrument they felt was helpful for their children. The FS2R was chosen as a reporting of health-related quality of life that is less dependent on child communication, includes more items like sleep, feeding, and observable behaviors, but does not have an established MCID. In the LAPS study, about a third of caregivers completed the FS2R for their children. About 80% of those children had at least moderately abnormal baseline functional status. And as Liz discussed previously in LAPS, the morbidity burden was substantial. 40% of all enrolled patients died or had a persistent and substantive decline three months after. Loss to follow-up was significant, but many of those patients had persistent decline even at 12 months. And importantly for LAPS, the most significant patient factor that increased the likelihood of recovery to or improvement from baseline was a lower baseline health-related quality of life. As Dr. Killian is gonna talk about in a few moments, factors were also strongly associated with a decreased return to baseline, including severity and duration of organ failure and hypoxic ischemic injuries or other neurologic events. So given the substantial burden of sepsis in children with neurologic disability at baseline and the challenges of assessing health-related quality of life in this population, we performed a secondary analysis of LAPS to describe the trajectory of health-related quality of life in children with chronic neurologic disease. We also assessed potential critical illness factors that were associated with failure to return to pre-illness health-related quality of life in these children. We defined children with neurologic disability as those with at least moderate disability on the PCPC. That's a score of three to five. And we assessed for critical illness factors and patient characteristics predictive of adverse outcomes in children with baseline neurologic disability, including those that were associated with worst outcome in the overall LAPS cohort. We also assessed for the contribution of baseline health-related quality of life prior to sepsis. We defined a persistent decline as a change of at least 10% from baseline. We standardized this across both scales. That represents about one and a half times the MCID for most subjects who use PSQL and about 0.5 times the standard deviation of the scale for both. Primary outcome we chose was persistent decline at the three-month time point. This was due to missing data and in the primary LAPS cohort relative stability between three and 12 months. About a third of our patients in the primary LAPS cohort met our definition of baseline neurologic disability, again, highlighting the importance of robust cohort data in assessing these patients. Patients who met this definition were older and received fewer critical care interventions, such as intubation or arterial line placement, and patients without baseline neurologic disability, but otherwise had similar acuity of illness based on PLAD scores. And really, we found that neurologically disabled children had less decline in health-related quality of life at day seven when talking to their families and at day 28 than those without neurologic disability. This difference was not statistically significant at three months and was not statistically significant at 12 months in a sensitivity analysis. So you can see here, just to highlight again, children who did not have baseline neurologic disability are in blue and those with neurologic disability were in red. In our multivariable model, we assessed for critical illness in patient factors in children with neurologic disability and found that baseline health-related quality of life and acute renal injury were independently associated with a persistent decline in health-related quality of life at three months. Our study's limitations include that we identified children with neurologic disability by baseline PCPC, and this is, of course, less granular and not self-reported. Another potential limitation is that these patients used different instruments for the most part. Most subjects evaluated by the FS2R had neurologic disease, and in the main lab study, there was attenuated decline in those evaluated by FS2R. That was about 35% versus 45% at the three-month time point. And I think when we're thinking about assessing health-related quality of life in these children, the baseline patient differences are really important. Again, an objective evaluation is required as opposed to subjective reporting or self-reporting, and small differences may be less observable to caregivers. Additionally, there may be differences in parents between parents of previously healthy children or children with other diseases and those of children with neurologic disability. Parents of children with neurologic disability may have more baseline resilience, they may have different expectations, and they may also experience a phenomenon called response shift, where living with a chronic illness changes your perception of what your health-related quality of life is, independent of any objective change. So, in conclusion, many children with septic shock have pre-existing disability and pre-existing neurologic disability. It's hard to measure health-related quality of life, and health-related quality of life is important in these children. Again, I think it's important for us to know, as we're counseling families and taking care of these children, that children with better health-related quality of life or baseline more commonly have persistent decline, and this is important as we're thinking about what to tell parents and how to think about these children. And then AKI, acute kidney injury, may be associated with worse long-term outcomes compared to other critical illness factors in this population and others. Thank you.

sepsis

pediatric critical illness

HRQoL

neurologic disabilities

acute kidney injury