this portion will be focused on advances in the pediatric patient. I have no conflicts of interest to disclose. For this portion of the presentation, we'll be discussing relevant updates to the management of critically ill pediatric patients with a focus on pediatric septic shock and pediatric acute respiratory distress syndrome. Let's start off by introducing our patient. OJ is a three-year-old who was admitted to the PICU last night for fluid refractory septic shock. Her chest x-ray reveals multifocal capacities, and she started on appropriate antibiotics and received fluid resuscitation. Despite this, she continues to have hypotension with her maps in the low 40s and is initiated on an epinephrine drip. Thinking about your current practice, would you start corticosteroids for patient OJ? And if so, what regimen would you use? Now, in the absence of definitive data, I anticipate there will be some variation in practice, which is what makes this an interesting topic to discuss. So let's go ahead and dive in. Corticosteroids are associated with a number of pros and cons when used for the treatment of septic shock. On the one hand, steroid therapy results in increased calcium availability, decreased reuptake of norepinephrine, and decreased production of nitric oxide and prostacycline, all of which are desirable for septic patients. On the other hand, steroids are also associated with hyperglycemia, myopathy, immune suppression, and salt and water retention, all of which are less desirable in septic patients. And unfortunately, what we don't know at this time is which way does the scale tip? Do the benefits outweigh the risks, or are we unnecessarily exposing our patients to side effects? Several studies have asked this very question throughout the years. All of the studies listed on the slide were retrospective in nature and unfortunately had several limitations. For the sake of time, we won't delve into the details, but for those who are interested, a supplemental slide can be found at the end of the PowerPoint with a brief overview of each study. What I would like to note, however, is the smiley faces on the left-hand side depicting inconsistent associations with positive, neutral, or negative outcomes. Because of these mixed results and the low quality of evidence, the most recent surviving sepsis guidelines for pediatric patients are only able to give a pretty neutral recommendation, saying they may or may not be beneficial for patients in shock. With that, I'd like to introduce the newest trial published earlier this year in PCCM. This trial was a planned secondary analysis of LAPS, the Life After Pediatric Sepsis Evaluation, which was a prospective observational multicenter study. In addition to being prospective in nature, what's unique about this trial is that the authors used a propensity-weighted analysis. This method allows researchers to create a pseudopopulation wherein confounding variables are equally distributed across groups, effectively creating a pseudorandomization process. The other unique aspect of this trial is its focus on patient-centered outcomes, including resolution of shock, survival, and quality of life. The trial included PICU patients initiated on vasoactive support for septic shock. Those who received hydrocortisone or methoprenisone within the first 48 hours of PICU admission were the active intervention arm, and those who did not receive steroid therapy in that timeframe served as the control arm. Here we can see that prior to weighting, there were notable differences between those who received early steroids and those who did not. The absolute standardized difference displayed in the right-hand column is a measure of how different the two groups are. With a propensity-weighted analysis, the goal is to have an absolute standardized difference of less than 10%. Prior to weighting, you can see that was not the case, with the early steroid group having a higher risk of mortality and vasoactive requirements. However, after weighting, you can see that the absolute standardized difference fell to less than 10%, creating a more level playing field. This table describes the use of steroids in the study and gives us an idea of general prescribing practices. While about half the population was in the early steroid therapy group, we see that about 20% of patients in the controlled group received steroid therapy at some point later on in their course. As expected, the most commonly used steroid was hydrocortisone, with a median dose of about two milligrams per kilogram per day for a median duration of five days. Of note, the median duration of vasoactive support in the study was three days, indicating that steroid therapy was continued for about two days after the discontinuation of vasoactive support. The primary outcomes of this study were resolution of shock, overall survival at one month, survival at one month without new morbidity, and severe deterioration in quality of life at one month. On the right, you can see results comparing early steroid therapy to no early steroid therapy. As you can see, there is no statistically significant difference between groups, leading the authors to conclude there was no association of improved outcomes with steroid therapy. Once again, we have a relatively neutral outcome. Before drawing our own conclusions, I'd like to highlight a few outstanding questions. This trial did not evaluate adverse effects, so it's unclear if there was harm associated with early steroid therapy. We also don't know the impact of duration and dose. If steroids were used for longer durations or at higher doses, would that have changed the outcome? Moreover, is there a specific vasoactive dose at which we should consider adding on steroid therapy? Without a randomized controlled trials, these questions are difficult to answer. Fortunately for us, such a trial is already underway. The SHIPS trial is an international randomized controlled trial enrolling patients receiving at least 0.1 mics per kilo per minute of epinephrine or norepinephrine. The intervention arm will receive a two milligram per kilogram hydrocortisone bolus, followed by a regimen of one milligram per kilogram IV every six hours for a maximum of seven days. This trial has enrolled 95 patients thus far and has an estimated completion date of December 2025. So, more to come in a few years. Now it's time to go back and see how our patient OJ is doing. Unfortunately, OJ was intubated shortly after PQ admission and has been requiring increasing support. Based on her last blood gas, her OI is 24, which is consistent with severe pediatric ARDS. Based on your current clinical practice, would you initiate a neuromuscular blocking agent for OJ? Once again, I expect variations in practice given the lack of robust pediatric data. As is the case with other disease states lacking pediatric data, it's helpful to know what practice looks like on the adult side. Two pivotal trials conducted in the adult population are the ACURASIS and ROSE trials. These studies had very similar patient populations and included adults with moderate to severe ARDS. Patients received cisatrachirum or a placebo for 48 hours. Now, despite similar methodology, the ACURASIS and ROSE trials had very different results. ACURASIS found improved 90-day survival in those receiving cisatrachirum, while the ROSE trial, which was conducted about 10 years later, found no difference in 90-day mortality. Notable differences between these two studies were that the ROSE trial used higher PEEP and lighter sedation in the control group than the ACURASIS trial. This might mean that differences in outcomes can be attributed to differences in practice over time, leaving us with even more questions on how to apply these studies to our pediatric population. Luckily, a pediatric-specific study was published in CCM just a few months ago. This trial is a secondary analysis of the RESTORE dataset, which was a cluster randomized clinical trial of intubated pediatric patients with ARDS. Patients with moderate to severe ARDS were stratified to early NMBA usage defined as those receiving NMBAs on days one and two after intubation versus those who did not receive early NMBA. Propensity score matching was used to stratify patients into five groups according to the probability of early NMBA usage. Those with the lowest risk of early NMBA usage were placed in the first quintile, while those with the highest risk of early NMBA usage were in the fifth quintile. Overall, the early NMBA group was unsurprisingly sicker with significantly higher PRISM scores and increased risk of mortality, more severe pediatric ARDS, and more organ dysfunction. However, when looking at the propensity score quintiles with the highest risk of NMBA usage, the population differences began to dissipate, the only exception being patients in the early NMBA group still had more severe ARDS. Since the patients in quintiles five and four are more likely to use early NMBAs, we'll focus our review of the results on these groups. The primary outcomes of this study were duration of mechanical ventilation and in-hospital mortality. For both quintiles, you can see those receiving NMBAs had a significantly longer duration of mechanical ventilation, but no difference in mortality. Secondary outcomes focused on morbidity, including cognitive, functional, and physical impairment. Across the board, there was no difference in morbidity in either quintile. This graph is a helpful visual of patients requiring mechanical ventilation. Along the X-axis, we have duration of mechanical ventilation, and along the Y-axis is the percent of patients requiring mechanical ventilation over time. The early NMBA groups in the highest risk quintiles are the red and black lines, and the no early NMBA groups in those same quintiles are the blue and green lines. Again, we can see that there was a higher percentage of patients requiring mechanical ventilation in those receiving early NMBAs, which was consistently true across all quintiles. The authors concluded that early NMBA usage was associated with longer mechanical ventilation and longer time to recovery. As with the previous trial we discussed, there are a few outstanding questions we need to ask ourselves. The authors did not divulge what mechanical ventilation settings were used, making it difficult to know if the current standards of practice were met. Moreover, patients in this study received NMBAs for a median duration of five days, which is notably longer than both the ACQUIRACES and ROSE trials. Paralytic dosing and monitoring was also not reported, both of which can significantly impact outcomes. Again, without a randomized control trial, these questions are difficult to answer. Once again, however, there is light at the end of the tunnel. The PAMP study is a randomized control trial currently underway. Pediatric patients with moderate to severe ARDS will receive rocuronium one milligram per kilogram, followed by a one milligram per kilogram per hour continuous infusion, or placebo, for 48 hours. The primary outcome is focused on morbidity at 12 months post-PICU discharge. We look forward to the results in the spring of 2024. In conclusion, the two studies we discussed today call us to review our current clinical practices. At this time, the role of steroid therapy in pediatric septic shock remains largely unknown. Moreover, neuromuscular blockade usage for the treatment of moderate to severe ARDS was not associated with improved outcomes and may in fact prolonged duration of mechanical ventilation. While these trials left us with a few thought provoking questions, there are randomized control trials in the works that will hopefully provide us some answers in the near future. Thank you to all those who listened in and please don't hesitate to reach out with any comments or questions. Thank you.

pediatric septic shock

pediatric acute respiratory distress syndrome

corticosteroids in septic shock

neuromuscular blocking agents in pediatric ARDS

randomized controlled trials