Well, so I have no disclosures related to this talk. I'm going to briefly, in the interest of time, review some of the challenges of research in this space. You've heard about some of those already. I'll talk very briefly about the importance of common definitions, outcomes, and common data elements, and then spend the bulk of the next several minutes talking about the research priorities that came out of this consensus conference process. So you've heard some of these sobering statistics already this morning. Traumatic injury is a leading cause of death in children and adolescents in the U.S., and we've unfortunately seen an increase over recent years in penetrating trauma and firearm-related injuries, and a rather sobering high mortality rate for children receiving massive transfusion after trauma. Despite this burden of injury, we really do lack high-quality evidence to guide our decisions. And so when we went through the structured literature search for the consensus conference process that you've heard about, looking at the pediatric trauma literature, the vast majority of the studies were cohort studies, either retrospective or prospective, with only one small pilot RCT. And certainly there are challenges to conducting research in this space. One of the challenges, particularly for pediatrics, is prompt identification for study enrollment. We know that triggers for massive transfusion vary across centers, and there really aren't yet robust ways to predict which children will develop hemorrhagic shock and or require massive transfusion. So it's challenging to identify ahead of time by either mechanism or physiology, though obviously there's a lot of ongoing work in this space. Patient numbers you heard about a little bit, and I think compounding the problem of the patient numbers is the patient heterogeneity, not only due to the trauma itself and physiologic heterogeneity and trauma-induced coagulopathy, but also the pediatric age range. Are the things that we should be doing for a 17-year-old the same as a two-year-old? And how do you study that? And of course, data collection challenges. When you're talking about interventions that are happening over a very compressed time, you really need minute-to-minute data collection and to know exactly when that blood product was given or that dose of TXA was given relative to what happens to the physiology, what happens to your biomarkers when you measure them. This has historically been a challenge. I think there are probably some technological solutions that are out there on the hike and available at some places, at least, that can help with this, but certainly remains a challenge, at least, in many places. And then, of course, a lack of standardized definitions and outcomes has been a barrier to try to synthesize data across the field. Speaking about that a little bit, certainly published definitions of life-threatening bleeding have varied and often are applied retrospectively based on how much blood was given, how much blood was allowed to use for a prospective study. Now, you saw the definition earlier this morning of what we came up with as a consensus conference, and it took some time and discussion to come to that definition. And though it makes a lot of physiologic sense, it also would be, I think, challenging to operationalize within studies as well. So I think ongoing work in that space. And certainly, partly because of those challenges, differences in case definitions and differences in outcomes have really challenged the ability to synthesize the data that we do have in moving forward. I'm not going to go through these papers in detail. I put the QR codes here so that you can see them. Some work in this field that is moving forward. So there are published consensus recommendations for primary outcomes for clinical trials for bleeding in general, as you see here, and one specific to bleeding and trauma, as you see here. Now, on to the research priorities. So recognizing, you know, going in, we had a sense, knew that the evidence base would be limited. We built into, I say we, really it was Rob, built into the process of developing research priorities during the consensus conference as a very important deliverable from the group. Just briefly, methods, you've seen, we had 16 members of a multidisciplinary panel, and then following that structured literature search in the clinical recommendation process, research topics that were aligned to the PICO questions were developed, and then were prioritized by an anonymous online survey. The entire list is here. It's in the paper. It's not meant for you to read here, but to show if you go to the paper, there'll be a table that will show the results of the voting and the prioritized list in order. I'm going to go through these individually. So breaking this up by theme, similar to Matt's presentation, there were a number of priorities that came out focused on the pre-hospital space. One was all of those decisions that are made in that pre-hospital space. We have very little data to know what is the optimum combination of how to move patients from their centers of presentation to destination centers, what are the modes of transport, timing of transport, what is the effect of prolonged on-scene time. There also is a dearth of evidence on airway management and what is the optimum airway management at pre-hospital and emergency department, quite frankly. Tourniquet use, and in particular, efficacy of education efforts to promote tourniquet use, as well as safety of tourniquet use and duration of tourniquet use related to safety and efficacy. In terms of resuscitation and hemostatic adjuncts, as you've just seen, one of the priorities that came out was looking at whole blood versus components, but importantly, recognizing that all whole blood is not the same, just like all red cells are not the same, if anybody's ever heard me speak, I say that often. So what is the optimum storage duration? What are optimum leukocyte reduction strategies? What are effects of Rh-positive whole blood in Rh-negative patients, Rh-negative girls? Those safety studies, very important to be conducting along the way. And then, of course, safety, efficacy, dosing, and pharmacokinetics of TXA. So really understanding what are, not just the drug versus placebo, but what are the effects of different dosing strategies as well. And then another priority that came up was thinking about those austere settings, including rural settings in the US, and what are shelf-stable hemostatic adjuncts and the effects of those, and the effects of deployment of those products into those settings. And then, finally, data monitoring and mechanisms. I lumped together here, and there was a lot of, as you see, the number two priority here, was thinking about how do we use the pre-hospital data that we have to be able to predict hemorrhagic shock, identify hemorrhagic shock early, and identify kids who need resuscitation early. I think that is a challenge in our field, and as you can see, rose to near the top of our list of priorities. Along the similar lines, the very next priority down was methods to define, standardize, and improve collection of common data elements. And importantly, to think about how to link data elements across the entire continuum of care, from the pre-hospital space to the initial hospital presentation, inter-facility transport, destination hospital, inpatient, and then rehabilitation for patients for whom that is applicable. So really thinking about how do we work together to link our data sets so that we can follow patients over time. We saw in the recommendations portion about viscoelastic monitoring, and really did identify that there is not much data in the pediatric trauma population. And so there was a priority that came out that we need those data. So what are the effects of using a traditional coagulation-based resuscitation strategy versus a balanced resuscitation strategy versus a viscoelastic monitoring-based resuscitation strategy? When should the test be deployed? How best do we use the tests? And even which types of viscoelastic monitoring to use? And then lastly, mechanisms of trauma-induced coagulopathy. We saw a little bit about the heterogeneity in fibrinolysis, but what other types of heterogeneity exist? What are effects of trauma on the endothelium? How does the endothelium interact with coagulation in the setting of trauma-induced coagulopathy? What is the immunologic response to trauma and to the interventions that we are providing, whether it be TXA or other hemostatic adjuncts, the blood products themselves? How does all of this fit together in complex systems? And then importantly for pediatrics, what are the effects of all of these things over the pediatric age range? Again, a two-year-old is probably not the same physiologically as a 17-year-old in this space, but we don't have a lot of data to really definitively say that. And so in conclusion, certainly I think we, this morning, have shown that we really do lack high-quality evidence to guide the management of life-threatening bleeding in children. Clinical research in this space is challenging, but it's possible. It can be done. It needs to be done. And certainly consensus-based definitions, outcomes, and research priorities can start to build that roadmap to getting this done. And thank you. Thank you.

pediatric trauma research

traumatic injury

firearm-related injuries

trauma-induced coagulopathy

data linkage