My name is Jason Sperry from the University of Pittsburgh. I'm a professor of surgery and critical care medicine. It's my pleasure to present early access to plasma and adjuncts in hemorrhagic shock, the early bird gets the worm. I have no conflicts. As an overview for the talk, I want to discuss early plasma for hemorrhagic shock, what the evidence is for early plasma, the who, what, and possibly why of how it may work, early tranexemic acid for hemorrhage, pre- hospital data, freeze-dried plasma, potential game-changer in trauma resuscitation, and what the future may hold. This is the difficult type of patient following traumatic injury and this is that we are focusing on and trying to reduce the morbidity and the mortality attributable to this type of hemorrhage. 2015 results from the PROPER trial which first author Dr. John Holcomb demonstrated that a trauma resuscitation using one-to-one-to-one, which is one unit of red cells, one unit of plasma, and one unit of platelets as compared to less plasma in a one-to-two fashion, may reduce death from exsanguination. The overall study outcome of 30-day mortality was not statistically different, but as you can see from these curves, the lower curve is those that patients that receive one-to-one-to-one. And this trial demonstrated that how we resuscitate trauma patients is important regarding getting them off the operating table and getting them to the ICU and attempting to manage the initial shock and hemorrhage from their injury. By us using different types of trauma resuscitation over time over the last decade and including one-to-one-to-one resuscitation, which attempts to recreate whole blood, all the components that someone's hemorrhaging, we have improved our management during the in-hospital phase of injured patients and the resuscitation phase during the in- hospital stay. Despite improvements in our in-hospital resuscitation, data from the PROPER trial and the PROMPT trial demonstrated that mortality occurs very early following traumatic hemorrhage, in the first one to three hours. This graph demonstrates the velocity of hemorrhage early on. And if you're going to intervene in the first hour of arrival at a trauma center, it really highlights the importance of the pre-hospital environment for that intervention to occur. Preventing these early deaths from traumatic hemorrhage sort of highlights the importance of the pre-hospital environment. If you're going to affect an outcome that occurs, a death that occurs in the first hour after trauma center arrival, there's really no intervention time that occurs in the hospital. You need to start focusing on things in the pre-hospital as close to the time of injury as possible. What's novel about traumatic injury is that there's a time zero, and similar to other medical care such as strokes, myocardial infarctions, it's close to the time of injury or the beginning of the event that you intervene, the more likely you have improved outcomes. And so the early bird gets the worm as close as to the time of injury, again likely suggesting that the pre-hospital environment may be a great place to intervene if at all feasible. The PAMPER trial was published in the New England Journal in 2018 and it demonstrated when we put thod plasma on helicopters in a randomized fashion that it resulted in approximately a 10% mortality benefit for all patients, enrolled 501 patients. The PAMPER trial was pragmatic and enrolled 501 severely injured patients that were transported by air medical transport, again demonstrating just under a 10% mortality benefit for all patients at 30 days. And it was demonstrated to be safe with no transfusion complications in the pre-hospital setting. These Keplin-Meier survival curves out to 30 days demonstrate early separation with the blue being standard care and the red being plasma. And you can see they separate early and then stay separated about equidistant over the time course of the study. So very early on there's a mortality benefit and those mortality benefits are maintained out to 30 days. In a secondary analysis of the the PAMPER trial we looked at those patients with traumatic brain injury that was documented on CAT scan soon after arrival and did a secondary analysis that was published in JAMA Open. This secondary analysis demonstrated that the majority of the survival benefit was demonstrated in patients with traumatic brain injury. And if you looked at a stratified analysis in patients without documented traumatic brain injury there was very little signal. In the deeper analysis we demonstrated that in these traumatic brain injured patients that early pre-hospital plasma had its primarily mortality benefit in patients that were transported from the scene rather than from the outside hospital. And the important differences between outside hospital transfer versus from the scene is that the plasma may be provided early, earlier to the patient, closer to the time of injury if you're transported from the scene. From a mechanistic understanding we took samples that were derived from enrolled PAMPER patients, which again was a multi-center study and all sites collected early samples. And we did cytokine measurements, endothelial cell markers, and looked at traumatic brain injury biomarkers also. And this work was done by Dr. Daniel Gruen at our facility in the University of Pittsburgh. In exploratory analysis we looked at the severity of injury and measurements of endothelial cell and inflammatory cell markers. And it demonstrated that patients at the highest injury severity in plasma had reduced levels of IL-6, MCP-1, Sinicin-1, an endothelial cell marker of injury and vascular endothelial cell growth factor. And these are markers of endothelial cell injury and pre-hospital plasma may reduce at the endotheliopathy following a traumatic injury. In further delving into the mechanistic underpinnings of why pre-hospital plasma may be beneficial from a recent publication in Cell Reports Medicine, a multi-omic analysis from our group, we demonstrated two different endotypes. Endotype 2 is the more severe injured cohort. And we looked at those patients that received pre-hospital plasma compared to not and showed that the survival benefit is primarily in the endotype 2 cohort in patients with traumatic brain injury. And it is in these patients where the blue arrows in the panel E demonstrate differences in protein expression in these cohorts at both 0 and 24 hour that is different if you did not receive plasma. And these proteins were primarily in the coagulation system families. So in secondary analyses from the PAMPER trial, we have demonstrated that early plasma is probably most beneficial. It's primarily based in the patient with polytrauma that includes concomitant traumatic brain injury. It's in the most severely injured, primarily blood injured with severe shock that required moderate transfusion requirements. That's a summary of multiple secondary analysis, some that weren't presented in this current talk. In addition to how we transfuse blood and blood components to trauma patients, we also have adjuncts such as tranexemic acid that have been shown and increasingly over the last decade to benefit patients that are bleeding following traumatic injury. The CRASH-2 trial demonstrated that tranexemic acid provided in the hospital soon after arrival, then the first three hours it has its most beneficial effect. And this overall trial outcomes demonstrated a 1.5 percent mortality benefit from any cause of death that was statistically significant. Secondary analysis of the CRASH-2 trial demonstrated the early, the importance of early treatment in the first three hours with the potential for harm if it's provided after three hours from arrival. This further highlights the importance and the recurrent theme of this talk that the early bird gets the worm. As you provide tranexemic acid early for inpatient therapy, it is more beneficial and this likely applies potentially to the pre-hospital setting. We were funded by the Department of Defense to look at pre-hospital tranexemic acid and patients at risk of hemorrhage. This is the STAMP trial that was published in JAMA Surgery and we enrolled over 900 patients that received in a double-blinded fashion tranexemic acid or placebo. The overall primary analysis from the STAMP trial demonstrated approximately a 1.8 percent lower mortality in those patients that received tranexemic acid, but this result or difference did not reach statistical significance in the 900 pre-hospital patients that we looked at. When we looked at coxhazard regression, again a hazard ratio of 0.81, but this did not reach statistical significance with a p-value of 0.18. When we looked at post hoc subgroup analysis, we looked at patients that received pre-hospital tranexemic acid in the first hour and there was a significant benefit in those patients and patients had had severe shock and less systolic blood pressure presenting qualifying vitals less than 70. At the same time the STAMP trial, Dr. Rao and Dr. Schreiber got funding from the Department of Defense to do a multi-center pre-hospital tranexemic trial in patients at risk of traumatic brain injury. Although the overall trial was not statistically different across the arms and they looked at it via subgroup analysis, patients with documented traumatic brain injury there was survival benefit. Based upon our post hoc analysis in the primary paper of the STAMP trial, we did a second a formal secondary analysis of the STAMP data looking at early pre-hospital tranexemic acid if it was given in the first hour as compared to what we deemed a late pre-hospital if it was given in the first between the first and second hour. Of note the inclusion criteria for the study that was to be given within two hours of estimated time of injury. When we looked at this, we looked at early pre-hospital tranexemic acid and it was associated with a 30-day survival via Kaplan-Meier comparison on the left and on the right was unadjusted 30-day survival in patients that received it in between the first and second hour as what we're calling delayed pre-hospital. To follow up our unadjusted Kaplan-Meier comparison, we did multivariate Cox hazard regression and we adjusted for differences in demographics, injury severity, pre-hospital crystalloid, pre-hospital blood transfusion, and initial GCS. And we verified a hazard ratio of 0.35 suggesting greater than a 70% lower risk of mortality if tranexemic acid was given in the first hour from the estimated time of injury rather than between the first and second hour or in delayed pre-hospital setting. And this relationship was statistically significant with the p-value of 0.001. There are secondary outcomes in this secondary analysis. We looked at the development of multiple organ failure and those patients that receive tranexemic acid early in the first hour also had a significantly lower rate of multiple organ failure that was not demonstrated in the delayed pre-hospital group. We also demonstrated lower transfusion requirements in the in the first six hours in patients that received early tranexemic acid as compared to the delayed group where there was no statistically significant differences between tranexemic acid and placebo. These results again demonstrate the common theme of this talk that the early bird gets the worm and early tranexemic acid in early pre-hospital environment is where the mortality benefit is and may reduce ultimate multiple the rate of multiple organ failure and reduce transfusion requirements. So I'd like to switch a little focus from thawed plasma to freeze-dried plasma and I believe that this has the potential to be a game-changer. As compared to freeze-dried plasma, fresh frozen plasma is associated with major logistical constraints for both civilian and military injured patients. There's both temperature and shelf life restraints. Freeze-dried plasma is needed for these austere environments where you're not able to have a refrigerator and you're not and you don't have only five days for thawed plasma as a shelf life. Currently there is no U.S. FDA approved product but freeze-dried plasma is available in both France, Germany, and South Africa. So these are the both France, Germany, and South Africa products that are currently available however there is no FDA U.S. product. There are three different types of products in the U.S. that are currently pending FDA approval. EasyPlas, Resussex, and then Terumobct freeze-dried plasma and these again are not FDA approved at this time but hopefully within the first in the next six months to two years these will become on market in the U.S. I wanted to talk a little bit about the future studies that are coming that may provide further evidence of this early bird-gets-the-worm theme and I want to highlight the LIGHTS Network which is a multi-center trauma network that's funded by the Department of Defense that is run out of the University of Pittsburgh in collaboration with the University of Colorado and University of Oregon. LIGHTS Network comprises of 33 trauma centers across the country that have the potential to be involved in multi-center pre-hospital or early emergency department interventional trials. Relevant to this talk the LIGHTS Network has been funded to study and characterize freeze-dried plasma via pre-hospital interventional trial. That is awaiting of U.S. approval of the product. Simultaneously we'll be looking at pre-hospital whole blood as compared to standard care during pre-hospital environment and those results that trial should be starting in the next six months and those results will be coming after four years of approximate enrollment. Although in this talk we did not talk about whole blood resuscitation my future prediction is that pre-hospital resuscitation for hemorrhagic shock will include for during air medical transport where it has the capabilities of storing blood products and have them in a cooling container will likely be whole blood which contains both red cells, plasma, and platelets and that will be the definitive pre-hospital resuscitation transfusion for severely injured trauma patients. The ground which doesn't have the capabilities to store and don't see trauma patients as commonly freeze-dried plasma will be in my future prediction and will be the game changer in the pre-hospital phase of care and environment. In the final few seconds I'd like to rehash the common theme of this talk that the early bird gets the worm the closer we intervene whether it's with blood products adjuncts or tourniquets no matter what it is the closest to the type of injury is associated with improvement in outcomes particularly mortality getting the patients to the trauma bay and to the OR as soon as possible. If there is a live session I'd be happy to answer any questions.

early access to plasma

adjuncts in hemorrhagic shock

intervene as close to time of injury as possible

pre-hospital environment

improve outcomes and reduce mortality

Shock Non Sepsis

Hematology

Resuscitation

Hemorrhage

Blood Blood Substitutes

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Blood and Blood Substitutes