Summary Background Plasma is integral to haemostatic resuscitation after injury, but the timing of administration remains controversial. Anticipating approval of lyophilised plasma by the US Food and Drug Administration, the US Department of Defense funded trials of prehospital plasma resuscitation. We investigated use of prehospital plasma during rapid ground rescue of patients with haemorrhagic shock before arrival at an urban level 1 trauma centre. Methods The Control of Major Bleeding After Trauma Trial was a pragmatic, randomised, single-centre trial done at the Denver Health Medical Center (DHMC), which houses the paramedic division for Denver city. Consecutive trauma patients in haemorrhagic shock (defined as systolic blood pressure [SBP] ≤70 mm Hg or 71–90 mm Hg plus heart rate ≥108 beats per min) were assessed for eligibility at the scene of the injury by trained paramedics. Eligible patients were randomly assigned to receive plasma or normal saline (control). Randomisation was achieved by preloading all ambulances with sealed coolers at the start of each shift. Coolers were randomly assigned to groups 1:1 in blocks of 20 according to a schedule generated by the research coordinators. If the coolers contained two units of frozen plasma, they were defrosted in the ambulance and the infusion started. If the coolers contained a dummy load of frozen water, this indicated allocation to the control group and saline was infused. The primary endpoint was mortality within 28 days of injury. Analyses were done in the as-treated population and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01838863. Findings From April 1, 2014, to March 31, 2017, paramedics randomly assigned 144 patients to study groups. The as-treated analysis included 125 eligible patients, 65 received plasma and 60 received saline. Median age was 33 years (IQR 25–47) and median New Injury Severity Score was 27 (10–38). 70 (56%) patients required blood transfusions within 6 h of injury. The groups were similar at baseline and had similar transport times (plasma group median 19 min [IQR 16–23] vs control 16 min [14–22]). The groups did not differ in mortality at 28 days (15% in the plasma group vs 10% in the control group, p=0∙37). In the intention-to-treat analysis, we saw no significant differences between the groups in safety outcomes and adverse events. Due to the consistent lack of differences in the analyses, the study was stopped for futility after 144 of 150 planned enrolments. Interpretation During rapid ground rescue to an urban level 1 trauma centre, use of prehospital plasma was not associated with survival benefit. Blood products might be beneficial in settings with longer transport times, but the financial burden would not be justified in an urban environment with short distances to mature trauma centres.

BACKGROUND Fibrinolysis is a physiologic process maintaining patency of the microvasculature. Maladaptive overactivation of this essential function (hyperfibrinolysis) is proposed as a pathologic mechanism of trauma-induced coagulopathy. Conversely, the shutdown of fibrinolysis has also been observed as a pathologic phenomenon. We hypothesize that there is a level of fibrinolysis between these two extremes that have a survival benefit for the severely injured patients. METHODS Thrombelastography and clinical data were prospectively collected on trauma patients admitted to our Level I trauma center from 2010 to 2013. Patients with an Injury Severity Score (ISS) of 15 or greater were evaluated. The percentage of fibrinolysis at 30 minutes by thrombelastography was used to stratify three groups as follows: hyperfibrinolysis (Q3%), physiologic (0.081-2.9%), and shutdown (0-0.08%). The threshold for hyperfibrinolysis was based on existing literature. The remaining groups were established on a cutoff of 0.8%, determined by the highest point of specificity and sensitivity for mortality on a receiver operating characteristic curve. RESULTS One hundred eighty patients were included in the study. The median age was 42 years (interquartile range [IQR], 28Y55 years), 70% were male, and 21% had penetrating injuries. The median ISS was 29 (IQR, 22-36), and the median base deficit was 9 mEq/L (IQR, 6-13 mEq/L). Distribution of fibrinolysis was as follows: shutdown, 64% (115 of 180); physiologic, 18% (32 of 180); and hyperfibrinolysis, 18% (33 of 180). Mortality rates were lower for the physiologic group (3%) compared with the hyperfibrinolysis (44%) and shutdown (17%) groups (p = 0.001). CONCLUSION We have identified a U-shaped distribution of death related to the fibrinolysis system in response to major trauma, with a nadir in mortality, with level of fibrinolysis after 30 minutes between 0.81% and 2.9%. Exogenous inhibition of the fibrinolysis system in severely injured patients requires careful selection, as it may have an adverse affect on survival. LEVEL OF EVIDENCE Prognostic study, level III.

Background Massive transfusion protocols (MTPs) have become standard of care in the management of bleeding injured patients, yet strategies to guide them vary widely. We conducted a pragmatic, randomized clinical trial (RCT) to test the hypothesis that an MTP goal directed by the viscoelastic assay thrombelastography (TEG) improves survival compared with an MTP guided by conventional coagulation assays (CCA). Methods This RCT enrolled injured patients from an academic level-1 trauma center meeting criteria for MTP activation. Upon MTP activation, patients were randomized to be managed either by an MTP goal directed by TEG or by CCA (ie, international normalized ratio, fibrinogen, platelet count). Primary outcome was 28-day survival. Results One hundred eleven patients were included in an intent-to-treat analysis (TEG = 56, CCA = 55). Survival in the TEG group was significantly higher than the CCA group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the CCA group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032). CCA patients required similar number of red blood cell units as the TEG patients [CCA: 5.0 (2–11), TEG: 4.5 (2–8)] (P = 0.317), but more plasma units [CCA: 2.0 (0–4), TEG: 0.0 (0–3)] (P = 0.022), and more platelets units [CCA: 0.0 (0–1), TEG: 0.0 (0–0)] (P = 0.041) in the first 2 hours of resuscitation. Conclusions Utilization of a goal-directed, TEG-guided MTP to resuscitate severely injured patients improves survival compared with an MTP guided by CCA and utilizes less plasma and platelet transfusions during the early phase of resuscitation.

Background Trauma induced coagulopathy (TIC) is associated with a four-fold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. PAI-1 degradation by activated protein C has been proposed as mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tPA has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation, but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA. Methods 86 consecutive trauma activation patients had blood collected at the earliest time after injury, and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared to 14 healthy controls using ELISAs for active tPA, active PAI-1 and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA-challenge as a functional assay for PAI-1 reserve. Results Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median 104 pM (IQR 48—201 pM) versus 115 pM (IQR 54—202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolysis than controls. Conversely, total tPA levels (active plus complex) were significantly higher in hyperfibrinolysis than controls: 139 pM (IQR 68—237 pM) versus 32 pM (IQR 16—37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA: median LY30 of 66.8% compared to 9.6% for controls. Conclusions Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of upregulation of tPA is critical to an understanding of hyperfibrinolysis in trauma.