Abstract

BACKGROUND Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING National Institute for Health Research Efficacy and Mechanism Evaluation.

Abstract

BACKGROUND A 2-gram bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a RCT. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected TBI when intracranial hemorrhage (ICH) is absent on initial CT. METHODS This study utilized data from a 2015-2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-gram bolus, 1-gram bolus plus 1-gram infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial CT negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: MI, DVT, seizure, pulmonary embolism, ARDS, cardiac failure, liver failure, renal failure, CVA, cardiac arrest, cerebral vasospasm, "any thromboembolism", hypernatremia, AKI, and infection. Other unfavorable outcomes analyzed include mortality at 28 days & 6 months, GOSE ≤4 at discharge & 6 months, ICU-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared to placebo. RESULTS No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury which were overrepresented in the 1-gram TXA bolus +1-gram TXA infusion. CONCLUSIONS Administration of either a 2-gram TXA bolus or a 1-gram TXA bolus plus 1-gram TXA 8-hour infusion in suspected-TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-gram bolus is associated with a mortality benefit it should be administered in suspected-TBI. LEVELS OF EVIDENCE Level II, Therapeutic.

Abstract

BACKGROUND Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators remain unclear. Recently the anaphylatoxin C4a has been shown to bind to thrombin receptors. While plasma-based resuscitation has been shown to modify the endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought to characterize the activation of complement after injury and the effect of fresh frozen plasma (FFP) on this inflammatory response. We hypothesized that trauma induces C4 activation, which is associated with worse outcomes and influenced by FFP resuscitation. METHODS Blood was collected from injured patients at a single Level I Trauma Center enrolled in the COMBAT randomized clinical trial. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. For the present observational study, concentrations of complement proteins were analyzed at multiple time points, compared between treatment groups, and correlated with outcomes. RESULTS C4 activation occurred over the first six hours post-injury with peak activation 6-24 hours. Tissue hypoperfusion, defined as base deficit >10 mEq/L, and requirement for massive transfusion were associated with greater C4 activation. C4 activation was associated with mortality, multiple organ failure, and longer ventilator requirement. Additionally, temporal trends of C1q, factor B, and C3 by outcome groups support the prevailing theory of primary classical pathway activation with alternative pathway amplification. Resuscitation with FFP over the first six hours was associated with increased C4 activation at 12 and 24 hours. CONCLUSIONS C4 activation has an important inflammatory role post-injury, and FFP has the potential to augment this complement activation during resuscitation. EVIDENCE Level III, Prognostic/Epidemiological.

Abstract

BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.

Abstract

OBJECTIVES Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. BACKGROUND The vascular endothelium is a critical regulator of hemostasis and organ function. The relationship between markers of endotheliopathy and fibrinolysis following trauma has not been evaluated. METHODS We performed a secondary analysis of prospectively collected biomarker data in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial. We stratified subjects by 24-hour thromboelastography (TEG) percent clot lysis (LY30) and plasma D-dimer (DD) levels and evaluated differences in endotheliopathy biomarkers and clinical outcomes between subjects with one of four 24-hour fibrinolysis phenotypes: LY30 0.9-2.9% (LY30(norm)), LY30 >2.9% (LY30(high)), LY30 <0.9% and low DD (LY30(low)+DD(low)), and LY30 <0.9% and high DD (LY30(low)+DD(high)). RESULTS The analysis included 168 subjects with LY30(norm), 32 with LY30(high), 147 with LY30(low)+DD(low) and 124 with LY30(low)+DD(high). LY30(low)+DD(high) subjects had greater injury severity and a higher incidence of severe head injury, multiorgan failure (MOF), and mortality than the other phenotypes. All endotheliopathy biomarkers were significantly higher in the LY30(low)+DD(high) phenotype. Adjusting for injury severity, mechanism and head trauma, 24-hour angiopoietin-2 and soluble thrombomodulin were independently associated with the LY30(low)+DD(high) phenotype. Both endothelial biomarkers were discriminating for MOF. Subjects with thrombomodulin level >9.5 ng/mL and angiopoietin-2 level >3.6 ng/mL accounted for 64% of subjects who developed MOF. CONCLUSIONS In a multicenter trauma cohort, subjects with a fibrinolysis phenotype characterized by low TEG lysis and elevated DD 24 hours after injury have significantly worse endotheliopathy and clinical outcomes. Our findings support mechanistic evaluations of the role of the endothelium in fibrinolysis dysregulation that may drive late-stage organ injury.

Abstract

BACKGROUND Early hemorrhage control after interpersonal violence is the most urgent requirement to preserve life and is now recognized as a responsibility of law enforcement. Although earlier entry of first responders is advocated, many shooting scenes remain unsafe for humans, necessitating first responses conducted by robots. Thus, robotic hemorrhage control warrants study as a care-under-fire treatment option. METHODS Two bomb disposal robots (Wolverine and Dragon Runner) were retrofitted with hemostatic wound clamps. The robots' ability to apply a wound clamp to a simulated extremity exsanguination while controlled by 4 experienced operators was tested. The operators were randomly assigned to perform 10 trials using 1 robot each. A third surveillance robot (Stair Climber) provided further visualization for the operators. We assessed the success rate of the application of the wound clamp to the simulated wound, the time to application of the wound clamp and the amount of fluid loss. We also assessed the operators' efforts to apply the wound clamp after an initial attempt was unsuccessful or after the wound clamp was dropped. RESULTS Remote robotic application of a wound clamp was demonstrated to be feasible, with complete cessation of simulated bleeding in 60% of applications. This finding was consistent across all operators and both robots. There was no difference in the success rates with the 2 robots (p = 1.00). However, there were differences in fluid loss (p = 0.004) and application time (p < 0.001), with the larger (Wolverine) robot being faster and losing less fluid. CONCLUSION Law enforcement tactical robots were consistently able to provide partial to complete hemorrhage control in a simulated extremity exsanguination. Consideration should be given to using this approach in care-under-fire and care-behind-the-barricade scenarios as well as further developing the technology and doctrine for robotic hemorrhage control.

Abstract

INTRODUCTION Exsanguination is the most preventable cause of death. Paradigms such as STOP THE BLEED recognize increased responsibility among the less experienced with Wound Packing (WP) being a critical skill. As even trained providers may perform poorly, we compared Video-modelling (VM), a form of behavioural modelling involving video demonstration prior to intervention against remote telementoring (RTM) involving remote real-time expert-guidance. METHODS Search and Rescue (SAR-Techs), trained in WP were asked to pack a wound on a standardized simulator randomized to RMT, VM, or control. RESULTS 24 SAR-Techs (median age 37, median 16.5 years experience) participated. Controls were consistently faster than RTM (p = 0.005) and VM (p = 0.000), with no difference between RTM and VM. However, 50% (n = 4) Controls failed to pack properly, compared to 100% success in both VM and RTM, despite all SAR-Techs feeling the task was "easy". DISCUSSION Performance of a life-saving technique was improved through either VM or RTM, suggesting that both techniques are beneficial and complementary to each other. Further work should be extended to law enforcement/lay public to examine logistical challenges.

Abstract

Balanced crystalloids may improve outcomes compared to saline for some critically ill adults. Lower tonicity of balanced crystalloids could worsen cerebral edema in patients with intracranial pathology. The effect of balanced crystalloids versus saline on clinical outcomes in patients with traumatic brain injury (TBI) requires further study. We planned an a priori subgroup analysis of TBI patients enrolled in the pragmatic, cluster-randomized, multiple-crossover Isotonic Solutions and Major Adverse Renal Events Trial (SMART) (ClinicalTrials.gov: NCT02444988, NCT02547779). Primary outcome was 30-day in-hospital mortality. Secondary outcomes included hospital discharge disposition (home, facility, death). Regression models adjusted for pre-specified baseline covariates compared outcomes. TBI patients assigned to balanced crystalloids (n=588) and saline (n=569) had similar baseline characteristics including Injury Severity Score 19 (10); mean maximum head/neck Abbreviated Injury Score, 3.4 (1.0). Isotonic crystalloid volume administered between ICU admission and first of hospital discharge or 30 days was 2037 (3470) mL and 1723 (2923) mL in the balanced crystalloids and saline groups, respectively (P=0.18). During the study period, 94 (16%) and 82 (14%) patients (16%) died in the balanced crystalloid and saline groups, respectively (aOR, 1.03; 95% confidence interval [CI], 0.60 to 1.75; P=0.913). Patients in the balanced crystalloid group were more likely to die or be discharged to another medical facility (aOR 1.38 [1.02-1.86]; P=0.04). Overall, balanced crystalloids were associated with worse discharge disposition in critically injured patients with TBI compared to saline. The confidence intervals cannot exclude a clinically relevant increase in mortality when balanced crystalloids are used for patients with TBI.

Abstract

Objective: The "Stop the Bleed" campaign was created to educate laypeople about bleeding control and make bleeding control kits available in public locations. Unfortunately, previous research has indicated that up to half of all laypeople cannot effectively apply a tourniquet. The purpose of this study was to determine if laypeople could apply tourniquets more effectively with just-in-time training using combined audio-written instructions versus written-only instructions.Methods: We conducted a prospective randomized study comparing the application of a tourniquet using a simulated bleeding arm. Participants were laypeople 18 years and older and excluded those with any previous tourniquet experience or training. Participants were randomized to just-in-time training using either audio-written or written-only instructions. Time in seconds to tourniquet application and the effectiveness of the tourniquet application was recorded. Effective application was defined as stopping the flow or significantly slowing the flow to a slow drip. Ineffective tourniquet placement was defined as not significantly changing the flow. Statistical analysis was performed using Fisher's exact, t-test, and linear regression.Results: Eighty-two participants were included; 40 were in the audio-written instructions group, and 58.5% were male. The audio-written group's effective application rate was 92.5% and that of the written-only group was 76.2%. A significantly higher rate of ineffective tourniquet application was noted for the written-only group, (23.8%), versus the audio-written group (7.5%), p=.04. Regardless of the type of instructions used, time to effective application of the tourniquet decreased as participant age increased (p = 0.02, 95%CI (-1.24, -0.13). There was no relationship between age and effective tourniquet application (p = 0.06). Time for tourniquet placement was not different between the audio-written (mean 100.4 seconds) and written-only (mean 106.1 seconds) groups (p = 0.58).Conclusion: This study suggests that combined audio-written instructions decrease the rate of ineffective tourniquet application by laypeople compared with written-only instructions. Further studies are needed to assess if audio instructions and just-in-time training can further maximize effective tourniquet application.

Abstract

BACKGROUND Resistance breathing amplifies the respiratory pump during inspiration, so may be an effective intervention for treatment of hemorrhagic injuries. In animal studies of actual hemorrhage, and human studies of simulated hemorrhage, resistance breathing protects arterial pressure, and improves tolerance to this stress. Anecdotally, resistance breathing also increases the coupling between sympathetic nerve activity and arterial pressure. The impact of resistance breathing on overall sympathetic nerve activity, however, has not been examined. We tested the hypothesis that resistance breathing increases sympathetic nerve activity during simulated hemorrhage in healthy humans. METHODS Lower body negative pressure (LBNP) was used to simulate hemorrhage in five human subjects (3M, 2F; 29.2 ± 6.8 y). Two experiments were conducted (randomized order): 1) a control condition in which LBNP was applied at 3 mmHg/min until the onset of presyncope, and 2) a resistance breathing condition in which the same LBNP protocol was used, but subjects breathed through a resistance device (set at -7 cm.H2O) during the final stages of the protocol. Arterial pressure and muscle sympathetic nerve activity (MSNA) of the radial nerve were monitored continuously. Bursts frequency (bursts/min) and burst incidence (burst/ 100 heart beats) were used to quantify MSNA. Coupling between diastolic arterial pressure (DAP) and MSNA was assessed by transfer function analysis coherence within the low frequency range (0.04-0.15 Hz). Two-way repeated measures ANOVAs were conducted for assessment of responses in the control and resistance breathing conditions, between baseline and at matched time points late in the LBNP protocol. RESULTS While LBNP induced increases in both MSNA burst frequency (P=0.003) and burst incidence (P=0.06), there was no effect of resistance breathing on MSNA for either index during LBNP (control, 57.9 ± 25.9 bursts/min vs. resistance breathing, 50.6 ± 21.7 bursts/min, P=0.99; control, 55.6 ± 25.6 b/100 heart beats vs. resistance breathing, 42.3 ± 18.3 b/100 heart beats, P=0.42). Additionally, there was no effect of resistance breathing on DAP (control, 73.2 ± 9.9 mmHg vs. resistance breathing, 72.8 ± 4.4 mmHg; P=0.99), or coherence between MSNA and DAP during LBNP (control, 0.53 ± 0.21 vs. resistance breathing, 0.69 ± 0.17; P=0.46). CONCLUSION Contrary to our hypothesis, resistance breathing had no effect on sympathetic nerve activity during LBNP. A limitation of this study is the low sample size (N=5), and high variability of MSNA. Future investigations with a larger sample size are needed to determine if respiratory dynamics can influence the coupling between MSNA and arterial pressure.