Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Frail Patients Undergoing Optimization Before Surgery: Preliminary Results.

BACKGROUND: It is estimated that 10% or more of patients older than 65 years are affected by frailty, a mental and physical state of vulnerability to adverse surgical outcomes. Frailty can be assessed using the Edmonton Frailty Scale: a reliable and convenient multidimensional assessment before surgery. The correlation between frailty score, presurgical optimization, and surgical outcomes was investigated in this preliminary pilot study. STUDY DESIGN: A retrospective study was performed on patients referred to the surgical optimization clinic and assessed for frailty from September 2020 to May 2023. Patients received presurgical optimization for reasons including diabetes, smoking cessation, prehabilitation and nutrition, and/or cardiopulmonary issues. Outcomes were evaluated whether they proceeded to surgery, were referred to the High-Risk Surgical Committee, surgical case canceled, or not scheduled. For those who proceeded to surgery, infection rates, complications, and 30-day emergency department (ED) and readmission rates were evaluated. RESULTS: Of 143 unique patients, 138 (men = 61, women = 77) were evaluated for this study. The average Edmonton frailty score for patients who proceeded to surgery was 7.013 (n = 78) vs 9.389 with cancelation and 9.600 for not scheduled or not optimized for surgery. Postoperative infection rates were <3%. However, 30-day ED and readmission rate was 21% (16 of 78). CONCLUSIONS: Patients with lower average Edmonton frailty scores were more likely to proceed to surgery, whereas those with higher average Edmonton frailty scores were more likely to have surgery canceled or delayed. Frail patients cleared for surgery were found to have a high 30-day ED and readmission rate.

Optimal Prehospital Crystalloid Resuscitation Volume in Trauma Patients at Risk for Hemorrhagic Shock.

BACKGROUND: Prehospital resuscitation guidelines vary widely, and blood products, although likely superior, are not available for most patients in the prehospital setting. Our objective was to determine the prehospital crystalloid volume associated with the lowest mortality among patients in hemorrhagic shock. STUDY DESIGN: This is a secondary analysis of the Prehospital Air Medical Plasma trial. Injured patients from the scene with hypotension and tachycardia or severe hypotension were included. Segmented regression and generalized additive models were used to evaluate nonlinear effects of prehospital crystalloid volume on 24-hour mortality. Logistic regression evaluated the association between risk-adjusted mortality and prehospital crystalloid volume ranges to identify optimal target volumes. Inverse propensity weighting was performed to account for patient heterogeneity. RESULTS: There were 405 patients included. Segmented regression suggested the nadir of 24-hour mortality lay within 377 to 1,419 mL prehospital crystalloid. Generalized additive models suggested the nadir of 24-hour mortality lay within 242 to 1,333 mL prehospital crystalloid. A clinically operationalized range of 250 to 1,250 mL was selected based on these findings. Odds of 24-hour mortality were higher for patients receiving less than 250 mL (adjusted odds ratio [aOR] 2.46; 95% CI 1.31 to 4.83; p = 0.007) and greater than 1,250 mL (aOR 2.57; 95% CI 1.24 to 5.45; p = 0.012) compared with 250 to 1,250 mL. Propensity-weighted regression similarly demonstrated odds of 24-hour mortality were higher for patients receiving less than 250 mL (aOR 2.62; 95% CI 1.34 to 5.12; p = 0.005) and greater than 1,250 mL (aOR 2.93; 95% CI 1.36 to 6.29; p = 0.006) compared with 250 to 1,250 mL. CONCLUSIONS: Prehospital crystalloid volumes between 250 and 1,250 mL are associated with lower mortality compared with lower or higher volumes. Further work to validate these finding may provide practical volume targets for prehospital crystalloid resuscitation.

Time to early resuscitative intervention association with mortality in trauma patients at risk for hemorrhage.

BACKGROUND: Hemorrhage is the leading cause of preventable death after injury. Others have shown that delays in massive transfusion cooler arrival increase mortality, while prehospital blood product resuscitation can reduce mortality. Our objective was to evaluate if time to resuscitation initiation impacts mortality. METHODS: We combined data from the Prehospital Air Medical Plasma (PAMPer) trial in which patients received prehospital plasma or standard care and the Study of Tranexamic Acid during Air and ground Medical Prehospital transport (STAAMP) trial in which patients received prehospital tranexamic acid or placebo. We evaluated the time to early resuscitative intervention (TERI) as time from emergency medical services arrival to packed red blood cells, plasma, or tranexamic acid initiation in the field or within 90 minutes of trauma center arrival. For patients not receiving an early resuscitative intervention, the TERI was calculated based on trauma center arrival as earliest opportunity to receive a resuscitative intervention and were propensity matched to those that did to account for selection bias. Mixed-effects logistic regression assessed the association of 30-day and 24-hour mortality with TERI adjusting for confounders. We also evaluated a subgroup of only patients receiving an early resuscitative intervention as defined above. RESULTS: Among the 1,504 propensity-matched patients, every 1-minute delay in TERI was associated with 2% increase in the odds of 30-day mortality (adjusted odds ratio [aOR], 1.020; 95% confidence interval [CI], 1.006-1.033; p < 0.01) and 1.5% increase in odds of 24-hour mortality (aOR, 1.015; 95% CI, 1.001-1.029; p = 0.03). Among the 799 patients receiving an early resuscitative intervention, every 1-minute increase in TERI was associated with a 2% increase in the odds of 30-day mortality (aOR, 1.021; 95% CI, 1.005-1.038; p = 0.01) and 24-hour mortality (aOR, 1.023; 95% CI, 1.005-1.042; p = 0.01). CONCLUSION: Time to early resuscitative intervention is associated with morality in trauma patients with hemorrhagic shock. Bleeding patients need resuscitation initiated early, whether at the trauma center in systems with short prehospital times or in the field when prehospital time is prolonged. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Evaluation of critical care burden following traumatic injury from two randomized controlled trials.

Trauma resuscitation practices have continued to improve with new advances targeting prehospital interventions. The critical care burden associated with severely injured patients at risk of hemorrhage has been poorly characterized. We aim to describe the individual and additive effects of multiorgan failure (MOF) and nosocomial infection (NI) on delayed mortality and resource utilization. A secondary analysis of harmonized data from two large prehospital randomized controlled trials (Prehospital Air Medical Plasma (PAMPer) Trial and Study of Tranexamic Acid during Air and Ground Medical Prehospital Transport (STAAMP) Trial) was conducted. Only those patients who survived beyond the first 24 hours post-injury and spent at least one day in the ICU were included. Patients were stratified by development of MOF only, NI only, both, or neither and diagnosis of early (≤ 3 days) versus late MOF (> 3 days). Risk factors of NI and MOF, time course of these ICU complications, associated mortality, and hospital resource utilization were evaluated. Of the 869 patients who were enrolled in PAMPer and STAAMP and who met study criteria, 27.4% developed MOF only (n = 238), 10.9% developed NI only (n = 95), and 15.3% were diagnosed with both MOF and NI (n = 133). Patients developing NI and/or MOF compared to those who had an uncomplicated ICU course had greater injury severity, lower GCS, and greater shock indexes. Early MOF occurred in isolation, while late MOF more often followed NI. MOF was associated with 65% higher independent risk of 30-day mortality when adjusting for cofounders (OR 1.65; 95% CI 1.04-2.6; p = 0.03), however NI did not significantly affect odds of mortality. NI was individually associated with longer mechanical ventilation, ICU stay, hospital stay, and rehabilitation requirements, and the addition of MOF further increased the burden of inpatient and post-discharge care. MOF and NI remain common complications for those who survive traumatic injury. MOF is a robust independent predictor of mortality following injury in this cohort, and NI is associated with higher resource utilization. Timing of these ICU complications may reveal differences in pathophysiology and offer targets for continued advancements in treatment.

Lipidomic signatures align with inflammatory patterns and outcomes in critical illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.

High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI.

OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation.

Prehospital plasma is associated with survival principally in patients transferred from the scene of injury: A secondary analysis of the PAMPer trial.

BACKGROUND: We sought to characterize if prehospital transfer origin from the scene of injury (SCENE) or from a referral emergency department (REF) alters the survival benefit attributable to prehospital plasma resuscitation in patients at risk of hemorrhagic shock. METHODS: We performed a secondary analysis of data from a recently completed prehospital plasma clinical trial. All of the enrolled patients from either the SCENE or REF groups were included. The demographics, injury characteristics, shock severity and resuscitation needs were compared. The primary outcome was a 30-day mortality. Kaplan-Meier analysis and Cox-hazard regression were used to characterize the independent survival benefits of prehospital plasma for transport origin groups. RESULTS: Of the 501 enrolled patients, the REF group patients (n = 111) accounted for 22% with the remaining (n = 390) originating from the scene. The SCENE group patients had higher injury severity and were more likely intubated prehospital. The REF group patients had longer prehospital times and received greater prehospital crystalloid and blood products. Kaplan-Meier analysis revealed a significant 30-day survival benefit associated with prehospital plasma in the SCENE group (P < .01) with no difference found in the REF group patients (P = .36). The Cox-regression verified after controlling for relevant confounders that prehospital plasma was independently associated with a 30-day survival in the SCENE group patients (hazard ratio 0.59; 95% confidence interval 0.39-0.89; P = .01) with no significant relationship found in the REF group patients (hazard ratio 1.03, 95% confidence interval 0.4-3.0). CONCLUSION: Important differences across the SCENE and REF cohorts exist that are essential to understand when planning prehospital studies. Prehospital plasma is associated with a survival benefit primarily in SCENE group patients. The results are exploratory but suggest transfer origin may be an important determinant of prehospital plasma benefit.

Evaluating the Cost-effectiveness of Prehospital Plasma Transfusion in Unstable Trauma Patients: A Secondary Analysis of the PAMPer Trial.

Importance: Prehospital plasma transfusion is lifesaving for trauma patients in hemorrhagic shock but is not commonly used owing to cost and feasibility concerns. Objective: To evaluate the cost-effectiveness of prehospital thawed plasma transfusion in trauma patients with hemorrhagic shock during air medical transport. Design, Setting, and Participants: A decision tree and Markov model were created to compare standard care and prehospital thawed plasma transfusion using published and unpublished patient-level data from the Prehospital Plasma in Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial conducted from May 2014 to October 2017, health care and trauma-specific databases, and the published literature. Prehospital transfusion, short-term inpatient care, and lifetime health care costs and quality of life outcomes were included. One-way, 2-way, and Monte Carlo probabilistic sensitivity analyses were performed across clinically plausible ranges. Data were analyzed in December 2019. Main Outcomes and Measures: Relative costs and health-related quality of life were evaluated by an incremental cost-effectiveness ratio at a standard willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). Results: The trial included 501 patients in the modified intention-to-treat cohort. Median (interquartile range) age for patients in the thawed plasma and standard care cohorts were 44 (31-59) and 46 (28-60) years, respectively. Overall, 364 patients (72.7%) were male. Thawed plasma transfusion was cost-effective with an incremental cost-effectiveness ratio of $50 467.44 per QALY compared with standard care. The preference for thawed plasma was robust across all 1- and 2-way sensitivity analyses. When considering only patients injured by a blunt mechanism, the incremental cost-effectiveness ratio decreased to $37 735.19 per QALY. Thawed plasma was preferred in 8140 of 10 000 iterations (81.4%) on probabilistic sensitivity analysis. A detailed analysis of incremental costs between strategies revealed most were attributable to the in-hospital and postdischarge lifetime care of critically ill patients surviving severe trauma. Conclusions and Relevance: In this study, prehospital thawed plasma transfusion during air medical transport for trauma patients in hemorrhagic shock was lifesaving and cost-effective compared with standard care and should become commonplace.

Dose-dependent association between blood transfusion and nosocomial infections in trauma patients: A secondary analysis of patients from the PAMPer trial.

BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) trial demonstrated a survival benefit to trauma patients who received thawed plasma as part of early resuscitation. The objective of our study was to examine the association between blood transfusion and nosocomial infections among trauma patients who participated in the PAMPer trial. We hypothesized that transfusion of blood products will be associated with the development of nosocomial infections in a dose-dependent fashion. METHODS: We performed a secondary analysis of prospectively collected data of patients in the PAMPer trial with hospital length of stay of at least 3 days. Demographics, injury characteristics, and number of blood products transfused were obtained to evaluate outcomes. Bivariate analysis was performed to identify differences between patients with and without nosocomial infections. Two logistic regression models were created to evaluate the association between nosocomial infections and (1) any transfusion of blood products, and (2) quantity of blood products. Both models were adjusted for age, sex, and Injury Severity Score. RESULTS: A total of 399 patients were included: age, 46 years (interquartile range, 29-59 years); Injury Severity Score, 22 (interquartile range, 12-29); 73% male; 80% blunt mechanism; and 40 (10%) deaths. Ninety-three (27%) developed nosocomial infections, including pneumonia (n = 67), bloodstream infections (n = 14), catheter-associated urinary tract infection (n = 10), skin and soft tissue infection (n = 8), Clostridium difficile colitis (n = 7), empyema (n = 6), and complicated intra-abdominal infections (n = 3). Nearly 80% (n = 307) of patients received packed red blood cells (PRBCs); 12% received cryoprecipitate, 69% received plasma, and 27% received platelets. Patients who received any PRBCs had more than a twofold increase in nosocomial infections (odds ratio, 2.15; 95% confidence interval, 1.01-4.58; p = 0.047). The number of PRBCs given was also associated with the development of nosocomial infection (odds ratio, 1.10; 95% confidence interval, 1.05-1.16; p < 0.001). CONCLUSION: Trauma patients in the PAMPer trial who received a transfusion of at least 1 U of PRBCs incurred a twofold increased risk of nosocomial infection, and the risk of infection was dose dependent. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Lactate as a mediator of prehospital plasma mortality reduction in hemorrhagic shock.

BACKGROUND: Prehospital plasma transfusion in trauma reduces mortality. However, the underlying mechanism remains unclear. Reduction in shock severity may play a role. Lactate correlates with physiologic shock severity and mortality after injury. Our objective was to determine if prehospital plasma reduces lactate and if this contributes to the mortality benefit of plasma. METHODS: Patients in the Prehospital Air Medical Plasma trial in the upper quartile of injury severity (Injury Severity Score, >30) were included to capture severe shock. Trial patients were randomized to prehospital plasma or standard care resuscitation (crystalloid ± packed red blood cells). Regression determined the associations between admission lactate, 30-day mortality, and plasma while adjusting for demographics, prehospital crystalloid, time, mechanism, and injury characteristics. Causal mediation analysis determined what proportion of the effect of plasma on mortality is mediated by lactate reduction. RESULTS: A total of 125 patients were included. The plasma group had a lower adjusted admission lactate than standard of care group (coefficient, -1.64; 95% confidence interval [CI], -2.96 to -0.31; p = 0.02). Plasma was associated with lower odds of 30-day mortality (odds ratio [OR], 0.27; 95% CI, 0.08-0.90; p = 0.03). When adding lactate to this model, the effect of plasma on 30-day mortality was no longer significant (OR, 0.36; 95% CI, 0.07-1.88; p = 0.23), while lactate was associated with mortality (OR, 1.74 per 1 mmol/L increase; 95% CI, 1.10-2.73; p = 0.01). Causal mediation demonstrated 35.1% of the total effect of plasma on 30-day mortality was mediated by the reduction in lactate among plasma patients. CONCLUSION: Prehospital plasma is associated with reduced 30-day mortality and lactate in severely injured patients. More than one third of the effect of plasma on mortality is mediated by a reduction in lactate. Thus, reducing the severity of hemorrhagic shock appears to be one mechanism of prehospital plasma benefit. Further study should elucidate other mechanisms and if a dose response exists. LEVEL OF EVIDENCE: Therapeutic, level II.

Age of thawed plasma does not affect clinical outcomes or biomarker expression in patients receiving prehospital thawed plasma: a PAMPer secondary analysis.

BACKGROUND: Prehospital plasma administration during air medical transport reduces the endotheliopathy of trauma, circulating pro-inflammatory cytokines, and 30-day mortality among traumatically injured patients at risk of hemorrhagic shock. No clinical data currently exists evaluating the age of thawed plasma and its association with clinical outcomes and biomarker expression post-injury. METHODS: We performed a secondary analysis from the prehospital plasma administration randomized controlled trial, PAMPer. We dichotomized the age of thawed plasma creating three groups: standard-care, YOUNG (day 0-1) plasma, and OLD (day 2-5) plasma. We generated HRs and 95% CIs for mortality. Among all patients randomized to plasma, we compared predicted biomarker values at hospital admission (T0) and 24 hours later (T24) controlling for key difference between groups with a multivariable linear regression. Analyses were repeated in a severely injured subgroup. RESULTS: Two hundred and seventy-one patients were randomized to standard-care and 230 to plasma (40% YOUNG, 60% OLD). There were no clinically or statistically significant differences in demographics, injury, admission vital signs, or laboratory values including thromboelastography between YOUNG and OLD. Compared with standard-care, YOUNG (HR 0.66 (95% CI 0.41 to 1.07), p=0.09) and OLD (HR 0.64 (95% CI 0.42 to 0.96), p=0.03) plasma demonstrated reduced 30-day mortality. Among those randomized to plasma, plasma age did not affect mortality (HR 1.04 (95% CI 0.60 to 1.82), p=0.90) and/or adjusted serum markers by plasma age at T0 or T24 (p>0.05). However, among the severely injured subgroup, OLD plasma was significantly associated with increased adjusted inflammatory and decreased adjusted endothelial biomarkers at T0. DISCUSSION: Age of thawed plasma does not result in clinical outcome or biomarker expression differences in the overall PAMPer study cohort. There were biomarker expression differences in those patients with severe injury. Definitive investigation is needed to determine if the age of thawed plasma is associated with biomarker expression and outcome differences following traumatic injury. LEVEL OF EVIDENCE: II.

Lipidomic Signatures Align with Inflammatory Patterns and Outcomes in Critical Illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of the pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. Early in the clinical course, Fresh Frozen Plasma administration led to improved survival in association with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers. Late over-representation of phosphatidylethanolamines with critical illness led to the validation of a Lipid Reprogramming Score that was prognostic not only in trauma but also severe COVID-19 patients. Our lipidomic findings provide a new paradigm for the lipid response underlying critical illness.

Prehospital Blood Product and Crystalloid Resuscitation in the Severely Injured Patient: A Secondary Analysis of the Prehospital Air Medical Plasma Trial.

OBJECTIVE: The aim of this study was to determine whether prehospital blood products reduce 30-day mortality in patients at risk for hemorrhagic shock compared with crystalloid only resuscitation. SUMMARY OF BACKGROUND DATA: Hemorrhage is the primary cause of preventable death after injury. Large volume crystalloid resuscitation can be deleterious. The benefits of prehospital packed red blood cells (PRBCs), plasma, or transfusion of both products among trauma patients is unknown compared with crystalloid. METHODS: Secondary analysis of the multicenter PAMPer trial was performed on hypotensive injured patients from the scene. The trial randomized 27 helicopter bases to prehospital plasma or standard resuscitation. Standard resuscitation at the sites was equally divided between crystalloid and crystalloid + PRBC. This led to 4 prehospital resuscitation groups: crystalloid only; PRBC; plasma; and PRBC+plasma. Cox regression determined the association between resuscitation groups and risk-adjusted 30-day mortality. The dose effect of resuscitation fluids was also explored. RESULTS: Four hundred seven patients were included. PRBC+plasma had the greatest benefit [hazard ratio (HR) 0.38; 95% confidence interval (95% CI) 0.26-0.55, P < 0.001], followed by plasma (HR 0.57; 95% CI 0.36-0.91, P = 0.017) and PRBC (HR 0.68; 95% CI 0.49-0.95, P = 0.025) versus crystalloid only. Mortality was lower per-unit of PRBC (HR 0.69; 95% CI 0.52-0.92, p = 0.009) and plasma (HR 0.68; 95% CI 0.54-0.88, P = 0.003). Crystalloid volume was associated with increased mortality among patients receiving blood products (HR 1.65; 95% CI 1.17-2.32, P = 0.004). CONCLUSION: Patients receiving prehospital PRBC+plasma had the greatest mortality benefit. Crystalloid only had the worst survival. Patients with hemorrhagic shock should receive prehospital blood products when available, preferably PRBC+plasma. Prehospital whole blood may be ideal in this population.

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses.

Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.

Association of Prehospital Plasma With Survival in Patients With Traumatic Brain Injury: A Secondary Analysis of the PAMPer Cluster Randomized Clinical Trial.

Importance: Prehospital plasma administration improves survival in injured patients at risk for hemorrhagic shock and transported by air ambulance. Traumatic brain injury (TBI) is a leading cause of death following trauma, but few early interventions improve outcomes. Objective: To assess the association between prehospital plasma and survival in patients with TBI. Design, Setting, and Participants: The Prehospital Air Medical Plasma (PAMPer) trial was a pragmatic, multicenter, phase 3, cluster randomized clinical trial involving injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center. The trial was conducted at 6 US sites with 9 level-I trauma centers (comprising 27 helicopter emergency services bases). The original trial analyzed 501 patients, including 230 patients who were randomized to receive plasma and 271 randomized to standard care resuscitation. This secondary analysis of a predefined subgroup included patients with TBI. Data analysis was performed from October 2019 to February 2020. Interventions: Patients were randomized to receive standard care fluid resuscitation or 2 units of thawed plasma. Main Outcomes and Measures: The primary outcome was mortality at 30 days. Patients with TBI were prespecified as a subgroup for secondary analysis and for measurement of markers of brain injury. The 30-day survival benefit of prehospital plasma in subgroups with and without TBI as diagnosed by computed tomography was characterized using Kaplan-Meier survival analysis and Cox proportional hazard regression. Results: In total, 166 patients had TBI (median [interquartile range] age, 43.00 [25.00-59.75] years; 125 men [75.3%]). When compared with the 92 patients who received standard care, the 74 patients with TBI who received prehospital plasma had improved 30-day survival even after adjustment for multiple confounders and assessment of the degree of brain injury with clinical variables and biomarkers (hazard ratio [HR], 0.55; 95% CI, 0.33-0.94; P = .03). Receipt of prehospital plasma was associated with improved survival among patients with TBI with a prehospital Glasgow Coma Scale score of less than 8 (HR, 0.56; 95% CI, 0.35-0.91) and those with polytrauma (HR, 0.50; 95% CI, 0.28-0.89). Patients with TBI transported from the scene of injury had improved survival following prehospital plasma administration (HR, 0.45; 95% CI, 0.26-0.80; P = .005), whereas patients who were transferred from an outside hospital showed no difference in survival for the plasma intervention (HR, 1.00; 95% CI, 0.33-3.00; P = .99). Conclusions and Relevance: These findings are exploratory, but they suggest that receipt of prehospital plasma is associated with improved survival in patients with computed tomography-positive TBI. The prehospital setting may be a critical period to intervene in the care of patients with TBI. Future studies are needed to confirm the clinical benefits of early plasma resuscitation following TBI and concomitant polytrauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01818427.

Characterization of unexpected survivors following a prehospital plasma randomized trial.

BACKGROUND: Prehospital plasma improves survival for severely injured trauma patients transported by air ambulance. We sought to characterize the unexpected survivors, patients who survived despite having high predicted mortality after traumatic injury. METHODS: The Prehospital Air Medical Plasma trial randomized severely injured patients (n = 501) to receive either standard care (crystalloid) or two units of prehospital plasma followed by standard care fluid resuscitation. We built a generalized linear model to estimate patient mortality. Area under the receiver operating characteristic curve was used to evaluate model performance. We defined unexpected survivors as patients who had a predicted mortality greater than 50% and survived to 30 days. We characterized patient demographics, clinical features, and outcomes of the unexpected survivors. Observed to expected (O/E) ratios and Z-statistics were calculated using model-estimated mortality for each cohort. RESULTS: Our model predicted mortality better than Injury Severity Score or Revised Trauma Score parameters and identified 36 unexpected survivors. Compared with expected survivors, unexpected survivors were younger (33 years [24, 52 years] vs. 47 years [32, 59 years], p = 0.013), were more severely injured (Injury Severity Score 34 [22, 50] vs. 18 [10, 27], p < 0.001), had worse organ dysfunction and hospital resource outcomes (multiple organ failure, intensive care unit, hospital length of stay, and ventilator days), and were more likely to receive prehospital plasma (67 vs. 46%, p = 0.031). Nonsurvivors with high predicted mortality were more likely to receive standard care resuscitation (p < 0.001). Unexpected survivors who received prehospital plasma had a lower observed to expected mortality than those that received standard care resuscitation (O/E 0.56 [0.33-0.84] vs. 1.0 [0.73-1.32]). The number of prehospital plasma survivors (24) exceeded the number of predicted survivors (n = 10) estimated by our model (p < 0.001). CONCLUSION: Prehospital plasma is associated with an increase in the number of unexpected survivors following severe traumatic injury. Prehospital interventions may improve the probability of survival for injured patients with high predicted mortality based on early injury characteristics, vital signs, and resuscitation measures. LEVEL OF EVIDENCE: Therapeutic Level III.

Prehospital plasma is associated with distinct biomarker expression following injury.

BACKGROUNDPrehospital plasma improves survival in severely injured patients transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage.METHODSWe sampled blood from 405 trauma patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites. We assayed samples for 21 inflammatory mediators and 7 markers associated with endothelial function and damage. We performed hierarchical clustering analysis (HCA) of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for differences across study and to assess any association with prehospital plasma resuscitation.RESULTSHCA distinguished two patient clusters with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of the most seriously injured patients, prehospital plasma was associated with an increase in adiponectin, IL-1ß, IL-17A, IL-23, and IL-17E upon admission, and a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E 24 hours later.CONCLUSIONPrehospital plasma may ameliorate immune dysfunction and the endotheliopathy of trauma. These effects of plasma may contribute to improved survival in injured patients.TRIAL REGISTRATIONNCT01818427.FUNDINGDepartment of Defense; National Institutes of Health, U.S. Army.

Massive transfusion and the response to prehospital plasma: It is all in how you define it.

BACKGROUND: A recent analysis derived from the Prehospital Air Medical Plasma trial data set demonstrated no significant independent plasma survival benefit in those who required massive transfusion (≥10 units of red cells in 24 hours). The definition of massive transfusion has evolved over time to minimize bias and predict those at highest risk of death. We sought to characterize the definition of massive transfusion, their associated mortality risks and the survival benefit associated with prehospital plasma. METHODS: A secondary analysis was performed using data from a recent prehospital plasma trial. Patients transferred directly from the scene were characterized. We defined historic massive transfusion using ≥10 units red cells in 24 hours and critical administration threshold (CAT) as ≥3 units per hour in the first hour (CAT1hr) or in any of the first 4 hours (CAT4hr) from arrival. The primary outcome was 30-day mortality. Kaplan-Meier analysis and Cox hazard regression were used to characterize the survival benefit of prehospital plasma. RESULTS: There were a total of 390 enrolled patients who were transferred from the scene and represent the study cohort. Overall, 126 patients were positive for the CAT1hr metric, 183 patients were positive for the CAT4hr metric and 84 patients were positive for historic massive transfusion metric. The overall study mortality rate for those patients who met each transfusion definition was 13.1%, 17.4% and 10.0%, respectively. The CAT4hr metric had the lowest potential for survival bias. Kaplan-Meier survival analysis demonstrated a prehospital plasma survival benefit in the patients who were CAT4hr positive. CONCLUSION: The current analysis demonstrates the superior utility of the CAT4hr definition with optimization of survival bias while conserving mortality risk prediction. This transfusion definition was associated with a prehospital plasma survival benefit and may be the most appropriate definition of massive transfusion for pragmatic studies which focus on hemorrhagic shock. LEVEL OF EVIDENCE: Epidemiologic, Level II.

Prehospital plasma in injured patients is associated with survival principally in blunt injury: Results from two randomized prehospital plasma trials.

INTRODUCTION: Recent evidence demonstrated that prehospital plasma in patients at risk of hemorrhagic shock was safe for ground transport and resulted in a 28-day survival benefit for air medical transport patients. Whether any beneficial effect of prehospital plasma varies across injury mechanism remains unknown. METHODS: We performed a secondary analysis using a harmonized data set derived from two recent prehospital plasma randomized trials. Identical inclusion/exclusion criteria and primary/secondary outcomes were used for the trials. Prehospital time, arrival shock parameters, and 24-hour transfusion requirements were compared across plasma and control groups stratified by mechanism of injury. Stratified survival analysis and Cox hazard regression were performed to determine the independent survival benefits of plasma across blunt and penetrating injury. RESULTS: Blunt patients had higher injury severity, were older, and had a lower Glasgow Coma Scale. Arrival indices of shock and coagulation parameters were similar across blunt and penetrating injury. The percentage of patients with a prehospital time less than 20 minutes was significantly higher for penetrating patients relative to blunt injured patients (28.0% vs. 11.6%, p < 0.01). Stratified Kaplan-Meier curves demonstrated a significant separation for blunt injured patients (n = 465, p = 0.01) with no separation demonstrated for penetrating injured patients (n = 161, p = 0.60) Stratified Cox hazard regression verified, after controlling for all important confounders, that prehospital plasma was associated with a 32% lower independent hazard for 28-day mortality in blunt injured patients (hazard ratio, 0.68; 95% confidence interval, 0.47-0.96; p = 0.03) with no independent survival benefit found in penetrating patients (hazard ratio, 1.16; 95% confidence interval, 0.4-3.1; p = 0.78). CONCLUSION: A survival benefit associated with prehospital plasma at 24 hours and 28 days exists primarily in blunt injured patients with no benefit shown in penetrating trauma patients. No detrimental effects attributable to plasma are demonstrated in penetrating injury. These results have important relevance to military and civilian trauma systems. LEVEL OF EVIDENCE: Therapeutic, I.