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 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.

Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock.

BACKGROUND: After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting. METHODS: To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport. The primary outcome was mortality at 30 days. RESULTS: A total of 501 patients were evaluated: 230 patients received plasma (plasma group) and 271 received standard-care resuscitation (standard-care group). Mortality at 30 days was significantly lower in the plasma group than in the standard-care group (23.2% vs. 33.0%; difference, -9.8 percentage points; 95% confidence interval, -18.6 to -1.0%; P=0.03). A similar treatment effect was observed across nine prespecified subgroups (heterogeneity chi-square test, 12.21; P=0.79). Kaplan-Meier curves showed an early separation of the two treatment groups that began 3 hours after randomization and persisted until 30 days after randomization (log-rank chi-square test, 5.70; P=0.02). The median prothrombin-time ratio was lower in the plasma group than in the standard-care group (1.2 [interquartile range, 1.1 to 1.4] vs. 1.3 [interquartile range, 1.1 to 1.6], P<0.001) after the patients' arrival at the trauma center. No significant differences between the two groups were noted with respect to multiorgan failure, acute lung injury-acute respiratory distress syndrome, nosocomial infections, or allergic or transfusion-related reactions. CONCLUSIONS: In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation. (Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).

The FRAIL Questionnaire: A Useful Tool for Bedside Screening of Geriatric Trauma Patients.

Frailty screening is a priority in acute care. Using secondary data from our prior study, we derived a 5-item FRAIL Questionnaire (instrument) score for 188 geriatric trauma patients and aimed to examine the influence of preinjury physical frailty (as measured by FRAIL) on 1-year outcomes. The study used a secondary data analysis design. Patients were 65 years and older admitted through the emergency department (ED) between October 2013 and March 2014. The 5 items of the FRAIL instrument were identified within data sources of our prior study, and a preinjury FRAIL score was created for each patient. For data analysis, frequencies, measures of central tendency, and linear and logistic regression models were used. Median age of the patients was 77 years (interquartile range [IQR] = 69-86), and median Injury Severity Score = 10 (IQR = 9-17). Upon admission to the ED, 63 patients (34%) were screened as frail (FRAIL score ≥3), 71 (38%) as prefrail (score = 1-2), and 54 (29%) as nonfrail (score = 0). Frequencies for components of the FRAIL score were as follows: fatigue (N = 123; 65%), resistance (N = 61; 32%), ambulation (N = 76; 40%), illnesses (N = 51; 27%), and loss of weight (N = 11; 6%). After controlling for age, comorbidities, injury severity, and cognitive status, preinjury FRAIL scores explained 13% of the variability in function as measured by the Barthel Index (N = 129, ß = .36, p < .001). Forty-seven patients died (26%) within 1 year. Logistic regression analysis revealed that the higher the preinjury FRAIL score, the greater the likelihood of mortality within 1 year (OR = 1.74, p = .001; 95% CI [1.27, 2.39)]. The FRAIL Questionnaire predicts 1-year functional status and mortality and is a useful tool for bedside screening.

Taking the Blood Bank to the Field: The Design and Rationale of the Prehospital Air Medical Plasma (PAMPer) Trial.

Hemorrhage and trauma induced coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. Interest in the use of prehospital plasma in hemorrhaging patients as a primary resuscitation agent has grown recently. Trauma center-based damage control resuscitation using early and aggressive plasma transfusion has consistently demonstrated improved outcomes in hemorrhaging patients. Additionally, plasma has been shown to have several favorable immunomodulatory effects. Preliminary evidence with prehospital plasma transfusion has demonstrated feasibility and improved short-term outcomes. Applying state-of-the-art resuscitation strategies to the civilian prehospital arena is compelling. We describe here the rationale, design, and challenges of the Prehospital Air Medical Plasma (PAMPer) trial. The primary objective is to determine the effect of prehospital plasma transfusion during air medical transport on 30-day mortality in patients at risk for traumatic hemorrhage. This study is a multicenter cluster randomized clinical trial. The trial will enroll trauma patients with profound hypotension (SBP ≤ 70 mmHg) or hypotension (SBP 71-90 mmHg) and tachycardia (HR ≥ 108 bpm) from six level I trauma center air medical transport programs. The trial will also explore the effects of prehospital plasma transfusion on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research with an investigational new drug approval from the U.S. Food and Drug Administration utilizing a multipronged community consultation process. It is one of three ongoing Department of Defense-funded trials aimed at expanding our understanding of the optimal therapeutic approaches to coagulopathy in the hemorrhaging trauma patient.

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.

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials.

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness. Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes. Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention. Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials. Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006. Level of evidence: II.

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.

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.

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.

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.

Critical care issues in managing complex open abdominal wound.

Over the past 30 years, surgical specialties have introduced and expanded the role of open abdominal management in complicated operative cases, necessitating an intensivist's understanding of the indications and unique intensive care unit (ICU) issues related to the open abdomen. When presented with the open abdomen, resuscitation to correct shock is of primary concern. This is accomplished by correction of hypothermia, acidosis, and coagulopathy in trauma and adequate resolution of intra-abdominal hypertension or source control in general surgery. These patients typically require deep sedation and often paralysis and benefit from low-volume ventilatory strategies to prevent and treat acute lung injury. Antibiotics must be tailored to the clinical situation, but in most cases, 24 hours of perioperative treatment is all that is required. In cases of gross contamination and peritonitis, a 5- to 7-day course of broad-spectrum antibiotics may be of benefit.Adequate source control has been demonstrated to have the greatest impact on outcome and when the patient's clinical milieu dictates, bedside washouts. Enteral nutrition should be instituted as early as possible after intestinal continuity has been reestablished. Additional protein is required to account for losses from the open abdomen. Reconstruction may require staging, but in general, should proceed following resolution of shock and control of sepsis. Elevated multiorgan dysfunction score, Acute Physiology And Chronic Health Evaluation II (APACHE II), and a rise in peak inspiratory pressure portend poor source control and could result in failure of fascial closure. If unable to proceed to fascial closure, then considerations should be made for planned ventral hernia and subsequent abdominal wall reconstruction.

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.

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.

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.

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.

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.

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.