Pragmatic, Randomized Optimal Platelet And Plasma Ratios Research Articles

Is there an association between inflammatory biomarkers and organ space surgical site infection after emergency laparotomy in massively transfused trauma patients?

BackgroundThe relationship between inflammatory biomarkers (IB) and organ space surgical site infections (OS-SSIs) after emergency laparotomy (EL) is poorly understood. MethodsRetrospective, single-center analysis of patients in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who underwent EL and survived 48 ​h after admission was performed. IB levels of IL-6, IL-8, G-CSF, MCP-1, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio were analyzed. IB and OS-SSIs association was evaluated using the Wilcoxon rank sum test. ResultsOf 74 eligible patients, 80 ​% were male, 69 ​% sustained blunt trauma, the injury severity score was 31 (24–41), and 22 ​% developed OS-SSIs. Levels of IL-6 (12, 24 ​h), IL-8 (2, 12, 24, 72 ​h), and MCP-1 (24 ​h) were higher in OS-SSI patients (P ​< ​0.05). ConclusionsIL-6, IL-8, and MCP-1 levels were associated with OS-SSIs in PROPPR patients who underwent EL. The IB may help to predict high-risk patients for OS-SSIs.

Benefits of Different Balanced Resuscitation Ratios for Thoracic vs Abdominopelvic Traumatic Hemorrhage

This comparative effectiveness research uses data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial to compare benefits with balanced resuscitation for thoracic vs abdominopelvic traumatic hemorrhage.

Hospital variation in adoption of balanced transfusion practices among injured patients requiring blood transfusions

BackgroundThis study sought to measure hospital variability in adoption of balanced transfusion following the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) guidelines. We hypothesized hospital adoption rates of balanced transfusion would be low, and vary significantly among hospitals after controlling for patient, injury and hospital characteristics. Study Design and MethodsThis was an observational cohort study of injured adult patients (≥16 years) in Trauma Quality Improvement Program hospitals 2016–2021. Inclusion criteria were hypotensive patients receiving one transfusion of packed red blood cells, fresh frozen plasma, platelets, or cryoprecipitate. Balanced transfusion was defined as ≥1 ratio of plasma to packed red blood cells or platelets to packed red blood cells or whole blood use at 4 hours. Hierarchical multivariable logistic regression quantified residual hospital-level variability in balanced transfusion rates after adjusting for patient and hospital characteristics. ResultsAmong 172,457 injured patients who received transfusions, 30,386 (17.6%) underwent balanced transfusion. Patient-level balanced transfusion rates were 11% in 2016, rose to 14.0% in 2019, and jumped up once whole blood transfusions were measured to 24.0% in 2020 and to 25.9% in 2021. Approximately 26% of the variability in balanced transfusion rates was attributable to the hospital. Verified level I hospitals had a 2.09 increased adjusted odds of balanced transfusion (95% CI 1.88–2.21) compared to nonverified hospitals. University teaching status had a 1.29 increased adjusted odds of balanced transfusion (95% CI 1.08–1.54) compared with community hospitals. Overall, 150 (23.5%) hospitals were high outliers (high performing) in balanced transfusion adoption and 124 (19.4%) hospitals were low outliers. ConclusionThere was significant variability in hospital adoption of balanced transfusion.

Diagnostic performance of the ABC score in the PROPPR trial

IntroductionThe Assessment of Blood Consumption (ABC) score is used to predict massive transfusions (MT). However, its diagnostic performance has not been widely examined, especially when used as an objective tool to enroll patients in multi-center clinical trials. The purpose of this study was to evaluate the performance of the ABC score in enrolling patients in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial. We hypothesized the ABC score would have a similar diagnostic performance to predict the need for massive transfusion as previous studies. MethodsThis is a retrospective analysis of the PROPPR trial. Patients were enrolled either on the basis of an ABC score ≥2, or by Physician Gestalt, when the ABC score was <2. We calculated the sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and likelihood ratios of the ABC score (≥2) for predicting MT (>10 units of red blood cells/24 h or transfusion of >3 units of red blood cells within the first hour). ResultsOf the 680 patients, 438 patients (64 %) had an ABC score of ≥2 and 242 (36 %) had an ABC score of <2. An ABC score of ≥2 had 66.8 % sensitivity and 37.0 % specificity for predicting the need for MT, with a PPV of 88.2 % and NPV of 13.1 %. Similarly, an ABC≥2 had 65.6 % sensitivity and 44.6 % specificity for predicting the need for >3 units RBCs in 1 hour, with a PPV of 89.5 % and NPV of 15.3 %. ConclusionThe ABC score had lower performance than previously reported for predicting MT, when applied to PROPPR trial patients. The performance for predicting the need for a 3-unit red blood cell transfusion (or more) in the first hour was slightly higher. Level of EvidenceLevel III, Prognostic

Decreased Glycocalyx Shedding on Presentation in Hemorrhaging Geriatric Trauma Patients

IntroductionPlasma levels of syndecan-1 (Sdc-1), a biomarker of endothelial glycocalyx (EG) damage, correlate with worse outcomes in trauma patients. However, EG injury is not well characterized in injured older adults (OA). The aims of this study were to characterize Sdc-1 shedding in OA trauma patients relative to younger adults (YA) and determine associations with putative regulators of EG sheddases. MethodsWe performed a secondary analysis of data from the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios (PROPPR) trial, stratifying bluntly injured subjects into OA and YA groups based on upper age quartile (57 y). Plasma Sdc-1 levels were compared in OA and YA at hospital arrival through postinjury day 3, and the independent association between age and Sdc-1 level at arrival was determined after adjusting for differences in gender, shock index (SI), and pre-existing comorbidities. In a follow-up analysis, case-control matching was used to create populations of OA and YA with equivalent SI and injury severity score. Levels of Sdc-1 were compared between these matched groups, and the relationships with candidate regulators of EG shedding were assessed. ResultsOf 680 subjects in the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios trial, 350 (51%) had blunt injuries, and 92 (26.3%) of these were OA. Plasma Sdc-1 levels at arrival, 2 h, and 6 h were significantly lower in OA compared to YA (all P < 0.05). After adjusting for sex, pre-existing morbidities and SI, age was associated with decreased Sdc-1 levels at arrival. In the matched analyses, Sdc-1, high-mobility group box 1 and tissue inhibitor of metalloproteinase–2 levels were lower in OA compared to YA. Both high-mobility group box-1 and tissue inhibitor of metalloproteinase–2 significantly correlated with arrival Sdc-1 and were inversely associated with age. ConclusionsThis study indicates that increased age is independently associated with decreased Sdc-1 levels among patients with blunt injuries. Suppressed plasma levels of sheddases in relation to diminished Sdc-1 shedding suggest that mechanisms regulating EG cleavage may be impaired in injured older adults. These findings provide novel insight into the age-dependent impact of injury on the vascular endothelium, which could have important implications for the clinical management of older adults following trauma.

Epidemiology of Trauma-Related Hemorrhage and Time to Definitive Care Across North America: Making the Case for Bleeding Control Education.

Uncontrolled trauma-related hemorrhage remains the primary preventable cause of death among those with critical injury. The purpose of this investigation was to evaluate the types of trauma associated with critical injury and trauma-related hemorrhage, and to determine the time to definitive care among patients treated at major trauma centers who were predicted to require massive transfusion. A secondary analysis was performed of the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) trial data (N = 680). All patients included were predicted to require massive transfusion and admitted to one of 12 North American trauma centers. Descriptive statistics were used to characterize patients, including demographics, type and mechanism of injury, source of bleeding, and receipt of prehospital interventions. Patient time to definitive care was determined using the time from activation of emergency services to responder arrival on scene, and time from scene departure to emergency department (ED) arrival. Each interval was calculated and then summed for a total time to definitive care. Patients were primarily white (63.8%), male (80.3%), with a median age of 34 (IQR 24-51) years. Roughly one-half of patients experienced blunt (49.0%) versus penetrating (48.2%) injury. The most common types of blunt trauma were motor vehicle injuries (83.5%), followed by falls (9.3%), other (3.6%), assaults (1.8%), and incidents due to machinery (1.8%). The most common types of penetrating injuries were gunshot wounds (72.3%), stabbings (24.1%), other (2.1%), and impalements (1.5%). One-third of patients (34.5%) required some prehospital intervention, including intubation (77.4%), chest or needle decompression (18.8%), tourniquet (18.4%), and cardiopulmonary resuscitation (CPR; 5.6%). Sources of bleeding included the abdomen (44.3%), chest (20.4%), limb/extremity (18.2%), pelvis (11.4%), and other (5.7%). Patients waited for a median of six (IQR4-10) minutes for emergency responders to arrive at the scene of injury and traveled a median of 27 (IQR 19-42) minutes to an ED. Time to definitive care was a median of 57 (IQR 44-77) minutes, with a range of 12-232 minutes. Twenty-four-hour mortality was 15% (n = 100) with 81 patients dying due to exsanguination or hemorrhage. Patients who experience critical injury may experience lengthy times to receipt of definitive care and may benefit from bystander action for hemorrhage control to improve patient outcomes.

LB 01.3 Factor XIII 24-Hour Trajectory Analysis in Severely Injured Patients: Post-hoc Analysis of the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study

LB 01.3 Factor XIII 24-Hour Trajectory Analysis in Severely Injured Patients: Post-hoc Analysis of the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study

Balanced resuscitation and earlier mortality end points: bayesian post hoc analysis of the PROPPR trial

IntroductionThe Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial failed to demonstrate a mortality difference for hemorrhaging patients receiving a balanced (1:1:1) vs a 1:1:2 resuscitation at 24 hours...

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies

It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Association of Opioid Administration During General Anesthesia and Survival for Severely Injured Trauma Patients: A Preplanned Secondary Analysis of the PROPPR Study.

There is a lack of reported clinical outcomes after opioid use in acute trauma patients undergoing anesthesia. Data from the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) study were analyzed to examine opioid dose and mortality. We hypothesized that higher dose opioids during anesthesia were associated with lower mortality in severely injured patients. PROPPR examined blood component ratios in 680 bleeding trauma patients at 12 level 1 trauma centers in North America. Subjects undergoing anesthesia for an emergency procedure were identified, and opioid dose was calculated (morphine milligram equivalents [MMEs])/h. After separation of those who received no opioid (group 1), remaining subjects were divided into 4 groups of equal size with low to high opioid dose ranges. A generalized linear mixed model was used to assess impact of opioid dose on mortality (primary outcome, at 6 hours, 24 hours, and 30 days) and secondary morbidity outcomes, controlling for injury type, severity, and shock index as fixed effect factors and site as a random effect factor. Of 680 subjects, 579 had an emergent procedure requiring anesthesia, and 526 had complete anesthesia data. Patients who received any opioid had lower mortality at 6 hours (odds ratios [ORs], 0.02-0.04; [confidence intervals {CIs}, 0.003-0.1]), 24 hours (ORs, 0.01-0.03; [CIs, 0.003-0.09]), and 30 days (ORs, 0.04-0.08; [CIs, 0.01-0.18]) compared to those who received none (all P < .001) after adjusting for fixed effect factors. The lower mortality at 30 days in any opioid dose group persisted after analysis of those patients who survived >24 hours (P < .001). Adjusted analyses demonstrated an association with higher ventilator-associated pneumonia (VAP) incidence in the lowest opioid dose group compared to no opioid (P = .02), and lung complications were lower in the third opioid dose group compared to no opioid in those surviving 24 hours (P = .03). There were no other consistent associations of opioid dose with other morbidity outcomes. These results suggest that opioid administration during general anesthesia for severely injured patients is associated with improved survival, although the no-opioid group was more severely injured and hemodynamically unstable. Since this was a preplanned post hoc analysis and opioid dose not randomized, prospective studies are required. These findings from a large, multi-institutional study may be relevant to clinical practice.

Admission Thromboelastography at the Intersection of Traumatic Coagulopathy and Inflammation: A Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study Subanalysis.

Acute traumatic coagulopathy (ATC) has many phenotypes and varying morbidity and mortality. The MA-R ratio, calculated from the admission thromboelastogram, serves as a biomarker to identify 1 phenotype of ATC and has previously been associated with significant derangements in the inflammatory response. This study evaluates outcomes related to abnormal MA-R ratios, including inflammatory responses, in a heterogeneous patient population. Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) dataset were included. The MA-R ratio was calculated from admission thromboelastography, with a CRITICAL ratio defined as 11 or less. Key inflammatory mediators were identified as a priori. Cytokine expression was assessed during 24 hours using multivariable logistic regression. Significant elevations in the proinflammatory cytokines IL-1b, IL-6, and IL-8, as well as in the chemokines eotaxin, IFN-γ-induced protein 10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1β, persisted during the first 24 hours. CRITICAL patients had significantly lower survival at 1, 3, 6, 12, and 18 hours and demonstrated significantly increased ARDS (odds ratio [OR] 1.817, 95% CI 1.082 to 3.051, p = 0.0239). CRITICAL patients had fewer ICU-free days (CRITICAL, 10 days, interquartile range [IQR] 0 to 25; vs NORMAL, 22 days, IQR 4 to 26, p < 0.0001) and fewer ventilator-free days (CRITICAL, 15 days, IQR 0 to 28; vs NORMAL, 26 days, IQR 9 to 28, p < 0.0001). CRITICAL patients were protected against systemic inflammatory response (OR 0.521, 95% CI 0.322 to 0.816, p = 0.0044). The subtype of ATC identified by the low MA-R ratio is associated with significant elevations in multiple proinflammatory cytokines at admission. Early mortality remains elevated in the CRITICAL group, in part due to coagulopathy. The MA-R ratio at admission is associated with a particularly morbid type of coagulopathy, associated with significant alterations in the inflammatory response after severe injury in heterogeneous patient populations.

Use of Bayesian Statistics to Reanalyze Data From the Pragmatic Randomized Optimal Platelet and Plasma Ratios Trial

Frequentist statistical approaches are the most common strategies for clinical trial design; however, bayesian trial design may provide a more optimal study technique for trauma-related studies. To describe the outcomes of bayesian statistical approaches using data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial. This quality improvement study performed a post hoc bayesian analysis of the PROPPR Trial using multiple hierarchical models to assess the association of resuscitation strategy with mortality. The PROPPR Trial took place at 12 US level I trauma centers from August 2012 to December 2013. A total of 680 severely injured trauma patients who were anticipated to require large volume transfusions were included in the study. Data analysis for this quality improvement study was conducted from December 2021 and June 2022. In the PROPPR Trial, patients were randomized to receive a balanced transfusion (equal portions of plasma, platelets, and red blood cells [1:1:1]) vs a red blood cell-heavy strategy (1:1:2) during their initial resuscitation. Primary outcomes from the PROPPR trial included 24-hour and 30-day all-cause mortality using frequentist statistical methods. Bayesian methods were used to define the posterior probabilities associated with the resuscitation strategies at each of the original primary end points. Overall, 680 patients (546 [80.3%] male; median [IQR] age, 34 [24-51] years, 330 [48.5%] with penetrating injury; median [IQR] Injury Severity Score, 26 [17-41]; 591 [87.0%] with severe hemorrhage) were included in the original PROPPR Trial. Between the groups, no significant differences in mortality were originally detected at 24 hours (12.7% vs 17.0%; adjusted risk ratio [RR], 0.75 [95% CI, 0.52-1.08]; P = .12) or 30 days (22.4% vs 26.1%; adjusted RR, 0.86 [95% CI, 0.65-1.12]; P = .26). Using bayesian approaches, a 1:1:1 resuscitation was found to have a 93% (Bayes factor, 13.7; RR, 0.75 [95% credible interval, 0.45-1.11]) and 87% (Bayes factor, 6.56; RR, 0.82 [95% credible interval, 0.57-1.16]) probability of being superior to a 1:1:2 resuscitation with regards to 24-hour and 30-day mortality, respectively. In this quality improvement study, a post hoc bayesian analysis of the PROPPR Trial found evidence in support of mortality reduction with a balanced resuscitation strategy for patients in hemorrhagic shock. Bayesian statistical methods offer probability-based results capable of direct comparison between various interventions and should be considered for future studies assessing trauma-related outcomes.

Time to Hemostasis After Trauma and Transfusion by Patient Blood Type.

Although evidence supports an increased risk of mortality after major trauma among patients with type O blood, the relationship between patient blood type and clinical outcomes aside from mortality has not been fully elucidated. To examine the relationship between patient blood type and time to hemostasis after trauma and massive transfusion. A secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was performed (N = 544). Blood type was dichotomized into type O versus non-type O. It was hypothesized that patients with non-type O blood would achieve hemostasis more quickly owing to the theoretical presence of increased clotting factors. Bivariate analysis and multiple Cox regression were conducted to test this assumption. No significant difference was found in time to hemostasis between patients with type O blood and those with non-type O blood. However, mechanism of injury, diastolic blood pressure, and international normalized ratio affected the time to hemostasis in these trauma patients. This study showed no significant difference in time to hemostasis by blood type.

Endotheliopathy is Associated with a 24-hour Fibrinolysis Phenotype Described by Low TEG Lysis and High D-Dimer after Trauma: a Secondary Analysis of the PROPPR Study.

Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. 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. 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% (LY30norm), LY30 >2.9% (LY30high), LY30 <0.9% and low DD (LY30low+DDlow), and LY30 <0.9% and high DD (LY30low+DDhigh). The analysis included 168 subjects with LY30norm, 32 with LY30high, 147 with LY30low+DDlow and 124 with LY30low+DDhigh. LY30low+DDhigh 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 LY30low+DDhigh phenotype. Adjusting for injury severity, mechanism and head trauma, 24-hour angiopoietin-2 and soluble thrombomodulin were independently associated with the LY30low+DDhigh 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. 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.

Balancing enrollment and mortality in hemorrhage control trials: A secondary analysis of the PROPPR trial.

Designing clinical trials on hemorrhage control requires carefully balancing the need for high enrollment numbers with the need of focusing on the sickest patients. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial enrolled patients within 2 hours of arrival to the emergency department for a trial of injured patients at risk for massive transfusion. We conducted a secondary analysis to determine how time-to-randomization affected patient outcomes and the balance between enrollment and mortality. Patients from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial were compared based on 30-minute time to randomization intervals. Outcomes included 24-hour and 30-day mortality, time to hemostasis, adverse events, and operative procedures. Additional analyses were conducted based on treatment arm allocation, mechanism of injury, and variation in start time (arrival vs. randomization). Randomization within 30 minutes of arrival was associated with higher injury severity (median Injury Severity Score, 29 vs. 26 overall; p < 0.01), lower systolic blood pressure (median, 91 vs. 102 mm Hg overall; p < 0.01), and increased penetrating mechanism (50% vs. 47% overall; p < 0.01). Faster time-to-randomization was associated with increased 24-hour (20% for 0- to 30 minute entry, 9% for 31-minute to 60-minute entry, 10% for 61-minute to 90-minute entry, 0% for 91-minute to 120-minute entry; p < 0.01) and 30-day mortality (p < 0.01). There were no significant associations between time-to-randomization and adverse event occurrence, operative interventions, or time to hemostasis. Increasing time to randomization in this large multicenter randomized trial was associated with increased survival. Fastest randomization (within 0-30 minutes) was associated with highest 24-hour and 30-day mortality, but only 57% of patients were enrolled within this timeframe. Only 3% of patients were enrolled within the last 30-minute window (91-120 minutes), with none of them dying within the first 24 hours. For a more optimal balance between enrollment and mortality, investigators should consider shortening the time to randomization when planning future clinical trials of hemorrhage control interventions. Prognostic and Epidemiologic; Level II.

Plasma: a Brief History, the Evidence, and Current Recommendations

The purpose of this chapter is to provide a brief history of the use of plasma, as well as to provide a review of currently available products, indications for usage, and benefits of transfusion. The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) trial, an observational study from ten level-one trauma centers, aimed to define the principles of Damage Control Resuscitation (DCR) and a balanced transfusion strategy. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was the first randomized controlled trial to address the question of transfusion ratios. Together these studies, along with the remainder of body of plasma literature, have led to current transfusion recommendations. The current cornerstones of therapy for the management of a trauma patient in hemorrhagic shock include early hemorrhage control, permissive hypotension, and damage control resuscitation. The American College of Surgeons’ Trauma Quality Improvement Program (TQIP) recommends a target balance between 1:1 and 1:2 for plasma to red blood cell ratio and one single donor apheresis or random donor platelet pool for each six units of RBC.

Early versus late venous thromboembolism: A secondary analysis of data from the PROPPR trial

BackgroundFactors predicting timing of post-traumatic venous thromboembolism (VTE) remain incompletely understood. Because the balance between hemorrhage and thrombosis is dynamic during a patient’s hospital course, early and late VTE may be physiologically discrete processes. This secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial aims to explore whether certain risk factors are associated with early versus late VTE. MethodsThe PROPPR trial investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Multinomial regression based on a threshold determined by cubic spline analysis tested the association of clinical variables with early or late VTE, a composite of deep vein thrombosis and pulmonary embolus, adjusting for predetermined confounders. ResultsOf the 87 patients (13%) with VTE, pulmonary embolus was predominant in the first 72 hours. A statistically determined threshold at 12 days corresponded to change in odds of early versus late events. Variables associated with early VTE included plasma transfusion (risk ratio [RR] 1.14; 95% confidence interval, 1.00, 1.30; P = .05), sepsis (RR 0.05; 95% confidence interval, 1.40, 6.64; P = .01), pelvic or femur fracture (RR 2.62; 95% confidence interval, 1.00, 6.90; P = .05). Late VTE was associated with dialysis (RR 7.37; 95% confidence interval, 1.59, 34.14; P = .01), older age (RR 1.02; 95% confidence interval 1.00, 1.04; P = .05), and delayed resuscitation approaching ratios of 1:1:1 among patients randomized to 1:1:2 therapy (RR 2.06; 95% confidence interval, 0.28, 3.83; P = .02). Cyroprecipitate increased risk of early (RR 1.04, 95% confidence interval, 1.00,1.08; P < .03) and late VTE (1.05; 95% confidence interval, 1.01, 1.09; P = .01). Prolonged lagtime (coeffcient 0.06, 95% confidence interval, 0.02, 0.10; P < .01) and time-to-peak thrombin generation (coeffcient 0.04, 95% confidence interval, 0.02, 0.07; P < .01) were associated with increased risk of early VTE. ConclusionEarly and late VTE may differ in their risk factors. Defining temporal trends in VTE may allow for a more individualized approach to thromboprophylaxis.

Characterizing red blood cell age exposure in massive transfusion therapy: the scalar age of blood index (SBI).

The mortality of trauma patients requiring massive transfusion to treat hemorrhagic shock approaches 17% at 24 hours and 26% at 30 days. The use of stored RBCs is limited to less than 42 days, so older RBCs are delivered first to rapidly bleeding trauma patients. Patients who receive a greater quantity of older RBCs may have a higher risk for mortality. Characterizing blood age exposure requires accounting for the age of each RBC unit and the quantity of transfused units. To address this challenge, a novel Scalar Age of Blood Index (SBI) that represents the relative distribution of RBCs received is introduced and applied to a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial (NCT01545232, https://clinicaltrials.gov/ct2/show/NCT01545232). The effect of the SBI is assessed on the primary PROPPR outcome, 24-hour and 30-day mortality. The distributions of blood storage ages successfully maps to a parameter (SBI) that fully defines the blood age curve for each patient. SBI was a significant predictor of 24-hour and 30-day mortality in an adjusted model that had strong predictive ability (odds ratio, 1.15 [1.01-1.29], p = 0.029, C-statistic, 0.81; odds ratio, 1.14 [1.02-1.28], p = 0.019, C-statistic, 0.88, respectively). SBI is a simple scalar metric of blood age that accounts for the relative distribution of RBCs among age categories. Transfusion of older RBCs is associated with 24-hour and 30-day mortality, after adjustment for total units and clinical covariates.

The impact of hypothermia on outcomes in massively transfused patients.

Hypothermia is associated with poor outcomes after injury. The relationship between hypothermia during contemporary large volume resuscitation and blood product consumption is unknown. We evaluated this association, and the predictive value of hypothermia on mortality. Patients predicted to receive massive transfusion at 12 level 1 trauma centers were randomized in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial and were grouped into those who were hypothermic (<36°C) or normothermic (36-38.5°C) within the first 6 hours of emergency department arrival. The impact of hypothermia or normothermia on the volume of blood product required during the first 24 hours was determined via negative binomial regression, adjusting for treatment arm, injury severity score, mechanism, demographics, pre-emergency department fluid volume, blood administered before becoming hypothermic, pulse and systolic blood pressure on arrival, and the time exposed to hypothermic or normothermic temperatures. Of 680 patients, 590 had a temperature measured during the first 6 hours in hospital, and 399 experienced hypothermia. The mean number of red blood cell (RBC) units given to all patients in the first 24 hours of admission was 8.8 (95% confidence interval [CI], 7.9-9.6). In multivariable analysis, every 1°C decrease in temperature below 36.0°C was associated with a 10% increase (incidence rate ratio, 0.90; 95% CI, 0.89-0.92; p < 0.00) in consumption of RBCs during the first 24 hours of admission. There was no association between RBC administration and a temperature above 36°C. Hypothermia on arrival was an independent predictor of mortality, with an adjusted odds ratio of 2.7 (95% CI, 1.7-4.5; p < 0.00) for 24-hour mortality and 1.8 (95% CI, 1.3-2.4; p < 0.00) for 30-day mortality. Hypothermia is associated with increase in blood product consumption and mortality. These findings support the maintenance of normothermia in trauma patients and suggest that further investigation on the impact of cooling or rewarming during massive transfusion is warranted. Prognostic, level III.

Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial

Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p < 0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165ng/dL [IQR 67 to 336 ng/dL] in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.