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Orthopaedic Trauma and Anemia: Conservative versus Liberal Transfusion Strategy: A Prospective Randomized Study
Mullis, B. H., Mullis, L. S., Kempton, L. B., Virkus, W., Slaven, J. E., Bruggers, J.
Journal of orthopaedic trauma. 2024;38(1):18-24
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Editor's Choice
Abstract
OBJECTIVES To determine whether it is safe to use a conservative packed red blood cell transfusion hemoglobin (Hgb) threshold (5.5 g/dL) compared with a liberal transfusion threshold (7.0 g/dL) for asymptomatic musculoskeletal injured trauma patients who are no longer in the initial resuscitative period. METHODS Design: Prospective, randomized, multicenter trial. SETTING Three level 1 trauma centers. PATIENT SELECTION CRITERIA Patients aged 18-50 with an associated musculoskeletal injury with Hgb less than 9 g/dL or expected drop below 9 g/dL with planned surgery who were stable and no longer being actively resuscitated were randomized once their Hgb dropped below 7 g/dL to a conservative transfusion threshold of 5.5 g/dL versus a liberal threshold of 7.0 g/dL. OUTCOME MEASURES AND COMPARISONS Postoperative infection, other post-operative complications and Musculoskeletal Functional Assessment scores obtained at baseline, 6 months, and 1 year were compared for liberal and conservative transfusion thresholds. RESULTS Sixty-five patients completed 1 year follow-up. There was a significant association between a liberal transfusion strategy and higher rate of infection (P = 0.01), with no difference in functional outcomes at 6 months or 1 year. This study was adequately powered at 92% to detect a difference in superficial infection (7% for liberal group, 0% for conservative, P < 0.01) but underpowered to detect a difference for deep infection (14% for liberal group, 6% for conservative group, P = 0.2). CONCLUSIONS A conservative transfusion threshold of 5.5 g/dL in an asymptomatic young trauma patient with associated musculoskeletal injuries leads to a lower infection rate without an increase in adverse outcomes and no difference in functional outcomes at 6 months or 1 year. LEVEL OF EVIDENCE Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
PICO Summary
Population
Musculoskeletal trauma patients with planned surgery (n= 99).
Intervention
Liberal transfusion threshold of 7.0 g/dL (n= 49).
Comparison
Conservative transfusion threshold of 5.5 g/dL (n= 50).
Outcome
Overall, 46/49 (93.9%) of the liberal group had a transfusion versus 23/50 (46.0%) of the conservative group had a transfusion after resuscitation and after enrollment in this study. Following resuscitation and enrollment in the study, patients in the liberal group received a median of 1 unit of blood transfused (range 0–12) and patients in the conservative group received a median of 0 units of blood (range 0–14). Sixty-five patients completed 1- year follow-up. There was a significant association between a liberal transfusion strategy and higher rate of infection, with no difference in functional outcomes at 6 months or 1 year.
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Outcomes of Patients Enrolled in a Prospective and Randomized Trial on Basis of Gestalt Assessment or ABC Score
Baird, E. W., Lammers, D. T., Abraham, P., Hashmi, Z. G., Griffin, R. L., Stephens, S. W., Jansen, J. O., Holcomb, J. B.
The journal of trauma and acute care surgery. 2024
Abstract
INTRODUCTION The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial rapidly enrolled patients based on an ABC ≥ 2 score, or Physician Gestalt (PG) when ABC score was <2. The objective of this study was to describe what patients were enrolled by the two methods and whether patient outcomes differed based these enrollments. We hypothesized that there would be no differences in outcomes based on whether patients were enrolled via ABC score or PG. METHODS Patients were enrolled with an ABC ≥ 2 or by PG when ABC was <2 by the attending trauma surgeon. We compared 1-, 3-, 6-, 12-, 18- and 24-hour mortality, 30-day mortality, time to hemostasis, emergent surgical or interventional radiology procedure and the proportion of patients who required either >10 units of blood in 24 hours or > 3 units in one hour. RESULTS Of 680 patients, 438 (64%) were enrolled on the basis of an ABC score ≥ 2 and 242 (36% by PG when the ABC score was <2. Patients enrolled by PG were older (median 44, IQR 28-59, p < 0.001), more likely to be white (70.3% vs 60.3%, p = 0.014), and more likely to have been injured by blunt mechanisms (77.3% vs 37.2%, p < 0.001). They were also less hypotensive and less tachycardic than patients enrolled by ABC score (both p < 0.001). The groups had similar Injury Severity Scores in the ABC ≥ 2 and PG groups (26 and 27 respectively) and were equally represented (49.1% and 50.8% respectively) in the 1:1:1 treatment arm. There were no significant differences between the ABC score and PG groups for mortality at any point. Time to hemostasis (108 for patients enrolled on basis of Gestalt, vs. 100 mins for patients enrolled on basis of ABC score), and the proportion of patients requiring a massive transfusion (>10 units/24 h) (44.2% vs. 47.3%), or meeting the critical administration threshold (>3 unit/1 hr) (84.7% vs. 89.5%) were similar (p = 0.071). CONCLUSION Early identification of trauma patients likely to require a massive transfusion is important for clinical care, resource use, and selection of patients for clinical trials. Patients enrolled in the PROPPR trial based on PG when the ABC score was <2 represented 36% of the patients and had identical outcomes to those enrolled on the basis of an ABC score of ≥2. LEVEL OF EVIDENCE Level III, Prognostic.
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Association of initial lactate levels and red blood cell transfusion strategy with outcomes after severe trauma: a post hoc analysis of the RESTRIC trial
Kosaki, Y., Hongo, T., Hayakawa, M., Kudo, D., Kushimoto, S., Tagami, T., Naito, H., Nakao, A., Yumoto, T.
World journal of emergency surgery : WJES. 2024;19(1):1
Abstract
BACKGROUND The appropriateness of a restrictive transfusion strategy for those with active bleeding after traumatic injury remains uncertain. Given the association between tissue hypoxia and lactate levels, we hypothesized that the optimal transfusion strategy may differ based on lactate levels. This post hoc analysis of the RESTRIC trial sought to investigate the association between transfusion strategies and patient outcomes based on initial lactate levels. METHODS We performed a post hoc analysis of the RESTRIC trial, a cluster-randomized, crossover, non-inferiority multicenter trials, comparing a restrictive and liberal red blood cell transfusion strategy for adult trauma patients at risk of major bleeding. This was conducted during the initial phase of trauma resuscitation; from emergency department arrival up to 7 days after hospital admission or intensive care unit (ICU) discharge. Patients were grouped by lactate levels at emergency department arrival: low (< 2.5 mmol/L), middle (≥ 2.5 and < 4.0 mmol/L), and high (≥ 4.0 mmol/L). We compared 28 days mortality and ICU-free and ventilator-free days using multiple linear regression among groups. RESULTS Of the 422 RESTRIC trial participants, 396 were analyzed, with low (n = 131), middle (n = 113), and high (n = 152) lactate. Across all lactate groups, 28 days mortality was similar between strategies. However, in the low lactate group, the restrictive approach correlated with more ICU-free (β coefficient 3.16; 95% CI 0.45 to 5.86) and ventilator-free days (β coefficient 2.72; 95% CI 0.18 to 5.26) compared to the liberal strategy. These findings persisted even after excluding patients with severe traumatic brain injury. CONCLUSIONS Our results suggest that restrictive transfusion strategy might not have a significant impact on 28-day survival rates, regardless of lactate levels. However, the liberal transfusion strategy may lead to shorter ICU- and ventilator-free days for patients with low initial blood lactate levels.
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Study of Whole blood in Frontline Trauma (SWiFT): implementation study protocol
Antonacci, G., Williams, A., Smith, J., Green, L.
BMJ open. 2024;14(2):e078953
Abstract
INTRODUCTION Uncontrolled bleeding is a major cause of death for patients with major trauma. Current transfusion practices vary, and there is uncertainty about the optimal strategy. Whole blood (WB) transfusion, which contains all components in one bag, is considered potentially advantageous, particularly for resuscitating patients with major bleeding in the prehospital setting. It could potentially improve survival, reduce donor risk and simplify the processes of delivering blood transfusions outside hospitals. However, the evidence supporting the effectiveness and safety of WB compared with the standard separate blood component therapy is limited. A multicentre randomised controlled trial will be conducted, alongside an implementation study, to assess the efficacy, cost-effectiveness and implementation of prehospital WB transfusion in the prehospital environment. The implementation study will focus on evaluating the acceptability and integration of the intervention into clinical settings and on addressing broader contextual factors that may influence its success or failure. METHODS AND ANALYSIS A type 1 effectiveness-implementation hybrid design will be employed. The implementation study will use qualitative methods, encompassing comprehensive interviews and focus groups with operational staff, patients and blood donor representatives. Staff will be purposefully selected to ensure a wide range of perspectives based on their professional background and involvement in the WB pathway. The study design includes: (1) initial assessment of current practice and processes in the WB pathway; (2) qualitative interviews with up to 40 operational staff and (3) five focus groups with staff and donor representatives. Data analysis will be guided by the theoretical lenses of the Normalisation Process Theory and the Theoretical Framework of Acceptability. ETHICS AND DISSEMINATION The study was prospectively registered and approved by the South Central-Oxford C Research Ethics Committee and the Health Research Authority and Health and Care Research Wales. The results will be published in peer-reviewed journals and provided to all relevant stakeholders. TRIAL REGISTRATION NUMBER ISRCTN23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072.
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Early Results of Orthopaedic Trauma and Anemia: Conservative Versus Liberal Transfusion Strategy
Mullis, B. H., Mullis, L. S., Kempton, L. B., Virkus, W., Slaven, J. E., Bruggers, J.
The Journal of the American Academy of Orthopaedic Surgeons. 2023
Abstract
INTRODUCTION The purpose of this study was to determine whether it is safe to use a conservative packed red blood cell transfusion hemoglobin threshold (5.5 g/dL) compared with a liberal transfusion threshold (7.0 g/dL) for asymptomatic patients with musculoskeletal-injured trauma out of the initial resuscitative period. METHODS This was a multicenter, prospective, nonblinded, randomized study done at three level 1 trauma centers. One hundred patients were enrolled. One patient was inappropriately enrolled, withdrawn from the study, and excluded from analysis leaving 99 patients (49 liberal and 50 conservative) with 30-day follow-up. After initial resuscitation, patients were enrolled and randomized to either a liberal or a conservative transfusion strategy. This strategy was followed throughout the index hospitalization. The primary outcome of the study was infection. Superficial infection was defined as clinical diagnosis of cellulitis or other superficial infection treated with oral antibiotics only. Deep infection was defined as clinical diagnosis of fracture-related infection requiring IV antibiotics and/or surgical débridement. RESULTS Ninety-nine patients were successfully followed for 30 days with 100% follow-up during this time. Seven infections (14%) occurred in the liberal group and none in the conservative group (P < 0.01). Five deep infections (10%) occurred in the liberal group and none in the conservative group (P = 0.03). Three superficial infections (6%) occurred in the liberal and none in the conservative group, which was not a significant difference (P = 0.1). No difference was observed in length of stay between groups. DISCUSSION Transfusing young healthy asymptomatic patients with orthopaedic trauma for hemoglobin <7.0 g/dL increases the risk of infection. No increased risk of anemia-related complications was identified with a conservative transfusion threshold of 5.5 g/dL. DATA AVAILABILITY AND TRIAL REGISTRATION NUMBERS Data are available on request. IRB protocol number is 1402557771. This study was registered with Clinicaltrials.gov identifier NCT02972593. LEVEL OF EVIDENCE Level 2, unblinded prospective randomized multicenter study.
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Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies
Thau MR, Liu T, Sathe NA, O'Keefe GE, Robinson BRH, Bulger E, Wade CE, Fox EE, Holcomb JB, Liles WC, et al
JAMA surgery. 2023
Abstract
IMPORTANCE 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. OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTS 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. EXPOSURES TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. MAIN OUTCOMES AND MEASURES 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. RESULTS 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). CONCLUSIONS AND RELEVANCE 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.
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The SWiFT trial (Study of Whole Blood in Frontline Trauma)-the clinical and cost effectiveness of pre-hospital whole blood versus standard care in patients with life-threatening traumatic haemorrhage: study protocol for a multi-centre randomised controlled trial
Smith, J. E., Barnard, E. B. G., Brown-O'Sullivan, C., Cardigan, R., Davies, J., Hawton, A., Laing, E., Lucas, J., Lyon, R., Perkins, G. D., et al
Trials. 2023;24(1):725
Abstract
BACKGROUND Early blood transfusion improves survival in patients with life-threatening bleeding, but the optimal transfusion strategy in the pre-hospital setting has yet to be established. Although there is some evidence of benefit with the use of whole blood, there have been no randomised controlled trials exploring the clinical and cost effectiveness of pre-hospital administration of whole blood versus component therapy for trauma patients with life-threatening bleeding. The aim of this trial is to determine whether pre-hospital leukocyte-depleted whole blood transfusion is better than standard care (blood component transfusion) in reducing the proportion of participants who experience death or massive transfusion at 24 h. METHODS This is a multi-centre, superiority, open-label, randomised controlled trial with internal pilot and within-trial cost-effectiveness analysis. Patients of any age will be eligible if they have suffered major traumatic haemorrhage and are attended by a participating air ambulance service. The primary outcome is the proportion of participants with traumatic haemorrhage who have died (all-cause mortality) or received massive transfusion in the first 24 h from randomisation. A number of secondary clinical, process, and safety endpoints will be collected and analysed. Cost (provision of whole blood, hospital, health, and wider care resource use) and outcome data will be synthesised to present incremental cost-effectiveness ratios for the trial primary outcome and cost per quality-adjusted life year at 90 days after injury. We plan to recruit 848 participants (a two-sided test with 85% power, 5% type I error, 1-1 allocation, and one interim analysis would require 602 participants-after allowing for 25% of participants in traumatic cardiac arrest and an additional 5% drop out, the sample size is 848). DISCUSSION The SWiFT trial will recruit 848 participants across at least ten air ambulances services in the UK. It will investigate the clinical and cost-effectiveness of whole blood transfusion versus component therapy in the management of patients with life-threatening bleeding in the pre-hospital setting. TRIAL REGISTRATION ISRCTN 23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072, 21 Dec 2021.
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Balanced resuscitation and earlier mortality end points: bayesian post hoc analysis of the PROPPR trial
Lammers, D., Rokayak, O., Uhlich, R., Sensing, T., Baird, E., Richman, J., Holcomb, J. B., Jansen, J.
Trauma surgery & acute care open. 2023;8(1):e001091
Abstract
INTRODUCTION The 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 and 30 days. Recent guidelines recommend earlier mortality end points for hemorrhage-control trials, and the use of contemporary statistical methods. The aim of this post hoc analysis of the PROPPR trial was to evaluate the impact of a balanced resuscitation strategy at early resuscitation time points using a Bayesian analytical framework. METHODS Bayesian hierarchical models were created to assess mortality differences at the 1, 3, 6, 12, 18, and 24 hours time points between study cohorts. Posterior probabilities and Bayes factors were calculated for each time point. RESULTS A 1:1:1 resuscitation displayed a 96%, 99%, 94%, 92%, 96%, and 94% probability for mortality benefit at 1, 3, 6, 12, 18, and 24 hours, respectively, when compared with a 1:1:2 approach. Associated Bayes factors for each respective time period were 21.2, 142, 14.9, 11.4, 26.4, and 15.5, indicating 'strong' to 'decisive' supporting evidence in favor of balanced transfusions. CONCLUSION This analysis provides evidence in support that a 1:1:1 resuscitation has a high probability of mortality benefit when compared with a 1:1:2 strategy, especially at the newly defined more proximate time points during the resuscitative period. Researchers should consider using Bayesian approaches, along with more proximate end points when assessing hemorrhage-related mortality, for the analysis of future clinical trials. LEVEL OF EVIDENCE Level III/Therapeutic.
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Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial
Davenport, R., Curry, N., Fox, E. E., Thomas, H., Lucas, J., Evans, A., Shanmugaranjan, S., Sharma, R., Deary, A., Edwards, A., et al
Jama. 2023
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Editor's Choice
Abstract
IMPORTANCE Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. OBJECTIVE To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. DESIGN, SETTING, AND PARTICIPANTS CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. INTERVENTION Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. RESULTS Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). CONCLUSIONS AND RELEVANCE Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
PICO Summary
Population
Bleeding patients with trauma enrolled in the CRYOSTAT-2 trial, at 26 UK and US major trauma centers (n= 1,604).
Intervention
Usual care plus 3 early pools of cryoprecipitate (n= 799).
Comparison
Standard care (n= 805).
Outcome
The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Data from 1,531 (95%) patients were included in the primary analysis population. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs. 25.3% in the cryoprecipitate group (odds ratio, 0.96; 95% CI [0.75, 1.23]). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs. cryoprecipitate group (12.9% vs. 12.7%).
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Acute respiratory distress syndrome, acute kidney injury, and mortality after trauma are associated with increased circulation of syndecan-1, soluble thrombomodulin, and receptor for advanced glycation end products
Dixon, A., Kenny, J. E., Buzzard, L., Holcomb, J., Bulger, E., Wade, C., Fabian, T., Schreiber, M.
The journal of trauma and acute care surgery. 2023
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Editor's Choice
Abstract
BACKGROUND Disruption of the vascular endothelium and endothelial glycocalyx (EG) has been described after severe trauma. Plasma has been suggested to restore microvascular integrity by preservation and repair of the EG. We sought to evaluate whether plasma administered in a 1:1:1 ratio was associated with less endothelial marker circulation than a 1:1:2 ratio. METHODS This is a secondary analysis of the PROPPR trial which investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2, 4, 6, 12, 24, 48, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points. RESULTS 308 patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point (p > 0.05). Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared to patients who did not develop these sequelae (p < 0.05). CONCLUSIONS Administration of FFP in a 1:1:1 ratio does not consistently affect circulation of endothelial biomarkers following significant trauma when compared to a 1:1:2 ratio. The development of post-traumatic ARDS, AKI, and death was associated with increased endothelial biomarker circulation. LEVEL OF EVIDENCE Secondary analysis of Level I evidence.
PICO Summary
Population
Trauma patients 15 years of age or older, enrolled in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial, in 12 Level I trauma centers across North America (n= 629).
Intervention
Plasma, platelets, and red blood cells administered in a 1:1:1 ratio (n= 321).
Comparison
Plasma, platelets, and red blood cells administered in a 1:1:2 ratio (n= 308).
Outcome
This is a secondary analysis of the PROPPR trial. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points. Three hundred eight patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point. Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared with patients who did not develop these sequelae.