Ketamine For Acute Pain After Trauma (KAPT): A Pragmatic, Randomized Clinical Trial.

INTRODUCTION: Non-narcotic intravenous medications may be a beneficial adjunct to oral multimodal pain regimens (MMPRs) which reduce but do not eliminate opioid exposure and prescribing after trauma. We hypothesized that the addition of a sub-dissociative ketamine infusion (KI) to a standardized oral MMPR reduces inpatient opioid exposure. METHODS: Eligible adult trauma patients admitted to the intermediate or intensive care unit were randomized upon admission to our institutional MMPR per usual care (UC) or UC plus sub-dissociative KI for 24 to 72 hours after arrival. The primary outcome was morphine milligram equivalents per day (MME/d) and secondary outcomes included total MME, discharge with an opioid prescription (OP%), and rates of ketamine side effects. Bayesian posterior probabilities (pp) were calculated using neutral priors. RESULTS: A total of 300 patients were included in the final analysis with 144 randomized to KI and 156 to UC. Baseline characteristics were similar between groups. The injury severity scores for KI were 19 [14, 29] versus UC 22 [14, 29]. The KI group had a lower rate of long-bone fracture (37% versus 49%) and laparotomy (16% versus 24%). Patients receiving KI had an absolute reduction of 7 MME/day, 96 total MME, and 5% in OP%. Additionally, KI had a relative risk (RR) reduction of 19% in MME/day (RR 0.81 [0.69 - 0.95], pp = 99%), 20% in total MME (RR 0.80 [0.64, 0.99], pp = 98%), and 8% in OP% (RR 0.92 [0.76, 1.11], pp = 81%). The KI group had a higher rate of delirium (11% versus 6%); however, rates of other side effects such as arrythmias and unplanned intubations were similar between groups. CONCLUSION: Addition of a sub-dissociative ketamine infusion to an oral MMPR resulted in a decrease in opioid exposure in severely injured patients. Sub-dissociative ketamine infusions can be used as a safe adjunct to decrease opioid exposure in monitored settings. LEVEL OF EVIDENCE: I; Therapeutic/Care Management.

Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

Objectives: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported. Methods: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography angle <60. Univariate and multivariable analyses assessed risk factors for HYPOFIB. Inverse probability of treatment weighting analyses assessed the relationship between cryoprecipitate administration and outcomes. Results: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood, <1%, 2%, and 7% were HYPOFIB. HYPOFIB patients were younger, had higher head Abbreviated Injury Scale value, and had worse coagulopathy and shock. HYPOFIB had lower survival (48% vs 82%, p<0.001), shorter time to death (median 28 (7, 50) vs 36 (14, 140) hours, p=0.012), and were more likely to die from head injury (72% vs 51%, p<0.001). Risk factors for HYPOFIB included increased age (OR (95% CI) 0.98 (0.96 to 0.99), p=0.03), head injury severity (OR 1.24 (1.06 to 1.46), p=0.009), lower arrival pH (OR 0.01 (0.001 to 0.20), p=0.002), and elevated prehospital red blood cell to platelet ratio (OR 1.20 (1.02 to 1.41), p=0.03). Among HYPOFIB patients, there was no difference in survival for those that received early cryoprecipitate (within 2 hours; 40 vs 47%; p=0.630). On inverse probability of treatment weighted analysis, early cryoprecipitate did not benefit the full cohort (OR 0.52 (0.43 to 0.65), p<0.001), nor the HYPOFIB subgroup (0.28 (0.20 to 0.39), p<0.001). Conclusions: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced resuscitation. Previously reported higher rates may be partially due to unbalanced resuscitation and/or delay in resuscitation initiation. Routine empiric inclusion of concentrated fibrinogen replacement in MTPs is not supported by the currently available data. Level of evidence: Level III.

Exposure to statin therapy decreases the incidence of venous thromboembolism after trauma.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in trauma patients, despite chemoprophylaxis. Statins have been shown capable of acting upon the endothelium. We hypothesized that statin therapy in the pre- or in-hospital settings leads to a decreased incidence of VTE. METHODS: We conducted a retrospective cohort study of injured patients who received statin therapy pre- or in-hospital. Adult, highest-level trauma activation patients admitted January 2018 - June 2022 were included. Patients on prehospital anticoagulants, history of inherited bleeding disorder, and who died within the first 24 hours were excluded. Statin users were matched to non-users by statin use indications including age, current heart and cardiovascular conditions and history, hyperlipidemia, injury severity, and body mass index. Time to in-hospital statin initiation and occurrence of VTE and other complications within 60 days were collected. Differences between groups were determined by univariate, multivariable logistic regression, and Cox proportional hazard analyses. RESULTS: Of 3,062 eligible patients, 79 were statin users that were matched to 79 non-users. There were no differences in admissions demographics, vital signs, injury pattern, transfusion volumes, lengths of stay, or mortality between groups. The overall VTE incidence was 10.8% (17/158). Incidence of VTE in statin users was significantly lower (3%) than non-users (19%; P = 0.003). Differences between statin users and non-users were observed for rates of DVT (0% vs 9%), PE (3% vs 15%), and sepsis (0% vs 5%). Exposure to statins was associated with an 82% decreased risk of developing VTE (hazard ratio = 0.18, 95% CI 0.04 - 0.86; P = 0.033). CONCLUSIONS: Statin exposure was associated with decline in VTE and lower individual rates of DVT, PE, and sepsis. Our findings indicate that statins should be evaluated further as a possible adjunctive therapy for VTE chemoprophylaxis after traumatic injury. LEVEL OF EVIDENCE AND STUDY TYPE: Level III, Retrospective Cohort Study.

Identifying Age-Specific Risk Factors for Poor Outcomes After Trauma With Machine Learning.

INTRODUCTION: Risk stratification for poor outcomes is not currently age-specific. Risk stratification of older patients based on observational cohorts primarily composed of young patients may result in suboptimal clinical care and inaccurate quality benchmarking. We assessed two hypotheses. First, we hypothesized that risk factors for poor outcomes after trauma are age-dependent and, second, that the relative importance of various risk factors are also age-dependent. METHODS: A cohort study of severely injured adult trauma patients admitted to the intensive care unit 2014-2018 was performed using trauma registry data. Random forest algorithms predicting poor outcomes (death or complication) were built and validated using three cohorts: (1) patients of all ages, (2) younger patients, and (3) older patients. Older patients were defined as aged 55 y or more to maintain consistency with prior trauma literature. Complications assessed included acute renal failure, acute respiratory distress syndrome, cardiac arrest, unplanned intubation, unplanned intensive care unit admission, and unplanned return to the operating room, as defined by the trauma quality improvement program. Mean decrease in model accuracy (MDA), if each variable was removed and scaled to a Z-score, was calculated. MDA change ≥4 standard deviations between age cohorts was considered significant. RESULTS: Of 5489 patients, 25% were older. Poor outcomes occurred in 12% of younger and 33% of older patients. Head injury was the most important predictor of poor outcome in all cohorts. In the full cohort, age was the most important predictor of poor outcomes after head injury. Within age cohorts, the most important predictors of poor outcomes, after head injury, were surgery requirement in younger patients and arrival Glasgow Coma Scale in older patients. Compared to younger patients, head injury and arrival Glasgow Coma Scale had the greatest increase in importance for older patients, while systolic blood pressure had the greatest decrease in importance. CONCLUSIONS: Supervised machine learning identified differences in risk factors and their relative associations with poor outcomes based on age. Age-specific models may improve hospital benchmarking and identify quality improvement targets for older trauma patients.

Weight-based enoxaparin thromboprophylaxis in young trauma patients: analysis of the CLOTT-1 registry.

Introduction: Optimal venous thromboembolism (VTE) enoxaparin prophylaxis dosing remains elusive. Weight-based (WB) dosing safely increases anti-factor Xa levels without the need for routine monitoring but it is unclear if it leads to lower VTE risk. We hypothesized that WB dosing would decrease VTE risk compared with standard fixed dosing (SFD). Methods: Patients from the prospective, observational CLOTT-1 registry receiving prophylactic enoxaparin (n=5539) were categorized as WB (0.45-0.55 mg/kg two times per day) or SFD (30 mg two times per day, 40 mg once a day). Multivariate logistic regression was used to generate a predicted probability of VTE for WB and SFD patients. Results: Of 4360 patients analyzed, 1065 (24.4%) were WB and 3295 (75.6%) were SFD. WB patients were younger, female, more severely injured, and underwent major operation or major venous repair at a higher rate than individuals in the SFD group. Obesity was more common among the SFD group. Unadjusted VTE rates were comparable (WB 3.1% vs. SFD 3.9%; p=0.221). Early prophylaxis was associated with lower VTE rate (1.4% vs. 5.0%; p=0.001) and deep vein thrombosis (0.9% vs. 4.4%; p<0.001), but not pulmonary embolism (0.7% vs. 1.4%; p=0.259). After adjustment, VTE incidence did not differ by dosing strategy (adjusted OR (aOR) 0.75, 95% CI 0.38 to 1.48); however, early administration was associated with a significant reduction in VTE (aOR 0.47, 95% CI 0.30 to 0.74). Conclusion: In young trauma patients, WB prophylaxis is not associated with reduced VTE rate when compared with SFD. The timing of the initiation of chemoprophylaxis may be more important than the dosing strategy. Further studies need to evaluate these findings across a wider age and comorbidity spectrum. Level of evidence: Level IV, therapeutic/care management.

Impact of Intra-Operative Shock and Resuscitation on Surgical Site Infections After Trauma Laparotomy.

Background: Patients undergoing trauma laparotomy experience high rates of surgical site infection (SSI). Although intra-operative shock is a likely contributor to SSI risk, little is known about the relation between shock, intra-operative restoration of physiologic normalcy, and SSI development. Patients and Methods: A retrospective review of trauma patients who underwent emergent definitive laparotomy was performed. Using shock index and base excess at the beginning and end of laparotomy, patients were classified as normal, persistent shock, resuscitated, or new shock. Univariable and multivariable analyses were performed to identify predictors of organ/space SSI, superficial/deep SSI, and any SSI. Results: Of 1,191 included patients, 600 (50%) were categorized as no shock, 248 (21%) as resuscitated, 109 (9%) as new shock, and 236 (20%) as persistent shock, with incidence of any SSI as 51 (9%), 28 (11%), 26 (24%), and 32 (14%), respectively. These rates were similar in organ/space and superficial/deep SSIs. On multivariable analysis, resuscitated, new shock, and persistent shock were associated with increased odds of organ/space SSI (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.5; p < 0.001) and any SSI (OR, 2.0; 95% CI, 1.4-3.2; p < 0.001), but no increased risk of superficial/deep SSI (OR, 1.4; 95% CI, 0.8-2.6; p = 0.331). Conclusions: Although the trajectory of physiologic status influenced SSI, the presence of shock at any time during trauma laparotomy, regardless of restoration of physiologic normalcy, was associated with increased odds of SSI. Further investigation is warranted to determine the relation between peri-operative shock and SSI in trauma patients.

Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients.

Background: Trauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds ("standard" CP; sCP), VTE rates remain high. In high-quality studies, aspirin has been shown to decrease VTE in postoperative elective surgical and orthopedic trauma patients. We hypothesized that inhibiting platelet function with aspirin as an adjunct to sCP would reduce the risk of VTE in trauma patients. Methods: We performed a retrospective observational study of prospectively collected data from all adult patients admitted to an American College of Surgeons Level I Trauma center from January 2012 to June 2015 to evaluate the addition of aspirin (sCP+A) to sCP regimens for VTE mitigation. Cox proportional hazard models were used to assess the potential benefit of adjunctive aspirin for symptomatic VTE incidence. Results: 10,532 patients, median age 44 (IQR 28 to 62), 68% male, 89% blunt mechanism of injury, with a median Injury Severity Score (ISS) of 12 (IQR 9 to 19), were included in the study. 8646 (82%) of patients received only sCP, whereas 1886 (18%) patients received sCP+A. The sCP+A cohort displayed a higher median ISS compared with sCP (13 vs 11; p<0.01). The overall median time of sCP initiation was hospital day 1 (IQR 0.8 to 2) and the median day for aspirin initiation was hospital day 3 (IQR 1 to 6) for the sCP+A cohort. 353 patients (3.4%) developed symptomatic VTE. Aspirin administration was independently associated with a decreased relative hazard of VTE (HR 0.57; 95% CI 0.36 to 0.88; p=0.01). There were no increased bleeding or wound complications associated with sCP+A (point estimate 1.23, 95% CI 0.68 to 2.2, p=0.50). Conclusion: In this large trauma cohort, adjunctive aspirin was independently associated with a significant reduction in VTE and may represent a potential strategy to safely mitigate VTE risk in trauma patients. Further prospective studies evaluating the addition of aspirin to heparinoid-based VTE chemoprophylaxis regimens should be sought. Level of evidence: Level III/therapeutic.

Hypofibrinogenemia following injury in 186 children and adolescents: identification of the phenotype, current outcomes, and potential for intervention.

Objectives: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. Methods: All patients <18 years of age presenting to our trauma center 11/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography (r-TEG) angle <60 degrees. Our analysis sought to define risk factors for presenting with HYPOFIB, the impact on outcomes, and whether early replacement improved mortality. Results: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. Conclusion: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. Level of Evidence: Level III - Therapeutic/Care Management.

Early Prediction of Massive Transfusion for Patients With Traumatic Hemorrhage: Development of a Multivariable Machine Learning Model.

Objective: Develop a novel machine learning (ML) model to rapidly identify trauma patients with severe hemorrhage at risk of early mortality. Background: The critical administration threshold (CAT, 3 or more units of red blood cells in a 60-minute period) indicates severe hemorrhage and predicts mortality, whereas early identification of such patients improves survival. Methods: Patients from the PRospective, Observational, Multicenter, Major Trauma Transfusion and Pragmatic, Randomized Optimal Platelet, and Plasma Ratio studies were identified as either CAT+ or CAT-. Candidate variables were separated into 4 tiers based on the anticipated time of availability during the patient's assessment. ML models were created with the stepwise addition of variables and compared with the baseline performance of the assessment of blood consumption (ABC) score for CAT+ prediction using a cross-validated training set and a hold-out validation test set. Results: Of 1245 PRospective, Observational, Multicenter, Major Trauma Transfusion and 680 Pragmatic, Randomized Optimal Platelet and Plasma Ratio study patients, 1312 were included in this analysis, including 862 CAT+ and 450 CAT-. A CatBoost gradient-boosted decision tree model performed best. Using only variables available prehospital or on initial assessment (Tier 1), the ML model performed superior to the ABC score in predicting CAT+ patients [area under the receiver-operator curve (AUC = 0.71 vs 0.62)]. Model discrimination increased with the addition of Tier 2 (AUC = 0.75), Tier 3 (AUC = 0.77), and Tier 4 (AUC = 0.81) variables. Conclusions: A dynamic ML model reliably identified CAT+ trauma patients with data available within minutes of trauma center arrival, and the quality of the prediction improved as more patient-level data became available. Such an approach can optimize the accuracy and timeliness of massive transfusion protocol activation.

Resuscitative endovascular balloon occlusion of the aorta and resuscitative thoracotomy are associated with similar outcomes in traumatic cardiac arrest.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive alternative to resuscitative thoracotomy (RT) for patients with hemorrhagic shock. However, the potential benefits of this approach remain subject of debate. The aim of this study was to compare the outcomes of REBOA and RT for traumatic cardiac arrest. METHODS: A planned secondary analysis of the United States Department of Defense-funded Emergent Truncal Hemorrhage Control study was performed. Between 2017 and 2018, a prospective observational study of noncompressible torso hemorrhage was conducted at six Level I trauma centers. Patients were dichotomized by REBOA or RT, and baseline characteristics and outcomes were compared between groups. RESULTS: A total of 454 patients were enrolled in the primary study, of which 72 patients were included in the secondary analysis (26 underwent REBOA and 46 underwent resuscitative thoracotomy). Resuscitative endovascular balloon occlusion of the aorta patients were older, had a greater body mass index, and were less likely to be the victims of penetrating trauma. Resuscitative endovascular balloon occlusion of the aorta patients also had less severe abdominal injuries and more severe extremity injuries, although the overall injury severity scores were similar. There was no difference in mortality between groups (88% vs. 93%, p = 0.767). However, time to aortic occlusion was longer in REBOA patients (7 vs. 4 minutes, p = 0.001) and they required more transfusions of red blood cells (4.5 vs. 2.5 units, p = 0.007) and plasma (3 vs. 1 unit, p = 0.032) in the emergency department. After adjusted analysis, mortality remained similar between groups (RR, 0.89; 95% confidence interval, 0.71-1.12, p = 0.304). CONCLUSION: Resuscitative endovascular balloon occlusion of the aorta and RT were associated with similar survival after traumatic cardiac arrest, although time to successful aortic occlusion was longer in the REBOA group. Further research is needed to better define the role of REBOA in trauma. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Randomized Controlled Trial of Surgical Rib Fixation to Nonoperative Management in Severe Chest Wall Injury.

OBJECTIVE: To compare the effectiveness of surgical stabilization of rib fractures (SSRFs) to nonoperative management in severe chest wall injury. BACKGROUND: SSRF has been shown to improve outcomes in patients with clinical flail chest and respiratory failure. However, the effect of SSRF outcomes in severe chest wall injuries without clinical flail chest is unknown. METHODS: Randomized controlled trial comparing SSRF to nonoperative management in severe chest wall injury, defined as: (1) a radiographic flail segment without clinical flail or (2) ≥5 consecutive rib fractures or (3) any rib fracture with bicortical displacement. Randomization was stratified by the unit of admission as a proxy for injury severity. Primary outcome was hospital length of stay (LOS). Secondary outcomes included intensive care unit (ICU) LOS, ventilator days, opioid exposure, mortality, and incidences of pneumonia and tracheostomy. Quality of life at 1, 3, and 6 months was measured using the EQ-5D-5L survey. RESULTS: Eighty-four patients were randomized in an intention-to-treat analysis (usual care = 42, SSRF = 42). Baseline characteristics were similar between groups. The numbers of total fractures, displaced fractures, and segmental fractures per patient were also similar, as were the incidences of displaced fractures and radiographic flail segments. Hospital LOS was greater in the SSRF group. ICU LOS and ventilator days were similar. After adjusting for the stratification variable, hospital LOS remained greater in the SSRF group (RR: 1.48, 95% CI: 1.17-1.88). ICU LOS (RR: 1.65, 95% CI: 0.94-2.92) and ventilator days (RR: 1.49, 95% CI: 0.61--3.69) remained similar. Subgroup analysis showed that patients with displaced fractures were more likely to have LOS outcomes similar to their usual care counterparts. At 1 month, SSRF patients had greater impairment in mobility [3 (2-3) vs 2 (1-2), P = 0.012] and self-care [2 (1-2) vs 2 (2-3), P = 0.034] dimensions of the EQ-5D-5L. CONCLUSIONS: In severe chest wall injury, even in the absence of clinical flail chest, the majority of patients still reported moderate to extreme pain and impairment of usual physical activity at one month. SSRF increased hospital LOS and did not provide any quality of life benefit for up to 6 months.

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

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.

Platelet dysfunction persists after trauma despite balanced blood product resuscitation.

BACKGROUND: Platelet activation and aggregation are critical to the initiation of hemostasis after trauma with hemorrhage. Platelet dysfunction is a well-recognized phenomenon contributing to trauma-induced coagulopathy. The goal of this study was to evaluate the timing and severity of platelet dysfunction in massively transfused, traumatically injured patients during the first 72 hours after injury and its association with 30-day survival. METHODS: A retrospective secondary cohort study of platelet count and function was performed using samples from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial. Platelet characteristics were measured at 8 timepoints during the first 72 hours of hospitalization and compared between 30-day survivors and nonsurvivors. Platelet counts were assessed via flow cytometry. Platelet function was analyzed with the use of serial thrombelastography and impedance aggregometry with agonists arachidonic acid, adenosine diphosphate, collagen, thrombin receptor activating peptide, and ristocetin. RESULTS: In total, 680 patients were included for analysis. Platelet counts were significantly lower from baseline to 72 hours after hospital admission with further 1.3 to 2-fold reductions noted in nonsurvivors compared to survivor patients. Platelet aggregation via adenosine diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, and ristocetin was significantly lower in nonsurvivors at all time points. The nadir of platelet aggregation was 2 to 6 hours after admission with significant improvements in viscoelastic maximum clot formation and agonist-induced aggregation by 12 hours without concomitant improvement in platelet count. CONCLUSION: Platelet aggregability recovers 12 hours after injury independent of worsening thrombocytopenia. Failure of platelet function to recover portends a poor prognosis.

Dysphagia is associated with worse clinical outcomes in geriatric trauma patients.

Introduction: Dysphagia is associated with increased morbidity, mortality, and resource utilization in hospitalized patients, but studies on outcomes in geriatric trauma patients with dysphagia are limited. We hypothesized that geriatric trauma patients with dysphagia would have worse clinical outcomes compared with those without dysphagia. Methods: Patients with and without dysphagia were compared in a single-center retrospective cohort study of trauma patients aged ≥65 years admitted in 2019. The primary outcome was mortality. Secondary outcomes included intensive care unit (ICU) length of stay (LOS), hospital LOS, discharge destination, and unplanned ICU admission. Multivariable regression analyses and Bayesian analyses adjusted for age, Injury Severity Score, mechanism of injury, and gender were performed to determine the association between dysphagia and clinical outcomes. Results: Of 1706 geriatric patients, 69 patients (4%) were diagnosed with dysphagia. Patients with dysphagia were older with a higher Injury Severity Score. Increased odds of mortality did not reach statistical significance (OR 1.6, 95% CI 0.6 to 3.4, p=0.30). Dysphagia was associated with increased odds of unplanned ICU admission (OR 4.6, 95% CI 2.0 to 9.6, p≤0.001) and non-home discharge (OR 5.2, 95% CI 2.4 to 13.9, p≤0.001), as well as increased ICU LOS (OR 4.9, 95% CI 3.1 to 8.1, p≤0.001), and hospital LOS (OR 2.1, 95% CI 1.7 to 2.6, p≤0.001). On Bayesian analysis, dysphagia was associated with an increased probability of longer hospital and ICU LOS, unplanned ICU admission, and non-home discharge. Conclusions: Clinically apparent dysphagia is associated with poor outcomes, but it remains unclear if dysphagia represents a modifiable risk factor or a marker of underlying frailty, leading to poor outcomes. This study highlights the importance of screening protocols for dysphagia in geriatric trauma patients to possibly mitigate adverse outcomes. Level of evidence: Level III.

Tissue plasminogen activator resistance is an early predictor of posttraumatic venous thromboembolism: A prospective study from the CLOTT research group.

BACKGROUND: Venous thromboembolism (VTE) remains a frequent postinjury complication with well established but nonmodifiable risk factors. We hypothesized that fibrinolysis shutdown (SD) as measured by thromboelastography (TEG) would be an independent risk factor for VTE in trauma patients. METHODS: A subgroup of patients enrolled in the CLOTT-2 (Consortium of Leaders in the Study of Traumatic Thromboembolism 2), multicenter prospective cohort study had kaolin TEG and tissue plasminogen activator (tPA)-TEG data at 12 and 24 hours postadmission. Patients underwent a screening duplex venous ultrasound examination during the first week unless clot was already detected on computed tomography. Injury factors associated with early fibrinolysis SD (defined as kaolin TEG Ly30 ≤0.3%) and/or tPA resistance (tPA-R) (defined as kaolin TEG with tPA 75 ng Ly30 <2.1%) were investigated as was the association of the TEG measurements with the development of VTE. RESULTS: A total of 141 patients had both TEG measurements at 24 hours, and 135 had both TEG measurements at 12 hours. Shutdown was evident at 12 hours in 71 of 135 (52.6%) patients and in 62 of 141 (44%) at 24 hours. Tissue plasminogen activator resistance was found in 61 of 135 (45.2%) at 12 hours and in 49 of 141 (34.3%) at 24 hours. Factors significantly associated with SD included receiving >4 U of FFP in the first 24 hours, the presence of a major brain injury or pelvic fracture, and the need for major surgery. In contrast, factors significantly associated with early tPA-R included >4 U of red blood cells transfused in the first 24 hours and the presence of a major chest injury or long bone fracture. Deep vein thrombosis was detected in 15 patients and pulmonary clots in 5 (overall VTE rate, 14.2%). Tissue plasminogen activator resistance at 12 hours was found to be an independent risk factor for VTE (hazard ratio, 5.57; 95% confidence interval, 1.39-22.39). CONCLUSION: Early development of a hypercoagulable state as defined by tPA-R at 12 hours after admission represents a potentially modifiable risk factor for postinjury VTE. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Ketamine for acute pain after trauma: the KAPT randomized controlled trial.

BACKGROUND: Evidence for effective pain management and opioid minimization of intravenous ketamine in elective surgery has been extrapolated to acutely injured patients, despite limited supporting evidence in this population. This trial seeks to determine the effectiveness of the addition of sub-dissociative ketamine to a pill-based, opioid-minimizing multi-modal pain regimen (MMPR) for post traumatic pain. METHODS: This is a single-center, parallel-group, randomized, controlled comparative effectiveness trial comparing a MMPR to a MMPR plus a sub-dissociative ketamine infusion. All trauma patients 16 years and older admitted following a trauma which require intermediate (IMU) or intensive care unit (ICU) level of care are eligible. Prisoners, patients who are pregnant, patients not expected to survive, and those with contraindications to ketamine are excluded from this study. The primary outcome is opioid use, measured by morphine milligram equivalents (MME) per patient per day (MME/patient/day). The secondary outcomes include total MME, pain scores, morbidity, lengths of stay, opioid prescriptions at discharge, and patient centered outcomes at discharge and 6 months. DISCUSSION: This trial will determine the effectiveness of sub-dissociative ketamine infusion as part of a MMPR in reducing in-hospital opioid exposure in adult trauma patients. Furthermore, it will inform decisions regarding acute pain strategies on patient centered outcomes. TRIAL REGISTRATION: The Ketamine for Acute Pain Management After Trauma (KAPT) with registration # NCT04129086 was registered on October 16, 2019.

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.

Objectives: Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. Background: The vascular endothelium is a critical regulator of hemostasis and organ function. The relationship between markers of endotheliopathy and fibrinolysis following trauma has not been evaluated. Methods: We performed a secondary analysis of prospectively collected biomarker data in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial. We stratified subjects by 24-hour thromboelastography (TEG) percent clot lysis (LY30) and plasma D-dimer (DD) levels and evaluated differences in endotheliopathy biomarkers and clinical outcomes between subjects with one of four 24-hour fibrinolysis phenotypes: LY30 0.9-2.9% (LY30norm), LY30 >2.9% (LY30high), LY30 <0.9% and low DD (LY30low+DDlow), and LY30 <0.9% and high DD (LY30low+DDhigh). Results: 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. Conclusions: In a multicenter trauma cohort, subjects with a fibrinolysis phenotype characterized by low TEG lysis and elevated DD 24 hours after injury have significantly worse endotheliopathy and clinical outcomes. Our findings support mechanistic evaluations of the role of the endothelium in fibrinolysis dysregulation that may drive late-stage organ injury.

Association of Changes in Antithrombin Activity Over Time With Responsiveness to Enoxaparin Prophylaxis and Risk of Trauma-Related Venous Thromboembolism.

Importance: Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity <80%). Objective: To examine time-dependent changes in antithrombin activity, responsiveness to enoxaparin, as measured by anti-factor Xa (anti-FXa) levels, and incidence of VTE after severe trauma and to assess the association of ex vivo antithrombin supplementation with patients' sensitivity to enoxaparin prophylaxis. Design, Setting, and Participants: This single-center, prospective cohort study was performed at a level 1 trauma center between January 7, 2019, and February 28, 2020. Adult trauma patients admitted to the trauma service at high risk for VTE, based on injury pattern and severity, were screened and enrolled. Patients who were older than 70 years, were pregnant, had a known immunologic or coagulation disorder, or were receiving prehospital anticoagulants were excluded. Exposures: Blood samples were collected on emergency department arrival and daily for the first 8 days of hospitalization. Main Outcomes and Measures: Patients' antithrombin activity and anti-FXa levels were measured by a coagulation analyzer, and thrombin generation was measured by calibrated automated thrombography. Responsiveness to enoxaparin was assessed by measuring anti-FXa levels 4 to 6 hours after the first daily enoxaparin dose and compared between patients who developed VTE and who did not. In addition, the associations of ex vivo supplementation of antithrombin with plasma anti-FXa levels were assessed. Results: Among 150 patients enrolled (median [IQR] age, 35 [27-53] years; 37 [24.7%] female and 113 [75.3%] male; 5 [3.3%] Asian, 32 [21.3%] Black, and 113 [75.3%] White; and 51 [34.0%] of Hispanic ethnicity), 28 (18.7%) developed VTE. Patients with VTE had significantly lower antithrombin activity on admission compared with patients without VTE (median [IQR], 91% [79%-104%] vs 100% [88%-112%]; P = .04), as well as lower antithrombin activity on hospital days 5 (median (IQR), 90% [83%-99%] vs 114% [99%-130%]; P = .011), 6 (median [IQR], 97% [81%-109%] vs 123% [104%-134%]; P = .003), 7 (median [IQR], 82% [74%-89%] vs 123% [110%-140%]; P < .001), and 8 (median [IQR], 99% [85%-100%] vs 123% [109%-146%]; P = .011). Anti-FXa levels were significantly lower in patients with VTE vs those without VTE at hospital day 4 (median [IQR], 0.10 [0.05-0.14] IU/mL vs 0.18 [0.13-0.23] IU/mL; P = .006), day 6 (median [IQR], 0.12 [0.08-0.14] IU/mL vs 0.22 [0.13-0.28] IU/mL; P = .02), and day 7 (median [IQR], 0.11 [0.08-0.12] IU/mL vs 0.21 [0.13, 0.28] IU/mL; P = .002). Multivariable analyses found that for every 10% decrease in antithrombin activity during the first 3 days, the risk of VTE increased 1.5-fold. Conclusions and Relevance: The results of this cohort study suggest that after severe trauma, antithrombin deficiency is common and contributes to enoxaparin resistance and VTE. Interventional studies are necessary to determine the efficacy of antithrombin supplementation in the reduction of VTE incidence.

The Geriatric Nutritional Risk Index as a predictor of complications in geriatric trauma patients.

BACKGROUND: Malnutrition is associated with increased morbidity and mortality after trauma. The Geriatric Nutritional Risk Index (GNRI) is a validated scoring system used to predict the risk of complications related to malnutrition in nontrauma patients. We hypothesized that GNRI is predictive of worse outcomes in geriatric trauma patients. METHODS: This was a single-center retrospective study of trauma patients 65 years or older admitted in 2019. Geriatric Nutritional Risk Index was calculated based on admission albumin level and ratio of actual body weight to ideal body weight. Groups were defined as major risk (GNRI <82), moderate risk (GNRI 82-91), low risk (GNRI 92-98), and no risk (GNRI >98). The primary outcome was mortality. Secondary outcomes included ventilator days, intensive care unit length of stay (LOS), hospital LOS, discharge home, sepsis, pneumonia, and acute respiratory distress syndrome. Bivariate and multivariable logistic regression analyses were performed to determine the association between GNRI risk category and outcomes. RESULTS: A total of 513 patients were identified for analysis. Median age was 78 years (71-86 years); 24 patients (4.7%) were identified as major risk, 66 (12.9%) as moderate risk, 72 (14%) as low risk, and 351 (68.4%) as no risk. Injury Severity Scores and Charlson Comorbidity Indexes were similar between all groups. Patients in the no risk group had decreased rates of death, and after adjusting for Injury Severity Score, age, and Charlson Comorbidity Index, the no risk group had decreased odds of death (odds ratio, 0.13; 95% confidence interval, 0.04-0.41) compared with the major risk group. The no risk group also had fewer infectious complications including sepsis and pneumonia, and shorter hospital LOS and were more likely to be discharged home. CONCLUSIONS: Major GNRI risk is associated with increased mortality and infectious complications in geriatric trauma patients. Further studies should target interventional strategies for those at highest risk based on GNRI. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Variations in clot phenotype following injury: The MA-R ratio and fragile clots.

INTRODUCTION: Trauma-induced coagulopathy is a continuum ranging from hypercoagulable to hypercoagulable phenotypes. In single-center studies, the maximum amplitude (MA) to r-time (R) (MA-R) ratio has identified a phenotype of injured patients with high mortality risk. The purpose of this study was to determine the relationship between MA-R and mortality using multicenter data and to investigate fibrinogen consumption in the development of this specific coagulopathy phenotype. METHODS: Using the Pragmatic Randomized Optimal Platelet and Plasma Ratios data set, patients were divided into blunt and penetrating injury cohorts. MA was divided by R time from admission thromboelastogram to calculate MA-R. MA-R was used to assess odds of early and late mortality using multivariable models. Multivariable models were used to assess thrombogram values in both cohorts. Refinement of the MA-R cut point was performed with Youden index. Repeat multivariable analysis was performed with a binary CRITICAL and NORMAL MA-R. RESULTS: In initial analysis, MA-R quartiles were not associated with mortality in the penetrating cohort. In the blunt cohort, there was an association between low MA-R and early and late mortality. A refined cut point of 11 was identified (CRITICAL: MA-R, ≤11; NORMAL: MA-R, >11). CRITICAL MA-R was associated with mortality in both penetrating and blunt subgroups. In further injury subgroup analysis, CRITICAL patients had significantly decreased fibrinogen levels in the blunt subgroup only. In both blunt and penetrating injury, there was no difference in time to initiation of thrombin burst (lagtime). However, both endogenous thrombin potential and peak thrombin levels were significantly lower in CRITICAL patients. CONCLUSIONS: MA-R identifies a trauma-induced coagulopathy phenotype characterized in blunt injury by impaired thrombin generation that is associated with early and late mortality. The endotheliopathy and tissue factor release likely plays a role in the cascade of impaired thrombin burst, possible early fibrinogen consumption and the weaker clot identified by MA-R. LEVEL OF EVIDENCE: Therapeutic/care management, level II.