Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock. BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury. METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality. RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups. CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

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.

Multi-modal Analgesic Strategies for Trauma (MAST): protocol for a pragmatic randomized trial.

BACKGROUND: Pain management after injury is critically important for functional recovery. Although opioids have been a mainstay for treatment of pain, they are associated with adverse events and may contribute to long-term use or abuse. Opioid-minimizing multimodal pain regimens have the potential to reduce exposure to opioids without compromising pain control. This article details an ongoing clinical trial comparing two pill-based, opioid-minimizing, multimodal pain strategies. METHODS: This is a single-center, parallel-group, randomized, controlled comparative effectiveness trial comparing two multimodal pain regimens in adult trauma patients. All patients 16 years and older admitted to the Red Duke Trauma Institute are eligible unless they are pregnant, a prisoner, under observation status, or a non-acute trauma patient. At admission to the trauma service, patients are enrolled and randomized to one of two multimodal pain regimens. The primary outcome is opioid use, measured by morphine milligram equivalents per patient per day. The secondary outcomes include pain scores, ventilator days, hospital and intensive care unit lengths of stay, occurrence of opioid-related complications, hospital and pharmacy costs, and incidence of hospital discharge with opioid prescription. Outcomes will be compared using Bayesian methods. DISCUSSION: This trial will determine the effectiveness of two multimodal pain treatment strategies on reducing in-hospital opioid exposure in adult trauma patients. Furthermore, it will compare the two strategies on pain control and patient safety. Knowledge gained in this study can improve quality of care at this hospital and other trauma centers regardless of which medication regimen proves superior.

An adapted Clavien-Dindo scoring system in trauma as a clinically meaningful nonmortality endpoint.

BACKGROUND: There is no consensus on reporting nonmortality trauma complications in a graded manner. The Clavien-Dindo scale of complications was originally for elective surgery and requires adaptation to provide meaningful data for trauma patients. In particular, the original score does not account for those treated without surgery. We report an adapted Clavien-Dindo in trauma (ACDiT) scale and apply it to patients managed operatively and nonoperatively. METHODS: A combined prospective and retrospective international multicenter observational study was undertaken to apply the ACDiT scale to 484 trauma patients at three university teaching hospitals (Birmingham, England (n = 303); Houston, Texas (n = 113); and Glasgow, Scotland (n = 68)). These included both intensive care unit (ICU) and non-ICU-managed patients. The Clavien-Dindo scoring system was adapted for trauma patients based on consensus amongst an international collaboration of trauma specialists at these sites. Data included whether initial patients were managed operatively or nonoperatively. Complication grades were compared with hospital-free and ICU-free days as other outcome measures of patient morbidity. RESULTS: Two hundred seventeen (44.8%) of 484 patients experienced complications, of whom 61 (28.1%) of 217 died (grade V). The remainder consisted of grades I (n = 20), II (n = 60), III (n = 24), and IV (n = 52). There was a strong association between higher ACDiT grade category and lower number of hospital-free and ICU-free days (p < 0.01). Eighty-eight patients with complications did not require surgery, validating the score's usefulness in patients managed nonoperatively. CONCLUSION: The ACDiT scale can be used to grade the severity of posttrauma complications in patients managed both operatively and nonoperatively. It provides clinically meaningful data for morbidity and mortality meetings and other quality improvement exercises. LEVEL OF EVIDENCE: Prognostic, level IV.

Every minute counts: Time to delivery of initial massive transfusion cooler and its impact on mortality.

BACKGROUND: American College of Surgeons Trauma Quality Improvement Best Practices recommends initial massive transfusion (MT) cooler delivery within 15 minutes of protocol activation, with a goal of 10 minutes. The current study sought to examine the impact of timing of first cooler delivery on patient outcomes. METHODS: Patients predicted to receive MT at 12 Level I trauma centers were randomized to two separate transfusion ratios as described in the PROPPR trial. Assessment of Blood Consumption score or clinician gestalt prediction of MT was used to randomize patients and call for initial study cooler. In this planned subanalysis, the time to MT protocol activation and time to delivery of the initial cooler were evaluated. The impact of these times on mortality and time to hemostasis were examined using both Wilcoxon rank sum and linear and logistic regression. RESULTS: Among 680 patients, the median time from patient arrival to MT protocol activation was 9 minutes with a median time from MT activation call to delivery of first cooler of 8 minutes. An increase in both time to MT activation and time to arrival of first cooler were associated with prolonged time to achieving hemostasis (coefficient, 1.09; p = 0.001 and coefficient, 1.16; p < 0.001, respectively). Increased time to MT activation and time to arrival of first cooler were associated with increased mortality (odds ratio [OR], 1.02; p = 0.009 and OR, 1.02; p = 0.012, respectively). Controlling for injury severity, physiology, resuscitation intensity, and treatment arm (1:1:1 vs. 1:1:2), increased time to arrival of first cooler was associated with an increased mortality at 24 hours (OR, 1.05; p = 0.035) and 30 days (OR, 1.05, p = 0.016). CONCLUSION: Delays in MT protocol activation and delays in initial cooler arrival were associated with prolonged time to achieve hemostasis and an increase in mortality. Independent of products ratios, every minute from time of MT protocol activation to time of initial cooler arrival increases odds of mortality by 5%. LEVEL OF EVIDENCE: Prognostic, level II; Therapeutic, level III.

Damage control laparotomy trial: design, rationale and implementation of a randomized controlled trial.

BACKGROUND: Damage control laparotomy (DCL) is an abbreviated operation intended to prevent the development of hypothermia, acidosis, and coagulopathy in seriously injured patients. The indications for DCL have since been broadened with no high-quality data to guide treatment. For patients with an indication for DCL, we aim to determine the effect of definitive laparotomy on patient morbidity. METHOD: This is a pragmatic, parallel-group, randomized controlled pilot trial. Emergent laparotomy is defined as admission directly to the operating room from the emergency department within 90 min of arrival. DCL indications excluded from the study include packing of the liver or retroperitoneum, abdominal compartment syndrome prophylaxis, to expedite interventional radiology for hemorrhage control, and the need for ongoing transfusions and/or continuous vasopressor support. When a surgeon determines a DCL is indicated, the patient will be screened for inclusion and exclusion criteria. Patients with any indication for DCL that is not excluded are eligible for randomization. Patients will be randomized intraoperatively to DCL (control) or definitive fascial closure of the laparotomy (intervention). The primary outcome will be major abdominal complication or death within 30 days. Major abdominal complication is a composite outcome including fascial dehiscence, organ/space surgical site infection, enteric suture line failure, and unplanned reopening of the abdomen. Outcomes will be compared using both frequentist and Bayesian statistics. DISCUSSION: In patients with an indication for DCL, this trial will determine the effect of definitive laparotomy on major abdominal complications and death and will inform clinicians on the risks and benefits of this procedure. Regardless of the study outcome, the results will improve the quality of care provided to injured patients. TRIAL REGISTRATION NUMBER: NCT02706041.

Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer.

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression by a primary tumor correlates with poor prognosis in breast cancer, including early spread to bone. Interleukin-8 (IL-8) stimulates osteoclastogenesis and resorption of bone, and elevated IL-8 levels predict early metastatic spread of breast cancer. The purpose of this study was to test our hypothesis that tumors that overexpress COX-2 induce IL-8 production. MATERIALS AND METHODS: We cotransfected MCF-10A (nonmalignant breast epithelial) cells, as well as MDA-231 (highly metastatic human breast cancer) cell lines with a pSG5-COX-2 vector and pEF1a-Luc-IRES-Neo vector (luciferase reporter). COX-2 overexpression was confirmed by Western blot and PGE2 (a product of the COX-2 pathway) immunoassay. IL-8 production was measured by immunoassay. In vivo testing used a nude mouse model to measure COX-2 and IL-8 production from breast cancer cells that had metastasized to bone (bone-seeking clones (BSCs)). Long bone metastases were localized and quantified by luciferase imaging (Xenogen IVIS system) and X-ray. BSCs were isolated and cultured and then tested for the production of PGE2 and IL-8. RESULTS: COX-2 overexpression caused a 4- to 5-fold increase in IL-8 production in both MCF-10A and MDA-231 cells in vitro. In vivo, we observed that the MDA-231-BSC (metastatic cells isolated from bone metastases) produced significantly greater levels of both PGE2 and IL-8 compared to the parental MDA-231 cells (P < 0.01). In contrast to the results obtained with these estrogen receptor-negative cell lines, COX-2 expression failed to induce IL-8 in the MCF-7 estrogen receptor-positive breast cancer cell line. Treatment with the COX-2 inhibitor NS-398 at a low 1-mu[scap]M dose reduced the production of IL-8 in COX-2-transfected MDA-231 cells by 30%, thus confirming the involvement of COX-2 in IL-8 induction. CONCLUSION: COX-2 expression induced formation of PGE2 and IL-8 in breast cancer cells. Since PGE2 and IL-8 stimulate osteoclasts to resorb bone, COX-2 inhibition is a potential target for treatment to prevent bone metastases.