IMPORTANCE: Both military and civilian clinical practice guidelines include early plasma transfusion to achieve a plasma to red cell ratio approaching 1:1 to 1:2. However, it was not known how early ...plasma should be given for optimal benefit. Two recent randomized clinical trials were published, with apparently contradictory results. The Prehospital Air Medical Plasma (PAMPer) clinical trial showed a nearly 30% reduction in mortality with plasma transfusion in the prehospital environment, while the Control of Major Bleeding After Trauma (COMBAT) clinical trial showed no survival improvement. OBJECTIVE: To facilitate a post hoc combined analysis of the COMBAT and PAMPer trials to examine questions that could not be answered by either clinical trial alone. We hypothesized that prehospital transport time influenced the effects of prehospital plasma on 28-day mortality. DESIGN, SETTING, AND PARTICIPANTS: A total of 626 patients in the 2 clinical trials were included. Patients with trauma and hemorrhagic shock were randomly assigned to receive either standard care or 2 U of thawed plasma followed by standard care in the prehospital environment. Data analysis was performed between September 2018 and January 2019. INTERVENTIONS: Prehospital transfusion of 2 U of plasma compared with crystalloid-based resuscitation. MAIN OUTCOMES AND MEASURES: The main outcome was 28-day mortality. RESULTS: In this post hoc analysis of 626 patients (467 men 74.6% and 159 women 25.4%; median interquartile range age, 42 27-57 years) who had trauma with hemorrhagic shock, a Cox regression analysis showed a significant overall survival benefit for plasma (hazard ratio HR, 0.65; 95% CI, 0.47-0.90; P = .01) after adjustment for injury severity, age, and clinical trial cohort (COMBAT or PAMPer). A significant association with prehospital transport time was detected (from arrival on scene to arrival at the trauma center). Increased mortality was observed in patients in the standard care group when prehospital transport was longer than 20 minutes (HR, 2.12; 95% CI, 1.05-4.30; P = .04), while increased mortality was not observed in patients in the prehospital plasma group (HR, 0.78; 95% CI, 0.40-1.51; P = .46). No serious adverse events were associated with prehospital plasma transfusion. CONCLUSIONS AND RELEVANCE: These data suggest that prehospital plasma is associated with a survival benefit when transport times are longer than 20 minutes and that the benefit-risk ratio is favorable for use of prehospital plasma. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01838863 (COMBAT) and NCT01818427 (PAMPer)
The aim of this study is to evaluate the association between burn injury and admission plasma levels of Syndecan-1 (SDC-1) and Tissue Factor Pathway Inhibitor (TFPI), and their ability to predict ...30-day mortality.
SDC-1 and TFPI are expressed by vascular endothelium and shed into the plasma as biomarkers of endothelial damage. Admission plasma biomarker levels have been associated with morbidity and mortality in trauma patients, but this has not been well characterized in burn patients.Methods: This cohort study enrolled burn patients admitted to a regional burn center between 2013 and 2017. Blood samples were collected within 4 h of admission and plasma SDC-1 and TFPI were quantified by ELISA. Demographics and injury characteristics were collected prospectively. The primary outcome was 30-day in-hospital mortality.
Of 158 patients, 74 met inclusion criteria. Most patients were male with median age of 41.5 years and burn TBSA of 20.5%. The overall mortality rate was 20.3%. Admission SDC-1 and TFPI were significantly higher among deceased patients. Plasma SDC-1 >34 ng/mL was associated with a 32-times higher likelihood of mortality OR: 32.65 (95% CI, 2.67-399.78); P = 0.006 and a strong predictor of mortality (area under the ROC AUROC 0.92). TFPI was associated with a nine-times higher likelihood of mortality OR: 9.59 (95% CI, 1.02-89.75); P = 0.002 and a fair predictor of mortality (AUROC 0.68).
SDC-1 and TFPI are associated with a higher risk of 30-day mortality. We propose the measurement of SDC-1 on admission to identify burn patients at high risk of mortality. However, further investigation with a larger sample size is warranted.
Hemorrhage is a significant cause of death among military working dogs and in civilian canine trauma. While research specifically aimed at canine trauma is limited, many principles from human trauma ...resuscitation apply. Trauma with significant hemorrhage results in shock and inadequate oxygen delivery to tissues. This leads to aberrations in cellular metabolism, including anaerobic metabolism, decreased energy production, acidosis, cell swelling, and eventual cell death. Considering blood and endothelium as a single organ system, blood failure is a syndrome of endotheliopathy, coagulopathy, and platelet dysfunction. In severe cases following injury, blood failure develops and is induced by inadequate oxygen delivery in the presence of hemorrhage, tissue injury, and acute stress from trauma. Severe hemorrhagic shock is best treated with hemostatic resuscitation, wherein blood products are used to restore effective circulating volume and increase oxygen delivery to tissues without exacerbating blood failure. The principles of hemostatic resuscitation have been demonstrated in severely injured people and the authors propose an algorithm for applying this to canine patients. The use of plasma and whole blood to resuscitate severely injured canines while minimizing the use of crystalloids and colloids could prove instrumental in improving both mortality and morbidity. More work is needed to understand the canine patient that would benefit from hemostatic resuscitation, as well as to determine the optimal resuscitation strategy for these patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ABSTRACTApproximately 10 years ago, the development of hemoglobin-based oxygen carriers (HBOCs) was largely stalled after two large phase 3 clinical trials failed to achieve licensure primarily ...because the safety profile was viewed as unsatisfactory when HBOCs were compared with red cells. Concerns were also raised that HBOCs, as a class, had inherent toxicities. Since then, clinical experience with HBOCs in expanded access programs and under licensure in South Africa has demonstrated that HBOCs can be used safely and effectively. In recent years, clinical studies have demonstrated that prehospital blood transfusion improves survival in severely injured patients with hemorrhage, especially when transport times are longer than 20 to 30 min. Yet, logistical constraints still limit use of blood products in the prehospital setting. As the urgent need for oxygen-carrying capacity for trauma patients for whom red cells are not available is becoming much more apparent, it is imperative that we reexamine the possibility of using HBOCs when red blood cell transfusion is not an option.
Randomized clinical trials (RCTs) support the use of prehospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most ...prehospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent prehospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that prehospital plasma is associated with hypocalcemia, which in turn is associated with lower survival.
We studied patients enrolled in two institutions participating in prehospital plasma RCTs (control, standard of care; experimental, plasma), with i-Ca collected before calcium supplementation. Adults with traumatic hemorrhagic shock (systolic blood pressure ≤70 mm Hg or 71-90 mm Hg + heart rate ≥108 bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca of 1.0 mmol/L or less.
Of 160 subjects (76% men), 48% received prehospital plasma (median age, 40 years interquartile range, 28-53 years) and 71% suffered blunt trauma (median Injury Severity Score ISS, 22 interquartile range, 17-34). Prehospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Prehospital plasma recipients had significantly higher rates of hypocalcemia compared with controls (53% vs. 36%; adjusted relative risk, 1.48; 95% confidence interval CI, 1.03-2.12; p = 0.03). Severe hypocalcemia was significantly associated with decreased survival (adjusted hazard ratio, 1.07; 95% CI, 1.02-1.13; p = 0.01) and massive transfusion (adjusted relative risk, 2.70; 95% CI, 1.13-6.46; p = 0.03), after adjustment for confounders (randomization group, age, ISS, and shock index).
Prehospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in prehospital hemotherapy.
Therapeutic, level II.
OBJECTIVE:To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal ...trials in patients within six categories of significant bleeding, 1) traumatic injury, 2) intracranial hemorrhage, 3) cardiac surgery, 4)gastrointestinal hemorrhage, 5) inherited bleeding disorders and 6) hypoproliferative thrombocytopenia.
BACKGROUND:A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators.
METHODS:An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23rd and 24th 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability.
CONCLUSIONS:For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6 hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.
Introduction: Traumatic shock and hemorrhage (TSH) is a leading cause of preventable death in military and civilian populations. Using a TSH model, we compared plasma with whole blood (WB) as ...prehospital interventions, evaluating restoration of cerebral tissue oxygen saturation (CrSO 2 ), systemic hemodynamics, colloid osmotic pressure (COP) and arterial lactate, hypothesizing plasma would function in a noninferior capacity to WB, despite dilution of hemoglobin (Hgb). Methods: Ten anesthetized male rhesus macaques underwent TSH before randomization to receive a bolus of O(-) WB or AB(+) plasma at T0. At T60, injury repair and shed blood (SB) to maintain MAP > 65 mm Hg began, simulating hospital arrival. Hematologic data and vital signs were analyzed via t test and two-way repeated measures ANOVA, data presented as mean ± SD, significance = P < 0.05. Results: There were no significant group differences for shock time, SB volume, or hospital SB. At T0, MAP and CrSO 2 significantly declined from baseline, though not between groups, normalizing to baseline by T10. Colloid osmotic pressure declined significantly in each group from baseline at T0 but restored by T30, despite significant differences in Hgb (WB 11.7 ± 1.5 vs. plasma 6.2 ± 0.8 g/dL). Peak lactate at T30 was significantly higher than baseline in both groups (WB 6.6 ± 4.9 vs. plasma 5.7 ± 1.6 mmol/L) declining equivalently by T60. Conclusions: Plasma restored hemodynamic support and CrSO 2 , in a capacity not inferior to WB, despite absence of additional Hgb supplementation. This was substantiated via return of physiologic COP levels, restoring oxygen delivery to microcirculation, demonstrating the complexity of restoring oxygenation from TSH beyond simply increasing oxygen carrying capacity.
The hemostatic properties of tranexamic acid (TXA) are well described, but the immunological effects of TXA administration after traumatic injury have not been thoroughly examined. We hypothesized ...TXA would reduce monocyte activation in bleeding trauma patients with severe injury.
This was a single center, double-blinded, randomized controlled trial (RCT) comparing placebo to a 2 g or 4 g intravenous TXA bolus dose in trauma patients with severe injury. Fifty patients were randomized into each study group. The primary outcome was a reduction in monocyte activation as measured by human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes 72 h after TXA administration. Secondary outcomes included kinetic assessment of immune and hemostatic phenotypes within the 72 h window post-TXA administration.
The trial occurred between March 2016 and September 2017, when data collection ended. 149 patients were analyzed (placebo,
= 50; 2 g TXA,
= 49; 4 g TXA,
= 50). The fold change in HLA-DR expression on monocytes reported as median (Q1-Q3) from pre-TXA to 72 h post-TXA was similar between placebo 0.61 (0.51-0.82), 2 g TXA 0.57 (0.47-0.75), and 4 g TXA 0.57 (0.44-0.89) study groups (
= 0.82). Neutrophil CD62L expression was reduced in the 4 g TXA group fold change: 0.73 (0.63-0.97) compared to the placebo group 0.97 (0.78-1.10) at 24 h post-TXA (
= 0.034). The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group 1.36 (0.87-2.42) compared to the placebo group 0.46 (0.19-1.69) at 72 h post-TXA (
= 0.028). There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points.
In trauma patients with severe injury, 4 g intravenous bolus dosing of TXA has minimal immunomodulatory effects with respect to leukocyte phenotypes and circulating cytokine levels.
www.ClinicalTrials.gov, identifier NCT02535949.
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