Showing papers by "Charles E. Wade published in 2018"

Clinical Cellular Therapeutics Accelerate Clot Formation.

Abstract: Clinical cellular therapeutics (CCTs) have shown preliminary efficacy in reducing inflammation after trauma, preserving cardiac function after myocardial infarction, and improving functional recovery after stroke. However, most clinically available cell lines express tissue factor (TF) which stimulates coagulation. We sought to define the degree of procoagulant activity of CCTs as related to TF expression. CCT samples from bone marrow, adipose, amniotic fluid, umbilical cord, multi-potent adult progenitor cell donors, and bone marrow mononuclear cells were tested. TF expression and phenotype were quantified using flow cytometry. Procoagulant activity of the CCTs was measured in vitro with thromboelastography and calibrated thrombogram. Fluorescence-activated cell sorting (FACS) separated samples into high- and low-TF expressing populations to isolate the contribution of TF to coagulation. A TF neutralizing antibody was incubated with samples to demonstrate loss of procoagulant function. All CCTs tested expressed procoagulant activity that correlated with expression of tissue factor. Time to clot and thrombin formation decreased with increasing TF expression. High-TF expressing cells decreased clotting time more than low-TF expressing cells when isolated from a single donor using FACS. A TF neutralizing antibody restored clotting time to control values in some, but not all, CCT samples. CCTs demonstrate wide variability in procoagulant activity related to TF expression. Time to clot and thrombin formation decreases as TF load increases and this procoagulant effect is neutralized by a TF blocking antibody. Clinical trials using CCTs are in progress and TF expression may emerge as a safety release criterion. Stem Cells Translational Medicine 2018;7:731-739.

Traumatic brain injury is associated with increased syndecan-1 shedding in severely injured patients.

Abstract: Head injury and exsanguination are the leading causes of death in trauma patients. Hemorrhagic shock triggers systemic endothelial glycocalyx breakdown, potentially leading to traumatic endotheliopathy (EoT). Levels of syndecan-1, a main glycocalyx component, have been used to assess the integrity of the glycocalyx. In TBI patients, it remains unclear whether syndecan-1 shedding occurs and its correlation with outcomes. We aimed to determine the frequency of EoT+, defined as a syndecan-1 level of 40 ng/ml or higher, after TBI in isolated and polytraumatic injury. We also investigated how the presence of EoT+ affected outcomes in TBI patients. Severely injured trauma patients were enrolled. From blood samples collected upon patients’ arrival to the hospital, we measured syndecan-1 (main biomarker of EoT+), soluble thrombomodulin (sTM, endothelial activation) adrenaline and noradrenaline (sympathoadrenal activation), and assessed TBI patients’ coagulation capacity. Of the enrolled patients (n = 331), those with TBI and polytrauma (n = 68) had the highest rate of EoT+ compared to isolated TBI (n = 58) and Non-TBI patients (n = 205) (Polytrauma-TBI 55.9% vs. Isolated-TBI 20.0% vs. non-TBI polytrauma 40.0%; p = 0.001). TBI patients with EoT+ exhibited marked increases in sTM, adrenaline and noradrenaline levels, and physiological and coagulation derangements. In isolated TBI patients, increasing syndecan-1 levels (β for every 10 ng/ml increase: 0.14; 95% CI: 0.02, 0.26) and hypocoagulability were negatively associated with survival. This study provides evidence of syndecan-1 shedding after TBI supporting the notion that breakdown of the glycocalyx contributes to the physiological derangements after TBI.

Management of blunt cerebrovascular injury (BCVI) in the multisystem injury patient with contraindications to immediate anti-thrombotic therapy

Abstract: Introduction Practice management guidelines for screening and treatment of patients with blunt cerebrovascular injury (BCVI) have been associated with a decreased risk of ischemic stroke. Treatment: of patients with BCVI and multisystem injuries that delays immediate antithrombotic therapy remains controversial. The purpose of this study was to determine the timing of BCVI treatment initiation, the incidence of stroke, and bleeding complications as a result of antithrombotic therapy in patients with isolated BCVI in comparison to those with BCVI complicated by multisystem injuries. Materials and methods This study was a retrospective review of all adult blunt trauma patients admitted to a level 1 trauma center from 2009 to 2014 with a diagnosis of BCVI. Results A total of 28,305 blunt trauma patients were admitted during the study period. Of these, 323 (1.1%) had 481 BCEVIs and were separated into two groups. Isolated BCVI was reported in 111 (34.4%) patients and 212 (65.6%) patients had accompanying multisystem injuries (traumatic brain injury (TBI), solid organ injury, or spinal cord injury) that contraindicated immediate antithrombotic therapy. Treatment: started in patients with isolated BCVI at a median time of 30.3 (15, 52) hours after injury in contrast to 62.4 (38, 97) hours for those with multisystem injuries (p Conclusion The lack of bleeding complications and equivalent stroke rates between groups suggests that the presence of TBI, solid organ injury, and spinal cord injury are not contraindications to anti-thrombotic therapy for stroke prevention in patients with BCVI.

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

Abstract: Background Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis Study Design We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis Significant variables at a value of p Results We included 512 patients Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p Conclusions Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis

Coagulopathy as a predictor of mortality after penetrating traumatic brain injury.

Abstract: Study hypothesis Traumatic brain injury (TBI) is a leading cause of mortality with penetrating TBI (p-TBI) patients having worse outcomes. These patients are more likely to be coagulopathic than blunt TBI (b-TBI) patients, thus we hypothesize that coagulopathy would be an early predictor of mortality. Methods We identified highest-level trauma activation patients who underwent an admission head CT and had ICU admission orders from August 2009–May 2013, excluding those with polytrauma and anticoagulant use. Rapid thrombelastography (rTEG) was obtained after emergency department (ED) arrival and coagulopathy was defined as follows: ACT ≥ 128 s, KT ≥ 2.5 s, angle ≤ 56°, MA ≤ 55 mm, LY-30 ≥ 3.0% or platelet count ≤ 150,000/μL. Regression modeling was used to assess the association of coagulopathy on mortality. Results 1086 patients with head CT scans performed and ICU admission orders were reviewed. After exclusion criteria were met, 347 patients with isolated TBI were analyzed-99 (29%) with p-TBI and 248 (71%) with b-TBI. Patients with p-TBI had a higher mortality (41% vs. 10%, p p p -value = 0.012). Conclusions This study demonstrates that p-TBI patients with significant coagulopathy have a poor prognosis. Coagulopathy, in conjunction with other factors, can be used to earlier identify p-TBI patients with worse outcomes and represents a possible area for intervention.

Plasma Resuscitation Improved Survival in a Cecal Ligation and Puncture Rat Model of Sepsis.

Abstract: Background:The paradigm shift from crystalloid to plasma resuscitation of traumatic hemorrhagic shock has improved patient outcomes due in part to plasma-mediated reversal of catecholamine and inflammation-induced endothelial injury, decreasing vascular permeability and attenuating organ inj

Severely injured trauma patients with admission hyperfibrinolysis: Is there a role of tranexamic acid? Findings from the PROPPR trial

Abstract: INTRODUCTIONAdministration of tranexamic acid (TXA) in coagulopathy of trauma gained popularity after the CRASH-2 trial. The aim of our analysis was to analyze the role of TXA in severely injured trauma patients with admission hyperfibrinolysis.METHODSWe reviewed the prospectively collected Pragmati

Multiplate and TEG platelet mapping in a population of severely injured trauma patients.

Abstract: SUMMARYObjectives The objectives of this study were to compare thromboelastography platelet mapping (TEG PM) with impedance aggregometry (Multiplate, MP) in a single trauma population and relate their results clinically. Background Platelet function as measured by thromboelastography and impedance aggregometry demonstrates significant reductions that persist for days following traumatic injury. However, no study compares these devices and the correlation between them is not known. Methods In level 1 trauma patients, TEG PM and MP were conducted at their initial presentation to the emergency department. Within-device repeatability and between-device association were determined using correlation analyses. Demographic variables, Injury Severity Score, blood product transfusion, laboratory test results and mortality rate were recorded. Results Ninety-two patients were enrolled. Within-device repeatability was high for TEG PM and MP for arachidonic acid (AA) and adenosine diphosphate (ADP) activation pathways. When comparing TEG PM with MP, results correlated poorly in the ADP pathway (Spearman's rho = 0·11, P = 0·44) and moderately in the AA pathway (Spearman's rho = 0·56, P < 0·0001). TEG PM was predictive of blood product transfusion and correlated with increased base deficit, whereas MP was only predictive of mortality. Conclusions Intra-device variability was low for TEG PM and MP, but the two point-of-care devices measuring platelet function correlate poorly with each other in injured trauma patients. Each device also had different clinical associations.

The hyperfibrinolytic phenotype is the most lethal and resource intense presentation of fibrinolysis in massive transfusion patients.

Abstract: BACKGROUND Among bleeding patients, we hypothesized that the hyperfibrinolytic (HF) phenotype would be associated with the highest mortality, whereas shutdown (SD) patients would have the greatest complication burden. METHODS Severely injured patients predicted to receive a massive transfusion at 12 Level I trauma centers were randomized to one of two transfusion ratios as described in the Pragmatic, Randomized, Optimal Platelet and Plasma Ratio trial. Fibrinolysis phenotypes were determined based on admission clot lysis at 30 minutes (LY30): SD ≤0.8%, physiologic (PHYS) 0.9-2.9%, and HF ≥3%. Univariate and multivariate analysis was performed. Logistic regression was used to adjust for age, gender, arrival physiology, shock, injury severity, center effect, and treatment arm. RESULTS Among the 680 patients randomized, 547(80%) had admission thrombelastography (TEG) values available to determine fibrinolytic phenotypes. Compared to SD and PHYS, HF patients had higher Injury Severity Score (25 vs. 25 vs. 34), greater base deficit (-8 vs. -6 vs. -12) and were more uniformly hypocoagulable on admission by PT, PTT, and TEG values; all p <0.001. HF patients also received more red blood cells, plasma, and platelets (at 3, 6, and 24 hours); had fewer ICU-, ventilator-, and hospital-free days; and had higher 24-hour and 30-day mortality. There were no differences in complications between the three phenotypes. Multivariate logistic regression demonstrated that HF on admission was associated with a threefold higher mortality (OR 3.06, 95% CI 1.57-5.95, p = 0.001). CONCLUSIONS Previous data have shown that both the SD and HF phenotypes are associated with increased mortality and complications in the general trauma population. However, in a large cohort of bleeding patients, HF was confirmed to be a much more lethal and resource-intense phenotype. These data suggest that further research into the understanding of SD and HF is warranted to improve outcomes in this patient population. LEVEL OF EVIDENCE Prognostic, level II.

The Incidence of Transfusion-Related Acute Lung Injury at a Large, Urban Tertiary Medical Center: A Decade's Experience.

Abstract: BACKGROUND:While transfusion-related acute lung injury (TRALI) remains the primary cause of transfusion-related fatalities (37%), recent reports estimate the incidence of TRALI at 0.008% per unit of plasma transfused and 0.004% per all products transfused. Because blood banks have moved toward male-

Platelet biomechanics, platelet bioenergetics, and applications to clinical practice and translational research.

Abstract: The purpose of this review is to explore the relationship between platelet bioenergetics and biomechanics and how this relationship affects the clinical interpretation of platelet function devices. Recent experimental and technological advances highlight platelet bioenergetics and biomechanics as alternative avenues for collecting clinically relevant data. Platelet bioenergetics drive energy production for key biomechanical processes like adhesion, spreading, aggregation, and contraction. Platelet function devices like thromboelastography, thromboelastometry, and aggregometry measure these biomechanical processes. Platelet storage, stroke, sepsis, trauma, or the activity of antiplatelet drugs alters measures of platelet function. However, the specific mechanisms governing these alterations in platelet function and how they relate to platelet bioenergetics are still under investigation.

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

Abstract: 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.

Protocol for a pilot randomized controlled trial comparing plasma with balanced crystalloid resuscitation in surgical and trauma patients with septic shock.

Abstract: Background Septic shock is a public health problem with high mortality. There remains a knowledge gap regarding the optimal resuscitation fluid to improve clinical outcomes, and the underlying mechanism by which fluids exert their effect. Shock-induced endotheliopathy (SHINE) is thought to be a shared pathophysiologic mechanism associated with worsened outcomes in critically ill trauma and sepsis patients. SHINE is characterized by breakdown of the glycocalyx—a network of membrane-bound proteoglycans and glycoproteins that covers the endothelium. This has been associated with capillary leakage and microvascular thrombosis, organ dysfunction, and mortality. Biomarkers of SHINE have been shown to correlate with clinical outcomes in patients with septic shock. Interventions to mitigate SHINE may improve outcomes in patients with septic shock. In surgical/trauma patients with septic shock, initial plasma resuscitation as compared with balanced crystalloid (BC) resuscitation will mitigate biomarkers of SHINE and improve clinical outcomes. Methods A pilot, single-center randomized controlled trial (RCT) will compare initial plasma to BC resuscitation in surgical and trauma patients with septic shock. Patients will be enrolled based on a Sepsis Screening Score of ≥4 with a suspected source of infection. Patient randomization only occurs if they meet the criteria: (1) hypotension with mean arterial pressure 4 mmol/L, altered mental status or decreased urine output of Results The primary outcome is a reduction in serum biomarkers at 6 hours. Secondary outcomes will include clinical outcomes such as intensive care unit-free days, organ dysfunction, and in-hospital mortality. Discussion This trial will provide insights into the effects of initial plasma resuscitation on SHINE. Furthermore, it will provide unbiased estimates regarding the feasibility, safety, and clinical efficacy of plasma resuscitation in septic shock on which to base subsequent adequately powered multicenter RCTs. Trail registration number ClinicalTrials.gov (NCT03366220).

Can We Identify Futility in Kids? An Evaluation of Admission Parameters Predicting 100% Mortality in 1,292 Severely Injured Children.

Abstract: Background Objective parameters predicting futility of care in severely injured pediatric patients are lacking. Although futility of care has been investigated in a limited number of studies in trauma patients, none of these studies achieves a 100% success rate in a large cohort of pediatric patients. The purpose of the current study was to identify extreme laboratory values that could be used to predict 100% mortality in severely injured children. Study Design We evaluated a registry-based, historical cohort of all severely injured children (Level I trauma, younger than 16 years old) who were not dead on arrival between January 2010 and December 2016 from a single Level I trauma center. Extreme arrival laboratory data were evaluated both alone and in conjunction with traumatic brain injury. Results There were 1,292 patients who met inclusion criteria, of which 1,169 (90.5%) survived and 123 (9.5%) died. Those who died were significantly younger, with higher head Abbreviated Injury Scale scores and overall Injury Severity Scores. Single extreme laboratory values were identified that predicted mortality perfectly (100% positive predictive value): international normalized ratio ≥3.0, pH ≤6.95, base excess ≤ -22, platelet count ≤30,000, hemoglobin ≤5.0 g/dL, rapid thromboelastography ≤30 mm, and rapid thromboelastography lysis at 30 minutes ≥50%. When 2 laboratory values or the presence of traumatic brain injury were added, lower thresholds for futility were noted. Conclusions Extreme admission laboratory values are capable of predicting 100% mortality and futility of additional care in severely injured children with a high level of accuracy. Validation of these single-center findings is warranted and, if supported, should initiate a discussion within the pediatric trauma community about application and cessation of resuscitation efforts to optimize resource use.

Utilizing Propensity Score Analyses in Prehospital Blood Product Transfusion Studies: Lessons Learned and Moving Toward Best Practice.

Abstract: Recently, observational studies analyzing prehospital blood product transfusions (PHT) for trauma have become more widespread in both military and civilian communities. Due to these studies' non-random treatment assignment, propensity score (PS) methodologies are often used to determine an intervention's effectiveness. However, there are no guidelines on how to appropriately conduct PS analyses in prehospital studies. Such analyses are complicated when treatments are given in emergent settings as the ability to administer treatment early, often before hospital admission, can interfere with assumptions of PS modeling. This study conducts a systematic review of literature from military and civilian populations to assess current practice of PS methodology in PHT analyses. The decision-making process from the multicenter Prehospital Resuscitation on Helicopter Study (PROHS) is discussed and used as a motivating example. Results show that researchers often omit or incorrectly assess variable balance between treatment groups and include inappropriate variables in the propensity model. When used correctly, PS methodology is an effective statistical technique to show that aggressive en route resuscitation strategies, including PHT, can reduce mortality in individuals with severe trauma. This review provides guidelines for best practices in study design and analyses that will advance trauma care.