Fibrinolysis is a physiologic process maintaining patency of the microvasculature. Maladaptive overactivation of this essential function (hyperfibrinolysis) is proposed as a pathologic mechanism of ...trauma-induced coagulopathy. Conversely, the shutdown of fibrinolysis has also been observed as a pathologic phenomenon. We hypothesize that there is a level of fibrinolysis between these two extremes that have a survival benefit for the severely injured patients.
Thrombelastography and clinical data were prospectively collected on trauma patients admitted to our Level I trauma center from 2010 to 2013. Patients with an Injury Severity Score (ISS) of 15 or greater were evaluated. The percentage of fibrinolysis at 30 minutes by thrombelastography was used to stratify three groups as follows: hyperfibrinolysis (≥3%), physiologic (0.081-2.9%), and shutdown (0-0.08%). The threshold for hyperfibrinolysis was based on existing literature. The remaining groups were established on a cutoff of 0.8%, determined by the highest point of specificity and sensitivity for mortality on a receiver operating characteristic curve.
One hundred eighty patients were included in the study. The median age was 42 years (interquartile range IQR, 28-55 years), 70% were male, and 21% had penetrating injuries. The median ISS was 29 (IQR, 22-36), and the median base deficit was 9 mEq/L (IQR, 6-13 mEq/L). Distribution of fibrinolysis was as follows: shutdown, 64% (115 of 180); physiologic, 18% (32 of 180); and hyperfibrinolysis, 18% (33 of 180). Mortality rates were lower for the physiologic group (3%) compared with the hyperfibrinolysis (44%) and shutdown (17%) groups (p = 0.001).
We have identified a U-shaped distribution of death related to the fibrinolysis system in response to major trauma, with a nadir in mortality, with level of fibrinolysis after 30 minutes between 0.81% and 2.9%. Exogenous inhibition of the fibrinolysis system in severely injured patients requires careful selection, as it may have an adverse affect on survival.
Prognostic study, level III.
Massive transfusion protocols (MTPs) have become standard of care in the management of bleeding injured patients, yet strategies to guide them vary widely. We conducted a pragmatic, randomized ...clinical trial (RCT) to test the hypothesis that an MTP goal directed by the viscoelastic assay thrombelastography (TEG) improves survival compared with an MTP guided by conventional coagulation assays (CCA).
This RCT enrolled injured patients from an academic level-1 trauma center meeting criteria for MTP activation. Upon MTP activation, patients were randomized to be managed either by an MTP goal directed by TEG or by CCA (ie, international normalized ratio, fibrinogen, platelet count). Primary outcome was 28-day survival.
One hundred eleven patients were included in an intent-to-treat analysis (TEG = 56, CCA = 55). Survival in the TEG group was significantly higher than the CCA group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the CCA group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032). CCA patients required similar number of red blood cell units as the TEG patients CCA: 5.0 (2-11), TEG: 4.5 (2-8) (P = 0.317), but more plasma units CCA: 2.0 (0-4), TEG: 0.0 (0-3) (P = 0.022), and more platelets units CCA: 0.0 (0-1), TEG: 0.0 (0-0) (P = 0.041) in the first 2 hours of resuscitation.
Utilization of a goal-directed, TEG-guided MTP to resuscitate severely injured patients improves survival compared with an MTP guided by CCA and utilizes less plasma and platelet transfusions during the early phase of resuscitation.
The acute coagulopathy of trauma is present in up to one third of patients by the time of admission, and the recent CRASH-2 and MATTERs trials have focused worldwide attention on hyperfibrinolysis as ...a component of acute coagulopathy of trauma. Thromboelastography (TEG) is a powerful tool for analyzing fibrinolyis, but a clinically relevant threshold for defining hyperfibrinolysis has yet to be determined. Recent data suggest that the accepted normal upper bound of 7.5% for 30-minute fibrinolysis (LY30) by TEG is inappropriate in severe trauma, as the risk of death rises at much lower levels of clot lysis. We wished to determine the validity of this hypothesis and establish a threshold value to treat fibrinolysis, based on prediction of massive transfusion requirement and risk of mortality.
Patients with uncontrolled hemorrhage, meeting the massive transfusion protocol (MTP) criteria at admission (n = 73), represent the most severely injured trauma population at our center (median Injury Severity Score ISS, 30; interquartile range, 20-38). Citrated kaolin TEG was performed at admission blood samples from this population, stratified by LY30, and evaluated for transfusion requirement and 28-day mortality. The same analysis was conducted on available field blood samples from all non-MTP trauma patients (n = 216) in the same period. These represent the general trauma population.
Within the MTP-activating population, the cohort of patients with LY30 of 3% or greater was shown to be at much higher risk for requiring a massive transfusion (90.9% vs. 30.5%, p = 0.0008) and dying of hemorrhage (45.5% vs. 4.8%, p = 0.0014) than those with LY30 less than 3%. Similar trends were seen in the general trauma population.
LY30 of 3% or greater defines clinically relevant hyperfibrinolysis and strongly predicts the requirement for massive transfusion and an increased risk of mortality in trauma patients presenting with uncontrolled hemorrhage. This threshold value for LY30 represents a critical indication for the treatment of fibrinolysis.
Prognostic study, level III.
Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation ...inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA.
Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme-linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve.
Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range IQR, 48-201 pM) versus 115 pM (IQR, 54-202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68-237 pM) versus 32 pM (IQR, 16-37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls).
Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma.
Prognostic and epidemiologic study, level II.
While the incidence of postinjury multiple-organ failure (MOF) has declined during the past decade, temporal trends of its morbidity, mortality, presentation patterns, and health care resources use ...have been inconsistent. The purpose of this study was to describe the evolving epidemiology of postinjury MOF from 2003 to 2010 in multiple trauma centers sharing standard treatment protocols.
"Inflammation and Host Response to Injury Collaborative Program" institutions that enrolled more than 20 eligible patients per biennial during the 2003 to 2010 study period were included. The patients were aged 16 years to 90 years, sustained blunt torso trauma with hemorrhagic shock (systolic blood pressure < 90 mm Hg, base deficit ≥ 6 mEq/L, blood transfusion within the first 12 hours), but without severe head injury (motor Glasgow Coma Scale GCS score < 4). MOF temporal trends (Denver MOF score > 3) were adjusted for admission risk factors (age, sex, body max index, Injury Severity Score ISS, systolic blood pressure, and base deficit) using survival analysis.
A total of 1,643 patients from four institutions were evaluated. MOF incidence decreased over time (from 17% in 2003-2004 to 9.8% in 2009-2010). MOF-related death rate (33% in 2003-2004 to 36% in 2009-2010), intensive care unit stay, and mechanical ventilation duration did not change over the study period. Adjustment for admission risk factors confirmed the crude trends. MOF patients required much longer ventilation and intensive care unit stay, compared with non-MOF patients. Most of the MOF-related deaths occurred within 2 days of the MOF diagnosis. Lung and cardiac dysfunctions became less frequent (57.6% to 50.8%, 20.9% to 12.5%, respectively), but kidney and liver failure rates did not change (10.1% to 12.5%, 15.2% to 14.1%).
Postinjury MOF remains a resource-intensive, morbid, and lethal condition. Lung injury is an enduring challenge and should be a research priority. The lack of outcome improvements suggests that reversing MOF is difficult and prevention is still the best strategy.
Epidemiologic study, level III.
Pipeline programs can help increase diversity in health care by engaging underrepresented minority groups to pursue higher education and training in medical fields. Here we describe the ...implementation of Health Career Collaborative, a pipeline program designed to connect high school students with health care professionals, and the transition to remote delivery of the curriculum.
This study is a retrospective, descriptive observational study where the baseline characteristics of participating students were evaluated via preparticipation surveys. This study took place in a community with an area deprivation index of 6 at a high school in southern California in conjunction with an academic medical center and level I trauma center. Due to the coronavirus disease 2019 pandemic, the program transitioned to a virtual setting in the second half of the academic year.
A total of 37 high school student participants enrolled in the 2019-2020 Health Career Collaborative program, with over 97% identifying as Hispanic, 89% female, and 92% between the ages of 15 and 17. Ninety-five percent of students indicated plans to graduate from high school and attend college, and 89% agreed with having a mentor to help plan for their future. While high school students had exposure to several health topics prior to the program, students reported a preference to learn about health topics from doctors compared to other sources.
An online platform helped facilitate more interaction with health care professionals and could improve feasibility of implementing pipeline programs because physical space and transportation are not required.
•Health Career Collaborative's virtual implementation increased connection with underrepresented minority students during COVID-19.•Baseline characteristics of participants can shape medical mentorship programs.•Online outreach programs can increase participation of varied health professionals.•Online outreach programs can alleviate transportation and venue barriers.
•Intrathoracic method of surgical stabilization of rib fractures introduced.•Learning curves analysis from time per plate and time per fracture.•Cumulative sum learning curve analysis.•No inflection ...point on learning curves for intrathoracic or extrathoracic method of SSRF.
Surgical stabilization of rib fractures (SSRF) is being done with increased frequency and new advances. Intrathoracic SSRF is a new less invasive approach compared to the traditional extrathoracic plating procedure. Educational assessment can be done through descriptive analysis of learning curves with operation time used as a proxy measurement for learning. The objective of this level 3 observational cohort study is to assess the learning curve of introducing the intrathoracic method of plating at a large academic medical institution.
Intrathoracic surgical stabilization of rib fractures was introduced at a tertiary trauma center in March of 2019. All patients that received SSRF beginning 11/2017 were included. Patients with abbreviated injury scale score of the head, abdomen, extremity, or face greater than three and days from injury to SSRF greater than 4 were excluded. Operation time was determined from time of incision to completion of skin closure. Time per fracture and time per plate were calculated using total operation time. Learning curves and CUSUM graphs for individual surgeons that had completed in more than 3 SSRF cases were generated using and trended for statistical significance.
After exclusions, there were 38 patients with extrathoracic SSRF between November 2017–September 2021 and 24 patients with intrathoracic plating between March 2019–Sept. 2021. There were 5 fellows and 6 residents that performed extrathoracic SSRF. Four fellows and 2 residents performed intrathoracic SSRF. Graphs of time per fracture and time per plate over time produced learning curves without an inflection point for extrathoracic or intrathoracic SSRF in any of the following categories: all surgeries (Figs. 1 and 2), academic year (July to June), individual attending surgeons, fellows, or residents.
There was no discernible inflection point on the generated learning curves. Time per plate and time per fracture did not decrease as surgeons gained more experience. Introducing intrathoracic SSRF in a large academic hospital may not need to account for a learning curve adjustment period.
Thromboelastography (TEG) is emerging as the standard in the management of acute coagulopathies in injured patients. Although TEG is sensitive in detecting abnormalities in clot strength, one ...shortcoming is differentiating between fibrinogen and platelet contributions to clot integrity. Current American algorithms suggest platelet transfusion, whereas European guidelines suggest fibrinogen concentrates for correcting low clot strength. Therefore, we hypothesized that a TEG-based functional fibrinogen (FF) assay would assess the contribution of fibrinogen and platelets to clot strength and provide insight to transfusion priorities. Blood samples were obtained from trauma patients on arrival to the emergency department or who were admitted to the surgical intensive care unit (n = 68). Citrated kaolin TEG, FF, and von Clauss fibrinogen levels (plasma-based clinical standard) were measured. Correlations were assessed using linear regression models. In vitro studies were also performed with adding fibrinogen concentrates to blood collected from healthy volunteers (n = 10). Functional fibrinogen and citrated kaolin TEG parameters were measured. Functional fibrinogen strongly correlated with von Clauss fibrinogen levels (R = 0.87) and clot strength (R = 0.80). The mean fibrinogen contribution to clot strength was 30%; however, there was a direct linear relationship with fibrinogen level and percent fibrinogen contribution to clot strength (R = 0.83). Traditional TEG parameters associated with fibrinogen activity (α angle and kinetic time) had significantly lower correlations with FF (R = 0.70 and 0.35). Furthermore, platelet count had only a moderate correlation to clot strength (R = 0.51). The addition of fibrinogen concentrate in in vitro studies increased clot strength (MA) (60.44 ± 1.48 to 68.12 ± 1.39) and percent fibrinogen contribution to clot strength (23.8% ± 1.8% to 37.7% ± 2.5%). Functional fibrinogen can be performed rapidly with TEG and correlates well with the standard von Clauss fibrinogen assay. Both fibrinogen and platelet contribution of clot strength can be derived from FF. Moreover, FF had a stronger correlation to clot strength, and increased levels were directly associated with increased percent contribution to clot strength. In vitro studies also demonstrated an increase in FF, clot strength, and percent fibrinogen contribution to clot strength with the addition of fibrinogen concentrate. These data suggest that fibrinogen should be addressed early in trauma patients manifesting acute coagulopathy of trauma.
Background
Geriatric burn trauma patients (age ≥65 years) have a 5-fold higher mortality rate than younger adults. With the population of the US aging, the number of elderly burn and trauma patients ...is expected to increase. A past study using the National Burn Repository revealed a linear increase in mortality for those >65 years old. We hypothesized that octogenarians with burn and trauma injuries would have a higher rate of in-hospital complications and mortality, than patients aged 65-79 years old.
Methods
The Trauma Quality Improvement Program (2010-2016) was queried for burn trauma patients. To detect mortality risk a multivariable logistic regression model was used.
Results
From 282 patients, there were 73 (25.9%) octogenarians and 209 (74.1%) aged 65-79 years old. The two cohorts had similar median injury severity scores (16 vs. 15 in octogenarians, P = .81), total body surface area burned (P = .30), and comorbidities apart from an increased smoking (12.9% vs. 4.1%, P = .04) and decreased hypertension (52.2% vs. 65.8%, P = .04) in the younger cohort. Octogenarians had similar complications, including acute respiratory distress syndrome, pulmonary embolism, deep vein thrombosis (P > .05), and mortality (15.1% vs. 10.5%, P = .30), compared to the younger cohort. Octogenarians were not associated with an increased mortality risk (odds ratio 1.51, confidence interval 0.24-9.56, P = .67).
Discussion
Among burn trauma patients ≥65 years, age should not be a sole predictor for mortality risk. Continued research is necessary in order to determine more accurate approaches to prognosticate mortality in geriatric burn trauma patients, such as the validation and refinement of a burn-trauma-related frailty index.
Cellular and organ metabolism affects organismal lifespan. Aging is characterized by increased risks for metabolic disorders, with age-associated degenerative diseases exhibiting varying degrees of ...mitochondrial dysfunction. The traditional view of the role of mitochondria generated reactive oxygen species (ROS) in cellular aging, assumed to be causative and simply detrimental for a long time now, is in need of reassessment. While there is little doubt that high levels of ROS are detrimental, mounting evidence points toward a lifespan extension effect exerted by mild to moderate ROS elevation. Dietary caloric restriction, inhibition of insulin-like growth factor-I signaling, and inhibition of the nutrient-sensing mechanistic target of rapamycin are robust longevity-promoting interventions. All of these appear to elicit mitochondrial retrograde signaling processes (defined as signaling from the mitochondria to the rest of the cell, for example, the mitochondrial unfolded protein response, or UPR(mt)). The effects of mitochondrial retrograde signaling may even spread to other cells/tissues in a noncell autonomous manner by yet unidentified signaling mediators. Multiple recent publications support the notion that an evolutionarily conserved, mitochondria-initiated signaling is central to the genetic and epigenetic regulation of cellular aging and organismal lifespan.
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