Geoffrey R. Nunns

Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine

BACKGROUND Tissue injury and hemorrhagic shock induce significant systemic metabolic reprogramming in animal models and critically injured patients. Recent expansions of the classic concepts of metabolomic aberrations in tissue injury and hemorrhage opened the way for novel resuscitative interventions based on the observed abnormal metabolic demands. We hypothesize that metabolic demands and resulting metabolic signatures in pig plasma will vary in response to isolated or combined tissue injury and hemorrhagic shock. METHODS A total of 20 pigs underwent either isolated tissue injury, hemorrhagic shock, or combined tissue injury and hemorrhagic shock referenced to a sham protocol (n = 5/group). Plasma samples were analyzed by UHPLC-MS. RESULTS Hemorrhagic shock promoted a hypermetabolic state. Tissue injury alone dampened metabolic responses in comparison to sham and hemorrhagic shock, and attenuated the hypermetabolic state triggered by shock with respect to energy metabolism (glycolysis, glutaminolysis, and Krebs cycle). Tissue injury and hemorrhagic shock had a more pronounced effect on nitrogen metabolism (arginine, polyamines, and purine metabolism) than hemorrhagic shock alone. CONCLUSION Isolated or combined tissue injury and hemorrhagic shock result in distinct plasma metabolic signatures. These findings indicate that optimized resuscitative interventions in critically ill patients are possible based on identifying the severity of tissue injury and hemorrhage.

Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator

BACKGROUND Fibrinolysis shutdown (SD) is an independent risk factor for increased mortality in trauma. High levels of plasminogen activator inhibitor-1 (PAI-1) directly binding tissue plasminogen activator (t-PA) is a proposed mechanism for SD; however, patients with low PAI-1 levels present to the hospital with a rapid TEG (r-TEG) LY30 suggestive SD. We therefore hypothesized that two distinct phenotypes of SD exist, one, which is driven by t-PA inhibition, whereas another is due to an inadequate t-PA release in response to injury. METHODS Trauma activations from our Level I center between 2014 and 2016 with blood collected within an hour of injury were analyzed with r-TEG and a modified TEG assay to quantify fibrinolysis sensitivity using exogenous t-PA (t-TEG). Using the existing r-TEG thresholds for SD (<0.9%), physiologic (LY30 0.9–2.9%), and hyperfibrinolysis (LY30 > 2.9%) patients were stratified into phenotypes. A t-TEG LY30 greater than 95th percentile of healthy volunteers (n = 140) was classified as t-PA hypersensitive and used to subdivide phenotypes. A nested cohort had t-PA and PAI-1 activity levels measured in addition to proteomic analysis of additional fibrinolytic regulators. RESULTS This study included 398 patients (median New Injury Severity Score, 18), t-PA-Sen was present in 27% of patients. Shutdown had the highest mortality rate (20%) followed by hyperfibinolysis (16%) and physiologic (9% p = 0.020). In the non–t-PA hypersensitive cohort, SD had a fivefold increase in mortality (15%) compared with non-SD patients (3%; p = 0.003) which remained significant after adjusting for Injury Severity Score and age (p = 0.033). Overall t-PA activity (p = 0.002), PAI-1 (p < 0.001), and t-PA/PAI-1 complex levels (p = 0.006) differed between the six phenotypes, and 54% of fibrinolytic regulator proteins analyzed (n = 19) were significantly different. CONCLUSION In conclusion, acute fibrinolysis SD is not caused by a single etiology, and is clearly associated with PAI-1 activity. The differential phenotypes require an ongoing investigation to identify the optimal resuscitation strategy for these patients. Level of Evidence Prognostic, level III.

Empiric transfusion strategies during life-threatening hemorrhage

Background: Resuscitation guided by thrombelastography improves survival after injury. If bleeding is rapid, however, or if no thrombelastography data are available, the optimal strategy remains controversial. Our current practice gives fresh frozen plasma and red blood cells (1:2) empirically in patients with life‐threatening hemorrhage, with subsequent administration based on rapid thrombelastography. We identified patients at risk of massive transfusion at 1 hour, examined their initial rapid thrombelastography, and used this value to provide empiric recommendations about transfusions. Methods: Massive transfusion was defined as >4 units of red blood cells in the first hour. Patients managed by a trauma activation (2014–2017) had an admission rapid thrombelastography analyzed to determine what proportion met thresholds for administration of cryoprecipitate or platelets. Results: Overall, 35 patients received >4 units of red blood cells in the first hour. Based on the admission rapid thrombelastography, 37% met criteria for both platelets and cryoprecipitate, 35% for either platelets or cryoprecipitate and 29% for neither. Kaplan‐Meier analysis showed a significant delay in the administration of cryoprecipitate and platelets compared to fresh frozen plasma. Conclusion: Patients who require >4 units of red blood cells within the first hour should receive cryoprecipitate and platelets if thrombelastography results are not available. Point‐of‐care devices are needed for optimal care of trauma‐induced‐coagulopathy, but these data offer guidance in their absence.

Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase–Activating protein in lung tissue

BACKGROUND Post-traumatic lung injury following trauma and hemorrhagic shock (T/HS) is associated with significant morbidity. Leukotriene-induced inflammation has been implicated in the development of post-traumatic lung injury through a mechanism that is only partially understood. Postshock mesenteric lymph returning to the systemic circulation is rich in arachidonic acid, the substrate of 5-lipoxygenase (ALOX5). ALOX5 is the rate-limiting enzyme in leukotriene synthesis and, following T/HS, contributes to the development of lung dysfunction. ALOX5 colocalizes with its cofactor, 5-lipoxygenase-activating protein (ALOX5AP), which is thought to potentiate ALOX5 synthetic activity. We hypothesized that T/HS results in the molecular association and nuclear colocalization of ALOX5 and ALOX5AP, which ultimately increases leukotriene production and potentiates lung injury. MATERIALS AND METHODS To examine these molecular interactions, a rat T/HS model was used. Post-T/HS tissue was evaluated for lung injury through both histologic analysis of lung sections and biochemical analysis of bronchoalveolar lavage fluid. Lung tissue was immunostained for ALOX5 and ALOX5AP with association and colocalization evaluated by fluorescence resonance energy transfer. In addition, rats undergoing T/HS were treated with MK-886, a known ALOX5AP inhibitor. RESULTS ALOX5 levels increase and ALOX5/ALOX5AP association occurred after T/HS, as evidenced by increases in total tissue fluorescence and fluorescence resonance energy transfer signal intensity, respectively. These findings coincided with increased leukotriene production and with the histological changes characteristic of lung injury. ALOX5/ALOX5AP complex formation, leukotriene production, and lung injury were decreased after inhibition of ALOX5AP with MK-886. CONCLUSIONS These results suggest that the association of ALOX5/ALOX5AP contributes to leukotriene-induced inflammation and predisposes the T/HS animal to lung injury.

Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion

Background. Thrombelastography platelet mapping is a useful assay to assess antiplatelet therapy. Inhibited response to the adenosine diphosphate receptor on platelets occurs early after injury, but recent work suggests this alteration occurs even with minor trauma. However, the utility of thrombelastography platelet mapping, specifically the percent of adenosine diphosphate receptor inhibition, in predicting outcomes and guiding platelet transfusion in trauma‐induced coagulopathy remains unknown We assessed the role of percent of adenosine diphosphate‐inhibition in predicting survival, requirement for massive transfusion or platelet transfusion in patients at risk for trauma‐induced coagulopathy. Methods. Thrombelastography platelet mapping was assessed in 303 trauma activation patients from 2014–2016 and in 89 healthy volunteers. Percent of adenosine diphosphate‐inhibition is presented as median and interquartile range. We compared the area under the receiver operating characteristic curve of percent of adenosine diphosphate‐inhibition, platelet count, and rapid thrombelastography maximum amplitude for in‐hospital mortality, massive transfusion (>10 red blood cells or death/6 hours), and platelet transfusion (>0 platelet units or death/6 hour). Results. Overall, 35 (11.5%) patient died, 27 (8.9%) required massive transfusion and 46, platelet transfusions (15.2%). Median percent of adenosine diphosphate‐inhibition was 42.5% (interquartile range: 22.4–69.1%), compared with 4.3 % (interquartile range: 0–13.5%) in healthy volunteers (P < .0001). Patients that died, had a massive transfusion, or platelet transfusion had higher percent of adenosine diphosphate‐inhibition than those that did not (P < .05 for all). However, percent of adenosine diphosphate‐inhibition did not add significantly to the predictive performance of maximum amplitude or platelet count for any of the 3 outcomes, after adjustment for confounders. Subgroup analyses by severe traumatic brain injury, severe injury and requirement of red blood cells showed similar results. Conclusion. Adenosine diphosphate receptor inhibition did not add predictive value to predicting mortality, massive transfusion, or platelet transfusion. Thus, the role of thrombelastography platelet mapping as a solitary tool to guide platelet transfusions in trauma requires continued refinement.