bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2021‒04‒04
nine papers selected by
Andreia Luís
Ludwig Boltzmann Institute

  1. J Trauma Acute Care Surg. 2021 Mar 12.
      BACKGROUND: Plasma has been shown to mitigate the endotheliopathy of trauma (EOT). Protection of the endothelium may be due in part to fibrinogen and other plasma-derived proteins found in cryoprecipitate, however the exact mechanisms remain unknown. Clinical trials are underway investigating early cryoprecipitate administration in trauma. In this study, we hypothesize that cryoprecipitate will inhibit endothelial cell (EC) permeability in vitro and will replicate the ability of plasma to attenuate pulmonary vascular permeability and inflammation induced by hemorrhagic shock and trauma (HS/T) in mice.METHODS: In vitro, barrier permeability of ECs subjected to thrombin challenge was measured by trans-endothelial electrical resistance. In vivo, using an established mouse model of HS/T, we compared pulmonary vascular permeability among mice resuscitated with 1) lactated Ringer's (LR), 2) fresh frozen plasma (FFP), or 3) cryoprecipitate. Lung tissue from the mice in all groups was analyzed for markers of vascular integrity, inflammation, and inflammatory gene expression via NanoString mRNA quantification.
    RESULTS: Cryoprecipitate attenuates EC permeability and EC junctional compromise induced by thrombin in vitro in a dose-dependent fashion. In vivo, resuscitation of HS/T mice with either FFP or cryoprecipitate attenuates pulmonary vascular permeability (sham: 297±155, LR: 848±331, FFP: 379±275, cryoprecipitate: 405±207; p<0.01 sham vs. LR, p<0.01 LR vs. FFP, and p<0.05 LR vs. cryoprecipitate). Lungs from cryoprecipitate- and FFP-treated mice demonstrate decreased lung injury, decreased infiltration of neutrophils and activation of macrophages, and preserved pericyte-endothelial interaction compared to LR-treated mice. Gene analysis of lung tissue from cryoprecipitate- and FFP-treated mice demonstrates decreased inflammatory gene expression, in particular IL-1β and NLRP3, compared to LR-treated mice.
    CONCLUSION: Our data suggest that cryoprecipitate attenuates the EOT in HS/T similar to FFP. Further investigation is warranted on active components and their mechanisms of action.
  2. Int J Mol Sci. 2021 Mar 23. pii: 3257. [Epub ahead of print]22(6):
      Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups (n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.
    Keywords:  High Mobility Group Box 1 (HMGB1); argon; inflammation; ischemia-reperfusion; multiorgan failure
  3. Biomolecules. 2021 Mar 31. pii: 522. [Epub ahead of print]11(4):
      Severe polytraumatic injury initiates a robust immune response. Broad immune dysfunction in patients with such injuries has been well-documented; however, early biomarkers of immune dysfunction post-injury, which are critical for comprehensive intervention and can predict the clinical course of patients, have not been reported. Current circulating markers such as IL-6 and IL-10 are broad, non-specific, and lag behind the clinical course of patients. General blockade of the inflammatory response is detrimental to patients, as a certain degree of regulated inflammation is critical and necessary following trauma. Exosomes, small membrane-bound extracellular vesicles, found in a variety of biofluids, carry within them a complex functional cargo, comprised of coding and non-coding RNAs, proteins, and metabolites. Composition of circulating exosomal cargo is modulated by changes in the intra- and extracellular microenvironment, thereby serving as a homeostasis sensor. With its extensively documented involvement in immune regulation in multiple pathologies, study of exosomal cargo in polytrauma patients can provide critical insights on trauma-specific, temporal immune dysregulation, with tremendous potential to serve as unique biomarkers and therapeutic targets for timely and precise intervention.
    Keywords:  exosomes; extracellular vesicles; inflammation; intercellular communication; trauma
  4. J Trauma Acute Care Surg. 2021 Mar 23.
      BACKGROUND: Avoidance of hypoxia and hyperoxia may reduce morbidity and mortality in critically ill civilian and military trauma patients. The objective of this study is to determine if a multimodal quality improvement intervention increases adherence to a consensus-based, targeted normoxia strategy. We hypothesized that this intervention would safely improve compliance with targeted normoxia.METHODS: This is a pre/post quasi-experimental pilot study to improve adherence to normoxia, defined as a pulse oximetry (SpO2) of 90-96% or an arterial partial pressure oxygen (PaO2) of 60-100mmHg. We used a multimodal informatics and educational intervention guiding clinicians to safely titrate supplemental oxygen to normoxia based on SpO2 monitoring in critically ill trauma patients admitted to the surgical-trauma or neurosurgical intensive care unit within 24 hours of emergency department arrival. The primary outcome was effectiveness in delivering targeted normoxia (i.e., an increase in the probability of being in the targeted normoxia range and/or a reduction in the probability of being on a higher FiO2).
    RESULTS: Analysis included 371 pre-intervention subjects and 201 post-intervention subjects. Pre-and post-intervention subjects were of similar age, race/ethnicity, and gender and had similar comorbidities and APACHE II scores. Overall, the adjusted probability of being hyperoxic while on supplemental oxygen was reduced during the post-intervention period (adjusted odds ratio (aOR) 0.74, 95% confidence interval (CI) 0.57-0.97). There was a higher probability of being on room air (fraction inspired oxygen concentration (FiO2)=0.21) in the post-intervention period (aOR 1.38, 95%CI 0.83-2.30). Additionally, there was a decreased amount of patient time spent on higher levels of FiO2 (FiO2 >40%) without a concomitant increase in hypoxia.
    CONCLUSIONS: A multimodal intervention targeting normoxia in critically ill trauma patients increased normoxia and lowered the use of supplemental oxygen. A large clinical trial is needed to validate the impact of this protocol on patient-centered clinical outcomes.
    LEVEL OF EVIDENCE: Therapeutic/Care Management, level II.
  5. Biomedicines. 2021 Mar 05. pii: 260. [Epub ahead of print]9(3):
      Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.
    Keywords:  B cells; HIF; ILC; T cells; hypoxia; macrophages; monocytes; neutrophils; oxygen
  6. J Trauma Acute Care Surg. 2021 Mar 12.
      BACKGROUND: Prehospital plasma transfusion in trauma reduces mortality. However, the underlying mechanism remains unclear. Reduction in shock severity may play a role. Lactate correlates with physiologic shock severity and mortality after injury. Our objective was to determine if prehospital plasma reduces lactate, and if this contributes to the mortality benefit of plasma.METHODS: Patients in the Prehospital Air Medical Plasma trial in the upper quartile of injury severity (ISS>30) were included to capture severe shock. Trial patients were randomized to prehospital plasma or standard care resuscitation (crystalloid +/- PRBC). Regression determined the associations between admission lactate, 30-day mortality, and plasma while adjusting for demographics, prehospital crystalloid, time, mechanism, and injury characteristics. Causal mediation analysis determined what proportion of the effect of plasma on mortality is mediated by lactate reduction.
    RESULTS: 125 patients were included. The plasma group had a lower adjusted admission lactate than standard of care group (coeff -1.64; 95%CI -2.96, -0.31, p=0.02). Plasma was associated with lower odds of 30-day mortality (OR 0.27; 95%CI 0.08-0.90, p=0.03). When adding lactate to this model, the effect of plasma on 30-day mortality was no longer significant (OR 0.36; 95%CI 0.07-1.88, p=0.23), while lactate was associated with mortality (OR 1.74 per 1mmol/L increase; 95%CI 1.10-2.73, p=0.01). Causal mediation demonstrated 35.1% of the total effect of plasma on 30-day mortality was mediated by the reduction in lactate among plasma patients.
    CONCLUSION: Prehospital plasma is associated with reduced 30-day mortality and lactate in severely injured patients. Over one-third of the effect of plasma on mortality is mediated by a reduction in lactate. Thus, reducing the severity of hemorrhagic shock appears to be one mechanism of prehospital plasma benefit. Further study should elucidate other mechanisms and if a dose response exists.
    LEVEL OF EVIDENCE: II, therapeutic.
  7. J Thromb Haemost. 2021 Mar 28.
      BACKGROUND: Coagulopathic bleeding is a major cause of mortality after trauma, and platelet dysfunction contributes to this problem. The causes of platelet dysfunction are relatively unknown, but a great deal can be learned from the plasma environment about the possible pathways involved.OBJECTIVE: Describe the changes in plasma proteomic profile associated with platelet dysfunction after trauma.
    METHODS: Citrated blood was collected from severely injured trauma patients at the time of their arrival to the Emergency Department. Samples were collected from 110 patients, and a subset of twenty-four patients was identified by a preserved (n=12) or severely impaired (n=12) platelet aggregation response to five different agonists. Untargeted proteomics was performed by nanoflow liquid chromatography tandem mass spectrometry. Protein abundance levels for each patient were normalized to total protein concentration to control for hemodilution by crystalloid fluid infusion prior to blood draw.
    RESULTS: Patients with platelet dysfunction were more severely injured but otherwise demographically similar to those with retained platelet function. Of 232 proteins detected, twelve were significantly different between groups. These proteins fall into several broad categories related to platelet function, including microvascular obstruction with platelet activation, immune activation, and protease activation.
    CONCLUSIONS: This observational study provides a description of the change in proteomic profile associated with platelet dysfunction after trauma and identifies twelve proteins with the most profound changes. The pathways involving these proteins are salient targets for immediate investigation to better understand platelet dysfunction after trauma and identify targets for intervention.
    Keywords:  Blood Platelet Disorders; Hemorrhage; Hemostasis; Multiple Trauma; Proteomics
  8. Mol Cell Endocrinol. 2021 Mar 30. pii: S0303-7207(21)00098-8. [Epub ahead of print] 111254
      The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long become clear that the RAS has pleiotropic actions that contribute to organ damage, including modulation of inflammation. Angiotensin II (Ang II) activates angiotensin type 1 receptors (AT1R) to promote an inflammatory response and organ damage. This represents the pathophysiological basis for the successful use of RAS blockers to prevent and treat kidney and heart disease. However, other RAS components could have a built-in capacity to brake proinflammatory responses. Angiotensin type 2 receptor (AT2R) activation can oppose AT1R actions, such as vasodilatation, but its involvement in modulation of inflammation has not been conclusively proven. Angiotensin-converting enzyme 2 (ACE2) can process Ang II to generate angiotensin-(1-7) (Ang-(1-7)), that activates the Mas receptor to exert predominantly anti-inflammatory responses depending on the context. We now review recent advances in the understanding of the interaction of the RAS with inflammation. Specific topics in which novel information became available recently include intracellular angiotensin receptors; AT1R posttranslational modifications by tissue transglutaminase (TG2) and anti-AT1R autoimmunity; RAS modulation of lymphoid vessels and T lymphocyte responses, especially of Th17 and Treg responses; interactions with toll-like receptors (TLRs), programmed necrosis, and regulation of epigenetic modulators (e.g. microRNAs and bromodomain and extraterminal domain (BET) proteins). We additionally discuss an often overlooked effect of the RAS on inflammation which is the downregulation of anti-inflammatory factors such as klotho, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), transient receptor potential ankyrin 1 (TRPA1), SNF-related serine/threonine-protein kinase (SNRK), serine/threonine-protein phosphatase 6 catalytic subunit (Ppp6C) and n-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Both transcription factors, such as nuclear factor κB (NF-κB), and epigenetic regulators, such as miRNAs are involved in downmodulation of anti-inflammatory responses. A detailed analysis of pathways and targets for downmodulation of anti-inflammatory responses constitutes a novel frontier in RAS research.
    Keywords:  Ac-SDKP; PGC-1α; Th17; angiotensin; inflammation; kidney; klotho; miRNA
  9. J Clin Med. 2021 Mar 03. pii: 1030. [Epub ahead of print]10(5):
      In trauma patients, bleeding can lead to coagulopathy, hemorrhagic shock, and multiorgan failure, and therefore is of fundamental significance in regard to early morbidity. We conducted a meta-analysis to evaluate the efficacy and safety of tranexamic acid (TXA) in civil and military settings and its impact on in-hospital mortality (survival to hospital discharge or 30-day survival), intensive care unit and hospital length of stay, incidence of adverse events (myocardial infarct and neurological complications), and volume of blood product transfusion. The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic review of the literature using PubMed, Scopus, EMBASE, Web of Science, and the Cochrane Central Register and Controlled Trials (CENTRAL) database was conducted from inception to 10 January 2021. In-hospital mortality was reported in 14 studies and was 15.5% for the TXA group as compared with 16.4% for the non-TXA group (OR = 0.81, 95% CI 0.62-1.06, I2 = 83%, p = 0.12). In a civilian TXA application, in-hospital mortality in the TXA and non-TXA groups amounted to 15.0% and 17.1%, respectively (OR = 0.69, 95% CI 0.51-0.93, p = 0.02, I2 = 78%). A subgroup analysis of the randomized control trial (RCT) studies showed a statistically significant reduction in in-hospital mortality in the TXA group (14.3%) as compared with the non-TXA group (15.7%, OR = 0.89, 95% CI 0.83-0.96, p = 0.003, I2 = 0%). To summarize, TXA used in civilian application reduces in-hospital mortality. Application of TXA is beneficial for severely injured patients who undergoing shock and require massive blood transfusions. Patients who undergo treatment with TXA should be monitored for clinical signs of thromboembolism, since TXA is a standalone risk factor of a thromboembolic event and the D-dimers in traumatic patients are almost always elevated.
    Keywords:  bleeding; emergency medicine; meta-analysis; mortality; systematic review; tranexamic acid; trauma