bims-heshmo 2021-05-02 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–05–02
ten papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Vasopressors in Trauma: A Never Event?
Hyperoxemia during resuscitation of trauma patients and increased intensive care unit length of stay: inverse probability of treatment weighting analysis.
The potential of adipokines in identifying multiple trauma patients at risk of developing multiple organ dysfunction syndrome.
Estradiol prevented intestinal ischemia and reperfusion-induced changes in intestinal permeability and motility in male rats.
Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study.
Therapeutically Targeting Microvascular Leakage In Experimental Hemorrhagic Shock: A Systematic Review and Meta-Analysis.
Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.
Vagus Nerve Stimulation Protects Enterocyte Glycocalyx After Hemorrhagic Shock Via The Cholinergic Anti-Inflammatory Pathway.
The use of pulse pressure variation for predicting impairment of microcirculatory blood flow.
Trauma-induced coagulopathy.

Anesth Analg. 2021 Apr 28.

Vasopressors in Trauma: A Never Event?

Justin E Richards, Tim Harris, Martin W Dünser, Pierre Bouzat, Tobias Gauss.

Vasopressor use in severely injured trauma patients is discouraged due to concerns that vasoconstriction will worsen organ perfusion and result in increased mortality and organ failure in hypotensive trauma patients. Hypotensive resuscitation is advocated based on limited data that lower systolic blood pressure and mean arterial pressure will result in improved mortality. It is classically taught that hypotension and hypovolemia in trauma are associated with peripheral vasoconstriction. However, the pathophysiology of traumatic shock is complex and involves multiple neurohormonal interactions that are ultimately manifested by an initial sympathoexcitatory phase that attempts to compensate for acute blood loss and is characterized by vasoconstriction, tachycardia, and preserved mean arterial blood pressure. The subsequent hypotension observed in hemorrhagic shock reflects a sympathoinhibitory vasodilation phase. The objectives of hemodynamic resuscitation in hypotensive trauma patients are restoring adequate intravascular volume with a balanced ratio of blood products, correcting pathologic coagulopathy, and maintaining organ perfusion. Persistent hypotension and hypoperfusion are associated with worse coagulopathy and organ function. The practice of hypotensive resuscitation would appear counterintuitive to the goals of traumatic shock resuscitation and is not supported by consistent clinical data. In addition, excessive volume resuscitation is associated with adverse clinical outcomes. Therefore, in the resuscitation of traumatic shock, it is necessary to target an appropriate balance with intravascular volume and vascular tone. It would appear logical that vasopressors may be useful in traumatic shock resuscitation to counteract vasodilation in hemorrhage as well as other clinical conditions such as traumatic brain injury, spinal cord injury, multiple organ dysfunction syndrome, and vasodilation of general anesthetics. The purpose of this article is to discuss the controversy of vasopressors in hypotensive trauma patients and advocate for a nuanced approach to vasopressor administration in the resuscitation of traumatic shock.

DOI: https://doi.org/10.1213/ANE.0000000000005552
World J Emerg Surg. 2021 Apr 29. 16(1): 19

Hyperoxemia during resuscitation of trauma patients and increased intensive care unit length of stay: inverse probability of treatment weighting analysis.

Japanese Association for Acute Medicine (JAAM) Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) Study Group

   BACKGROUND: Information on hyperoxemia among patients with trauma has been limited, other than traumatic brain injuries. This study aimed to elucidate whether hyperoxemia during resuscitation of patients with trauma was associated with unfavorable outcomes.
METHODS: A post hoc analysis of a prospective observational study was carried out at 39 tertiary hospitals in 2016-2018 in adult patients with trauma and injury severity score (ISS) of > 15. Hyperoxemia during resuscitation was defined as PaO2 of ≥ 300 mmHg on hospital arrival and/or 3 h after arrival. Intensive care unit (ICU)-free days were compared between patients with and without hyperoxemia. An inverse probability of treatment weighting (IPW) analysis was conducted to adjust patient characteristics including age, injury mechanism, comorbidities, vital signs on presentation, chest injury severity, and ISS. Analyses were stratified with intubation status at the emergency department (ED). The association between biomarkers and ICU length of stay were then analyzed with multivariate models.
RESULTS: Among 295 severely injured trauma patients registered, 240 were eligible for analysis. Patients in the hyperoxemia group (n = 58) had shorter ICU-free days than those in the non-hyperoxemia group [17 (10-21) vs 23 (16-26), p < 0.001]. IPW analysis revealed the association between hyperoxemia and prolonged ICU stay among patients not intubated at the ED [ICU-free days = 16 (12-22) vs 23 (19-26), p = 0.004], but not among those intubated at the ED [18 (9-20) vs 15 (8-23), p = 0.777]. In the hyperoxemia group, high inflammatory markers such as soluble RAGE and HMGB-1, as well as low lung-protective proteins such as surfactant protein D and Clara cell secretory protein, were associated with prolonged ICU stay.
CONCLUSIONS: Hyperoxemia until 3 h after hospital arrival was associated with prolonged ICU stay among severely injured trauma patients not intubated at the ED.
TRIAL REGISTRATION: UMIN-CTR, UMIN000019588 . Registered on November 15, 2015.

Keywords:  Critically ill; Hyperoxemia; Hyperoxia; ICU length of stay; Mortality; Trauma

DOI:  https://doi.org/10.1186/s13017-021-00363-2
Eur J Med Res. 2021 Apr 30. 26(1): 38

The potential of adipokines in identifying multiple trauma patients at risk of developing multiple organ dysfunction syndrome.

Julian Haupt, Niels Krysiak, Marina Unger, Viktoria Bogner-Flatz, Peter Biberthaler, Marc Hanschen, Martijn van Griensven, Alexander T Haug.

   BACKGROUND: Multiple organ dysfunction syndrome (MODS) and the consecutive multiple organ failure (MOF) are severe and dreaded complications with a high mortality in multiple trauma patients. The aim of this study was to investigate the potential of the adipokines leptin, resistin, interleukin-17A and interleukin-33 as possible biomarkers in the early posttraumatic inflammatory response and for identifying severely traumatized patients at risk of developing MODS.
METHODS: In total, 14 multiple trauma patients with an injury severity score (ISS) ≥ 16 as well as a control group of 14 non-multiple trauma patients were included in this study and blood samples were taken at the time points 0, 6, 24, 48 and 72 h after admission. For the trauma patients, the SIRS and Denver MOF score were determined daily. The quantitative measurement of the plasma concentrations of the adipokines was performed using ELISA.
RESULTS: In the statistical analysis, the multiple trauma patients showed statistically significant higher plasma concentrations of leptin, resistin, IL-17A and IL-33 compared to the control group. In addition, there was a statistically significant positive correlation between the concentrations of resistin, IL-17A and IL-33 and the corresponding SIRS scores and between the concentrations of resistin, IL-17A and IL-33 and the corresponding Denver MOF scores. Finally, ROC curve analysis revealed that the adipokines leptin and IL-17A are suitable diagnostic markers for the discrimination between multiple trauma patients with and without MOF.
CONCLUSIONS: Leptin and IL-17A could be suitable diagnostic markers to identify severely injured patients with a developing SIRS and MOF earlier, to adjust surgical therapy planning and intensive care.

Keywords:  Adipokines; Interleukin-17A; Interleukin-33; Leptin; Multiple organ dysfunction syndrome; Multiple organ failure; Multiple trauma; Resistin

DOI:  https://doi.org/10.1186/s40001-021-00511-z
Clinics (Sao Paulo). 2021 ;pii: S1807-59322021000100261. [Epub ahead of print]76 e2683

Estradiol prevented intestinal ischemia and reperfusion-induced changes in intestinal permeability and motility in male rats.

Fernanda Yamamoto Ricardo-da-Silva, Evelyn Thaís Fantozzi, Sara Rodrigues-Garbin, Helori Vanni Domingos, Ricardo Martins Oliveira-Filho, Bernardo Boris Vargaftig, Yanira Riffo-Vasquez, Ana Cristina Breithaupt-Faloppa, Wothan Tavares-de-Lima.

OBJECTIVES: Ischemia and reperfusion (I/R) in the intestine could lead to severe endothelial injury, compromising intestinal motility. Reportedly, estradiol can control local and systemic inflammation induced by I/R injury. Thus, we investigated the effects of estradiol treatment on local repercussions in an intestinal I/R model.
METHODS: Rats were subjected to ischemia via the occlusion of the superior mesenteric artery (45 min) followed by reperfusion (2h). Thirty minutes after ischemia induction (E30), 17β-estradiol (E2) was administered as a single dose (280 μg/kg, intravenous). Sham-operated animals were used as controls.
RESULTS: I/R injury decreased intestinal motility and increased intestinal permeability, accompanied by reduced mesenteric endothelial nitric oxide synthase (eNOS) and endothelin (ET) protein expression. Additionally, the levels of serum injury markers and inflammatory mediators were elevated. Estradiol treatment improved intestinal motility, reduced intestinal permeability, and increased eNOS and ET expression. Levels of injury markers and inflammatory mediators were also reduced following estradiol treatment.
CONCLUSION: Collectively, our findings indicate that estradiol treatment can modulate the deleterious intestinal effects of I/R injury. Thus, estradiol mediates the improvement in gut barrier functions and prevents intestinal dysfunction, which may reduce the systemic inflammatory response.

DOI: https://doi.org/10.6061/clinics/2021/e2683
Trauma Surg Acute Care Open. 2021 ;6(1): e000703

Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study.

Taleen A MacArthur, Julie Goswami, Laurie Moon Tasson, Alexander Tischer, Kent R Bailey, Grant M Spears, Jing-Fei Dong, Matthew Auton, Rosemary Kozar, Myung S Park.

   Background: Von Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF-platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.
Methods: We assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.
Results: REAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0-264.0) vs. 92.0 (71.0-114.0), p<0.002) and at 6 hours (167.5 (108.0-312.5.0) vs. 92.0 (71.0-114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51-0.94) vs. 1.00 (0.89-1.09), p=0.010) and at 6 hours (0.653 (0.531-0.821) vs. 1.00 (0.89-1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.
Discussion: Trauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.
Level of evidence: Prospective case cohort study.

Keywords:  coagulopathy; multiple trauma; thromboembolism; venous thromboembolism

DOI:  https://doi.org/10.1136/tsaco-2021-000703
Shock. 2021 Apr 22.

Therapeutically Targeting Microvascular Leakage In Experimental Hemorrhagic Shock: A Systematic Review and Meta-Analysis.

Anoek L I van Leeuwen, Marieke P Borgdorff, Nicole A M Dekker, Charissa E van den Brom.

BACKGROUND: Microvascular leakage is proposed as main contributor to disturbed microcirculatory perfusion following hemorrhagic shock and fluid resuscitation, leading to organ dysfunction and unfavorable outcome. Currently, no drugs are available to reduce or prevent microvascular leakage in clinical practice. We therefore aimed to provide an overview of therapeutic agents targeting microvascular leakage following experimental hemorrhagic shock and fluid resuscitation.
METHODS: PubMed, EMBASE.com and Cochrane Library were searched in January 2021 for preclinical studies of hemorrhagic shock using any therapeutic agent on top of standard fluid resuscitation. Primary outcome was vascular leakage, defined as edema, macromolecule extravasation or glycocalyx degradation. Drugs were classified by targeting pathways and subgroup analyses were performed per organ.
RESULTS: Forty-five studies, published between 1973 and 2020, fulfilled eligibility criteria. The included studies tested 54 different therapeutics mainly in pulmonary and intestinal vascular beds. Most studies induced trauma besides hemorrhagic shock. Forty-four therapeutics (81%) were found effective to reduce microvascular leakage, edema formation or glycocalyx degradation in at least one organ. Targeting oxidative stress and apoptosis was the predominantly effective strategy (SMD: -2.18, CI [-3.21,-1.16], P < 0.0001). Vasoactive agents were found non-effective in reducing microvascular leakage (SMD: -0.86, CI [-3.07,1.36], P = 0.45).
CONCLUSION: Pharmacological modulation of pathways involved in cell metabolism, inflammation, endothelial barrier regulation, sex hormones and especially oxidative stress and apoptosis were effective in reducing microvascular leakage in experimental hemorrhagic shock with fluid resuscitation. Future studies should investigate whether targeting these pathways can restore microcirculatory perfusion and reduce organ injury following hemorrhagic shock.
SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018095432.

DOI: https://doi.org/10.1097/SHK.0000000000001796
Arterioscler Thromb Vasc Biol. 2021 Apr 29. ATVBAHA121316191

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

Zhongyue Pu, Yuuki Shimizu, Kazuhito Tsuzuki, Junya Suzuki, Ryo Hayashida, Kazuhisa Kondo, Yusuke Fujikawa, Kazumasa Unno, Koji Ohashi, Mikito Takefuji, Yasuko K Bando, Noriyuki Ouchi, John W Calvert, Rei Shibata, Toyoaki Murohara.

   OBJECTIVE: Lymphatic vessels are distributed throughout the body and tightly collaborate with blood vessels to maintain tissue homeostasis. However, the functional roles of lymphangiogenesis in the process of reparative angiogenesis in ischemic tissues are largely unknown. Accordingly, we investigated potential roles of lymphangiogenesis using a mouse model of ischemia-induced angiogenesis. Approach and Results: Male C57BL/6J mice were subjected to unilateral hindlimb ischemia, in which not only angiogenesis but also lymphangiogenesis was induced. Next, the excessive and prolonged tissue edema model significantly deteriorated reparative angiogenesis and blood perfusion recovery in ischemic limbs. Finally, implantation of adipose-derived regenerative cells augmented ischemia-induced lymphangiogenesis, which was accompanied by reduced tissue edema and inflammation, resulting in improving reparative angiogenesis and blood perfusion recovery. In addition, inhibition of lymphangiogenesis by MAZ51, a specific VEGFR3 (vascular endothelial cell growth factor receptor 3) inhibitor, resulted in enhanced inflammatory cell infiltration, gene expression of TNF (tumor necrosis factor)-α, IL (interleukin)-1β, IL-6, TGF (transforming growth factor)-β, angiostatin, vasohibin, and endostatin, and tissue edema, resulting in reduced angiogenesis.
CONCLUSIONS: The lymphatic system may have a clearance role of tissue edema and inflammation, which contribute to functional reparative angiogenesis in response to tissue ischemia. Modulation of lymphangiogenesis would become a novel therapeutic strategy for severe ischemic disease in addition to ordinary vascular intervention and therapeutic angiogenesis.

Keywords:  homeostasis; inflammation; lymphangiogenesis; perfusion; tissues

DOI:  https://doi.org/10.1161/ATVBAHA.121.316191
Shock. 2021 Apr 22.

Vagus Nerve Stimulation Protects Enterocyte Glycocalyx After Hemorrhagic Shock Via The Cholinergic Anti-Inflammatory Pathway.

Juan Wu, Yushuang Yin, Mingzhe Qin, Kun Li, Fang Liu, Xiang Zhou, Xiaoyang Song, Bixi Li.

INTRODUCTION: Electrical vagal nerve stimulation is known to decrease gut permeability and alleviate gut injury caused by traumatic hemorrhagic shock. However, the specific mechanism of action remains unclear. Glycocalyx, located on the surface of the intestinal epithelium, is associated with the buildup of the intestinal barrier. Therefore, the goal of our study was to explore whether vagal nerve stimulation affects enterocyte glycocalyx, gut permeability, gut injury, and remote lung injury.
METHODS: Male Sprague Dawley rats were anesthetized and their cervical nerves were exposed. The rats underwent traumatic hemorrhagic shock (with maintenance of mean arterial pressure of 30-35 mmHg for 60 min) with fluid resuscitation. Vagal nerve stimulation was added to two cohorts of animals before fluid resuscitation, and one of them was injected with methyllycaconitine to block the cholinergic anti-inflammatory pathway. Intestinal epithelial glycocalyx was detected using immunofluorescence. Intestinal permeability, the degree of gut and lung injury, and inflammation factors were also assessed.
RESULTS: Vagal nerve stimulation alleviated the damage to the intestinal epithelial glycocalyx and decreased intestinal permeability by 43% compared with the shock/resuscitation phase (P < 0.05). Methyllycaconitine partly eliminated the effects of vagal nerve stimulation on the intestinal epithelial glycocalyx (P < 0.05). Vagal nerve stimulation protected against traumatic hemorrhagic shock/fluid resuscitation-induced gut and lung injury, and some inflammatory factor levels in the gut and lung tissue were downregulated after vagal nerve stimulation (P < 0.05).
CONCLUSIONS: Vagal nerve stimulation could relieve traumatic hemorrhagic shock/fluid resuscitation-induced intestinal epithelial glycocalyx damage via the cholinergic anti-inflammatory pathway.

DOI: https://doi.org/10.1097/SHK.0000000000001791
Sci Rep. 2021 Apr 28. 11(1): 9215

The use of pulse pressure variation for predicting impairment of microcirculatory blood flow.

Christoph R Behem, Michael F Graessler, Till Friedheim, Rahel Kluttig, Hans O Pinnschmidt, Anna Duprée, E Sebastian Debus, Daniel A Reuter, Sabine H Wipper, Constantin J C Trepte.

Dynamic parameters of preload have been widely recommended to guide fluid therapy based on the principle of fluid responsiveness and with regard to cardiac output. An equally important aspect is however to also avoid volume-overload. This accounts particularly when capillary leakage is present and volume-overload will promote impairment of microcirculatory blood flow. The aim of this study was to evaluate, whether an impairment of intestinal microcirculation caused by volume-load potentially can be predicted using pulse pressure variation in an experimental model of ischemia/reperfusion injury. The study was designed as a prospective explorative large animal pilot study. The study was performed in 8 anesthetized domestic pigs (German landrace). Ischemia/reperfusion was induced during aortic surgery. 6 h after ischemia/reperfusion-injury measurements were performed during 4 consecutive volume-loading-steps, each consisting of 6 ml kg-1 bodyweight-1. Mean microcirculatory blood flow (mean Flux) of the ileum was measured using direct laser-speckle-contrast-imaging. Receiver operating characteristic analysis was performed to determine the ability of pulse pressure variation to predict a decrease in microcirculation. A reduction of ≥ 10% mean Flux was considered a relevant decrease. After ischemia-reperfusion, volume-loading-steps led to a significant increase of cardiac output as well as mean arterial pressure, while pulse pressure variation and mean Flux were significantly reduced (Pairwise comparison ischemia/reperfusion-injury vs. volume loading step no. 4): cardiac output (l min-1) 1.68 (1.02-2.35) versus 2.84 (2.15-3.53), p = 0.002, mean arterial pressure (mmHg) 29.89 (21.65-38.12) versus 52.34 (43.55-61.14), p < 0.001, pulse pressure variation (%) 24.84 (17.45-32.22) versus 9.59 (1.68-17.49), p = 0.004, mean Flux (p.u.) 414.95 (295.18-534.72) versus 327.21 (206.95-447.48), p = 0.006. Receiver operating characteristic analysis revealed an area under the curve of 0.88 (CI 95% 0.73-1.00; p value < 0.001) for pulse pressure variation for predicting a decrease of microcirculatory blood flow. The results of our study show that pulse pressure variation does have the potential to predict decreases of intestinal microcirculatory blood flow due to volume-load after ischemia/reperfusion-injury. This should encourage further translational research and might help to prevent microcirculatory impairment due to excessive fluid resuscitation and to guide fluid therapy in the future.

DOI: https://doi.org/10.1038/s41598-021-88458-3
Nat Rev Dis Primers. 2021 Apr 29. 7(1): 30

Trauma-induced coagulopathy.

Ernest E Moore, Hunter B Moore, Lucy Z Kornblith, Matthew D Neal, Maureane Hoffman, Nicola J Mutch, Herbert Schöchl, Beverley J Hunt, Angela Sauaia.

Uncontrolled haemorrhage is a major preventable cause of death in patients with traumatic injury. Trauma-induced coagulopathy (TIC) describes abnormal coagulation processes that are attributable to trauma. In the early hours of TIC development, hypocoagulability is typically present, resulting in bleeding, whereas later TIC is characterized by a hypercoagulable state associated with venous thromboembolism and multiple organ failure. Several pathophysiological mechanisms underlie TIC; tissue injury and shock synergistically provoke endothelial, immune system, platelet and clotting activation, which are accentuated by the 'lethal triad' (coagulopathy, hypothermia and acidosis). Traumatic brain injury also has a distinct role in TIC. Haemostatic abnormalities include fibrinogen depletion, inadequate thrombin generation, impaired platelet function and dysregulated fibrinolysis. Laboratory diagnosis is based on coagulation abnormalities detected by conventional or viscoelastic haemostatic assays; however, it does not always match the clinical condition. Management priorities are stopping blood loss and reversing shock by restoring circulating blood volume, to prevent or reduce the risk of worsening TIC. Various blood products can be used in resuscitation; however, there is no international agreement on the optimal composition of transfusion components. Tranexamic acid is used in pre-hospital settings selectively in the USA and more widely in Europe and other locations. Survivors of TIC experience high rates of morbidity, which affects short-term and long-term quality of life and functional outcome.

DOI: https://doi.org/10.1038/s41572-021-00264-3