bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2021–05–23
nine papers selected by
Andreia Luís, Ludwig Boltzmann Institute
  1. Extrathoracic multiple trauma dysregulates neutrophil function and exacerbates pneumonia-induced lung injury.
  2. Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia.
  3. The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats.
  4. P-selectin antibody treatment after blunt thoracic trauma prevents early pulmonary arterial thrombosis without changes in viscoelastic measurements of coagulation.
  5. An Ovine Model of Haemorrhagic Shock and Resuscitation, to Assess Recovery of Tissue Oxygen Delivery and Oxygen Debt, and Inform Patient Blood Management.
  6. Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs.
  7. Injury Prevention and long-term Outcomes following Trauma-the IPOT project: a protocol for prospective nationwide registry-based studies in Norway.
  8. Development of an Endovascular Model of Pelvic Hemorrhage Using Volumetric Computed Tomography Validation.
  9. Hypoxia-dependent signaling in perioperative and critical care medicine.
  1. J Trauma Acute Care Surg. 2021 Jun 01. 90(6): 924-934
    Extrathoracic multiple trauma dysregulates neutrophil function and exacerbates pneumonia-induced lung injury.
    Jennifer M Leonard, Christina X Zhang, Liang Lu, Mark H Hoofnagle, Anja Fuchs, Regina A Clemens, Sarbani Ghosh, Shin-Wen Hughes, Grant V Bochicchio, Richard Hotchkiss, Isaiah R Turnbull.
       BACKGROUND: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined as two or more severe injuries in at least two areas of the body, induces emergency hematopoiesis characterized by accelerated myelopoiesis in the bone marrow and increased myeloid cell frequency in the peripheral tissues. We hypothesized that PT alone induces priming of neutrophils, resulting in hyperactivation upon secondary exposure to bacteria and causing acute lung injury and increased susceptibility to secondary exposure to Pseudomonas aeruginosa pneumonia.
    METHODS: C57BL/6 mice were subjected to PT consisting of a lower extremity pseudofracture, liver crush injury, and 15% blood-volume hemorrhage. Pneumonia was induced by intratracheal injection of 5 × 106 CFU live P. aeruginosa or 1 × 107 of heat-killed P. aeruginosa (HKPA). For reactive oxygen species (ROS), studies polymorphonuclear neutrophils (PMNs) were isolated by immunomagnetic bead negative selection and stimulated ex-vivo with HKPA. Reactive oxygen species production was measured by immunofluorescence. For histology, lung sections were stained by hematoxylin-eosin and analyzed by a blinded grader.
    RESULTS: Polytrauma induced persistent changes in immune function at baseline and to secondary infection. Pneumonia after injury resulted in increased mortality (60% vs. 5% p < 0.01). Blood neutrophils from PT mice had higher resting (unstimulated) ROS production than in naive animals (p < 0.02) demonstrating priming of the neutrophils following PT. After intratracheal HKPA injection, bronchoalveolar lavage PMNs from injured mice had higher ROS production compared with naive mice (p < 0.01), demonstrating an overexuberant immunopathologic response of neutrophils following PT.
    CONCLUSION: Polytrauma primes neutrophils and causes immunopathologic PMN ROS production, increased lung injury and susceptibility to secondary bacterial pneumonia. These results suggest that trauma-induced immune dysfunction can cause immunopathologic response to secondary infection and suggests neutrophil-mediated pulmonary damage as a therapeutic target for posttrauma pneumonia.
    DOI:  https://doi.org/10.1097/TA.0000000000003147
  2. Front Pharmacol. 2021 ;12 616253
    Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia.
    Amaresh K Ranjan, Zhong Zhang, Seema Briyal, Anil Gulati.
      Background: Centhaquine (CQ) (Lyfaquin®) is in late stage clinical development as a safe and effective first-in-class resuscitative agent for hemorrhagic shock patients (NCT02408731, NCT04056065, and NCT04045327). Acute kidney injury (AKI) is known to be associated with hemorrhagic shock. Hence, effect of CQ on protection of kidneys from damage due to hemorrhagic shock was investigated. Methods: To assess effect of CQ on AKI in shock, we created a rat model with hemorrhagic shock and AKI. Renal arteries were clamped and de-clamped to induce AKI like ischemia/reperfusion model and hemorrhage was carried out by withdrawing blood for 30 min. Rats were resuscitated with CQ (0.02 mg/kg) for 10 min. MAP, heart rate (HR), and renal blood flow (RBF) were monitored for 120 min. Results: CQ produced a significant improvement in RBF compared to vehicle (p< 0.003) even though MAP and HR was similar in CQ and vehicle groups. Blood lactate level was lower (p = 0.0064) in CQ than vehicle at 120 min post-resuscitation. Histopathological analysis of tissues indicated greater renal damage in vehicle than CQ. Western blots showed higher HIF-1α (p = 0.0152) and lower NGAL (p = 0.01626) levels in CQ vs vehicle. Immunofluorescence in the kidney cortex and medulla showed significantly higher (p< 0.045) expression of HIF-1α and lower expression of Bax (p< 0.044) in CQ. Expression of PHD 3 (p< 0.0001) was higher, while the expression of Cytochrome C (p = 0.01429) was lower in the cortex of CQ than vehicle. Conclusion: Results show CQ (Lyfaquin®) increased renal blood flow, augmented hypoxia response, decreased tissue damage and apoptosis following hemorrhagic shock induced AKI, and may be explored to prevent/treat AKI. Translational Statement: Centhaquine (CQ) is safe for human use and currently in late stage clinical development as a first-in-class resuscitative agent to treat hemorrhagic shock. In the current study, we have explored a novel role of CQ in protection from hemorrhagic shock induced AKI, indicating its potential to treat/prevent AKI.
    Keywords:  acute kidney injury; centhaquine; hemorrhage; hypoxia inducible factors; resuscitation; shock
    DOI:  https://doi.org/10.3389/fphar.2021.616253
  3. Intensive Care Med Exp. 2021 May 17. 9(1): 23
    The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats.
    Anoek L I van Leeuwen, Nicole A M Dekker, Paul Van Slyke, Esther de Groot, Marc G Vervloet, Joris J T H Roelofs, Matijs van Meurs, Charissa E van den Brom.
       BACKGROUND: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function.
    METHODS: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis.
    RESULTS: Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p < 0.0001) and cremaster perfusion (12 ± 2 to 5 ± 2 perfused vessels, p < 0.0001) compared to baseline values. Fluid resuscitation partially restored both perfusion parameters, but both remained below baseline values (renal perfusion 120 ± 58, p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p < 0.0001 compared to baseline). Hemorrhagic shock increased circulating angiopoietin-1 (p < 0.0001), angiopoietin-2 (p < 0.0001) and soluble Tie2 (p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p < 0.0001). Hemorrhagic shock induced renal injury, as assessed by increased levels of plasma neutrophil gelatinase-associated lipocalin (NGAL: p < 0.05), kidney injury marker-1 (KIM-1; p < 0.01) and creatinine (p < 0.05). Vasculotide did not improve renal perfusion (p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p < 0.05).
    CONCLUSION: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.
    Keywords:  Acute kidney injury; Contrast-enhanced ultrasonography; Endothelium; Hemorrhage; Microcirculatory perfusion; Vascular leakage
    DOI:  https://doi.org/10.1186/s40635-021-00389-5
  4. J Trauma Acute Care Surg. 2021 Jun 01. 90(6): 1032-1039
    P-selectin antibody treatment after blunt thoracic trauma prevents early pulmonary arterial thrombosis without changes in viscoelastic measurements of coagulation.
    Linda M Schutzman, Rob R Rigor, Yung-Ling J Lin, An N Dang, Peter H Le, Harjeet B Singh, Bohan Yu, Peter H Wisner, Cristien C Musson, Isaiah J Clark, Joseph M Galante, Ian E Brown.
       INTRODUCTION: Previously, in a murine model of blunt thoracic trauma, we provided evidence of primary pulmonary thrombosis associated with increased expression of the cell adhesion molecule, P-selectin. In this study, mice are treated with P-selectin blocking antibody after injury to investigate the clinical viability of this antibody for the prevention of pulmonary thrombosis. In addition, viscoelastic testing is performed to investigate if P-selectin inhibition has a detrimental impact on normal hemostasis.
    METHODS: A murine model of thoracic trauma was used. Mice were divided into sham control and experimental injury groups. Thirty minutes after trauma, mice were treated with the following: P-selectin blocking antibody, isotype control antibody, low-dose heparin, high-dose heparin, or normal saline. At 90 minutes, whole blood was collected for characterization of coagulation by viscoelastic coagulation monitor (VCM Vet; Entegrion, Durham, NC). Mean clotting time, clot formation time, clot kinetics (α angle), and maximum clot firmness were compared between each treatment group.
    RESULTS: Mice that received P-selectin antibody 30 minutes after blunt thoracic trauma had four- to fivefold less (p < 0.001) arterial fibrin accumulation than those that received the isotype control. In both sham and trauma groups, compared with vehicle (normal saline) alone, no statistical difference was noted in any coagulation parameters after injection with P-selectin antibody, isotype control, or low-dose heparin. In addition, blinded histopathological evaluation yielded no difference in hemorrhage scores between injured mice treated with P-selectin blocking antibody and those treated with isotype antibody control.
    CONCLUSION: This study supports the clinical use of P-selectin blocking antibody for the prevention of pulmonary thrombosis by confirming its efficacy when given after a blunt thoracic trauma. In addition, we demonstrated that the administration of P-selectin antibody does not adversely affect systemic coagulation as measured by viscoelastic testing, suggesting that P-selectin antibody can be safely given during the acute posttraumatic period.
    DOI:  https://doi.org/10.1097/TA.0000000000003162
  5. Shock. 2021 May 19.
    An Ovine Model of Haemorrhagic Shock and Resuscitation, to Assess Recovery of Tissue Oxygen Delivery and Oxygen Debt, and Inform Patient Blood Management.
    Wayne B Dyer, John-Paul Tung, Gianluigi Li Bassi, Karin Wildi, Jae-Seung Jung, Sebastiano Maria Colombo, Sacha Rozencwajg, Gabriela Simonova, Sara Chiaretti, Fergal T Temple, Carmen Ainola, Tristan Shuker, Chiara Palmieri, Aryeh Shander, Jacky Y Suen, David O Irving, John F Fraser.
       BACKGROUND: Aggressive fluid or blood component transfusion for severe haemorrhagic shock may restore macrocirculatory parameters, but not always improve microcirculatory perfusion and tissue oxygen delivery. We established an ovine model of haemorrhagic shock to systematically assess tissue oxygen delivery and repayment of oxygen debt; appropriate outcomes to guide patient blood management.
    METHODS: Female Dorset-cross sheep were anaesthetised, intubated, and subjected to comprehensive macrohaemodynamic, regional tissue oxygen saturation (StO2), sublingual capillary imaging and arterial lactate monitoring, confirmed by invasive organ-specific microvascular perfusion, oxygen pressure and lactate/pyruvate levels, in brain, kidney, liver and skeletal muscle. Shock was induced by stepwise withdrawal of venous blood until mean arterial pressure (MAP) was 30mmHg, mixed venous oxygen saturation (SvO2) < 60%, and arterial lactate >4 mM. Resuscitation with PlasmaLyte® was dosed to achieve MAP > 65mmHg.
    RESULTS: Haemorrhage impacted primary outcomes between baseline and development of shock: MAP 89 ± 5 to 31 ± 5 mmHg (p < 0.01), SvO2 70 ± 7 to 23 ± 8% (p < 0.05), cerebral regional tissue oxygen saturation (StO2) 77 ± 11 to 65 ± 9% (p < 0.01), peripheral muscle StO2 66 ± 8 to 16 ± 9% (p < 0.01), arterial lactate 1.5 ± 1.0 to 5.1 ± 0.8 mM (p < 0.01), and base excess 1.1 ± 2.2 to -3.6 ± 1.7 mM (p < 0.05). Invasive organ-specific monitoring confirmed reduced tissue oxygen delivery; oxygen tension decreased and lactate increased in all tissues, but moderately in brain. Blood volume replacement with PlasmaLyte® improved primary outcome measures toward baseline, confirmed by organ-specific measures, despite haemoglobin reduced from baseline 10.8 ± 1.2 to 5.9 ± 1.1 g/dl post-resuscitation (p < 0.01).
    CONCLUSION: Non-invasive measures of tissue oxygen delivery and oxygen debt repayment are suitable outcomes to inform Patient Blood Management of haemorrhagic shock, translatable for pre-clinical assessment of novel resuscitation strategies.
    DOI:  https://doi.org/10.1097/SHK.0000000000001805
  6. Am J Physiol Regul Integr Comp Physiol. 2021 05 19.
    Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs.
    Stephanie Franzén, Erik Näslund, Helen Wang, Robert Frithiof.
      Angiotensin II (AngII) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma AngII levels and is associated with increased risk of acute kidney injury. We hypothesized that AngII antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared and randomized to intravenous losartan (1.5 mg kg-1 h-1, n=8) or an equal volume of intravenous Ringer's acetate (vehicle-treated, n=8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial blood pressure of <50 mmHg for 30 minutes. Plasma AngII levels, hemodynamics and oxygenation were assessed 60 minutes pre-hemorrhage, 30-minutes after the start of hemorrhage and 60 minutes post-hemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma AngII levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, AngII antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.
    Keywords:  hemorrhage; hypoxia; kidney; losartan; pig
    DOI:  https://doi.org/10.1152/ajpregu.00073.2021
  7. BMJ Open. 2021 May 18. 11(5): e046954
    Injury Prevention and long-term Outcomes following Trauma-the IPOT project: a protocol for prospective nationwide registry-based studies in Norway.
    Jo Steinson Stenehjem, Olav Røise, Trond Nordseth, Thomas Clausen, Bård Natvig, Svetlana O Skurtveit, Torsten Eken, Thomas Kristiansen, Jon Michael Gran, Leiv Arne Rosseland.
       INTRODUCTION: Traumatic injuries constitute a major cause of mortality and morbidity. Still, the public health burden of trauma in Norway has not been characterised using nationwide registry data. More knowledge is warranted on trauma risk factors and the long-term outcomes following trauma. The Injury Prevention and long-term Outcomes following Trauma project will establish a comprehensive research database. The Norwegian National Trauma Registry (NTR) will be merged with several data sources to pursue the following three main research topics: (1) the public health burden of trauma to society (eg, excess mortality and disability-adjusted life-years (DALYs)), (2) trauma aetiology (eg, socioeconomic factors, comorbidity and drug use) and (3) trauma survivorship (eg, survival, drug use, use of welfare benefits, work ability, education and income).
    METHODS AND ANALYSIS: The NTR (n≈27 000 trauma patients, 2015-2018) will be coupled with the data from Statistics Norway, the Norwegian Patient Registry, the Cause of Death Registry, the Registry of Primary Health Care and the Norwegian Prescription Database. To quantify the public health burden, DALYs will be calculated from the NTR. To address trauma aetiology, we will conduct nested case-control studies with 10 trauma-free controls (drawn from the National Population Register) matched to each trauma case on birth year, sex and index date. Conditional logistic regression models will be used to estimate trauma risk according to relevant exposures. To address trauma survivorship, we will use cohort and matched cohort designs and time-to-event analyses to examine various post-trauma outcomes.
    ETHICS AND DISSEMINATION: The project is approved by the Regional Committee for Medical Research Ethics. The project's data protection impact assessment is approved by the data protection officer. Results will be disseminated to patients, in peer-reviewed journals, at conferences and in the media.
    Keywords:  anaesthetics; clinical pharmacology; epidemiology; orthopaedic & trauma surgery; pain management
    DOI:  https://doi.org/10.1136/bmjopen-2020-046954
  8. J Endovasc Ther. 2021 May 21. 15266028211016422
    Development of an Endovascular Model of Pelvic Hemorrhage Using Volumetric Computed Tomography Validation.
    Hossam Abdou, Jonathan Du, Melike N Harfouche, Neerav Patel, Joseph Edwards, Michael Richmond, Noha Elansary, Jonathan J Morrison.
       PURPOSE: Uncontrolled pelvic hemorrhage from trauma is associated with mortality rates above 30%. The ability of an intervention to reduce blood loss from pelvic trauma is paramount to its success. The objective of this study was to determine if computed tomography volumetric analysis could be used to quantify blood loss in a porcine endovascular pelvic hemorrhage model.
    MATERIALS AND METHODS: Yorkshire swine under general anesthesia underwent balloon dilation and rupture of the profunda femoris artery, which was confirmed by digital subtraction angiography. Computed tomography angiography and postprocessing segmentation were performed to quantify pelvic hemorrhage volume at 5 and 30 minutes after injury. Continuous hemodynamic and iliofemoral flow data were obtained. Baseline and postinjury hemoglobin, hematocrit and lactate were collected.
    RESULTS: Of 6 animals enrolled, 5 survived the 30-minute post-injury period. One animal died at 15 minutes. Median volume of pelvic hemorrhage was 141±106 cm3 at 5 minutes and 302±79 cm3 at 30 minutes with a 114% median increase in hematoma volume over 25 minutes (p=0.040). There was a significant decrease in mean arterial pressure (107 to 71 mm Hg, p=0.030) and iliofemoral flow (561 to 122 mL/min, p=0.014) at 30 minutes postinjury, but no significant changes in hemoglobin, hematocrit, or heart rate.
    CONCLUSION: Computed tomography volumetric analysis can be used to quantify rate and volume of blood loss in a porcine endovascular pelvic hemorrhage model. Future studies can incorporate this approach when evaluating the effect of hemorrhage control interventions associated with pelvic fractures.
    Keywords:  CT volumetric analysis; endovascular trauma; hemorrhage control; pelvic hemorrhage; retroperitoneal hemorrhage; vascular trauma
    DOI:  https://doi.org/10.1177/15266028211016422
  9. J Anesth. 2021 May 18.
    Hypoxia-dependent signaling in perioperative and critical care medicine.
    Kiichi Hirota.
      A critical goal of patient management for anesthesiologists and intensivists is to maintain oxygen homeostasis in patients admitted to operation theaters and intensive care units. For this purpose, it is imperative to understand the strategies of the body against oxygen imbalance-especially oxygen deficiency (hypoxia). Adaptation to hypoxia and maintenance of oxygen homeostasis involve a wide range of responses that occur at different organizational levels in the body. These responses are greatly influenced by perioperative patient management including factors such as perioperative drugs. Herein, the influence of perioperative patient management on the body's response to oxygen imbalance was reviewed with a special emphasis on hypoxia-inducible factors (HIFs), transcription factors whose activity are regulated by the perturbation of oxygen metabolism. The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who made outstanding achievements in this field. While previous studies have reported the effect of perioperatively used drugs on hypoxia-induced gene expression mediated by HIFs, this review focused on effects of subacute or chronic hypoxia changes in gene expression that are mediated by the transcriptional regulator HIFs. The clinical implications and perspectives of these findings also will be discussed. Understanding the basic biology of the transcription factor HIF can be informative for us since anesthesiologists manage patients during the perioperative period facing the imbalances the oxygen metabolism in organ and tissue. The clinical implications of hypoxia-dependent signaling in critical illness, including Coronavirus disease (COVID-19), in which disturbances in oxygen metabolism play a major role in its pathogenesis will also be discussed.
    Keywords:  Anesthesia; Hypoxia; Hypoxia-inducible factor; Oxygen metabolism; Perioperative care
    DOI:  https://doi.org/10.1007/s00540-021-02940-w
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