bims-heshmo 2021-12-26 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–12–26
eight papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Blood product resuscitation mitigates the effects of aeromedical evacuation after polytrauma.
Intramuscular uptake of tranexamic acid during haemorrhagic shock in a swine model.
Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways.
A Novel Insight Into the Fate of Cardiomyocytes in Ischemia-Reperfusion Injury: From Iron Metabolism to Ferroptosis.
Dangers of hyperoxia.
Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury.
Friend or Foe? The Roles of Antioxidants in Acute Lung Injury.
Hyperspectral Imaging for the Evaluation of Microcirculatory Tissue Oxygenation and Perfusion Quality in Haemorrhagic Shock: A Porcine Study.

J Trauma Acute Care Surg. 2022 Jan 01. 92(1): 12-20

Blood product resuscitation mitigates the effects of aeromedical evacuation after polytrauma.

Taylor E Wallen, Kathleen E Singer, Mackenzie C Morris, Thomas Blakeman, Sabre M Stevens-Topie, Richard Strilka, Timothy A Pritts, Michael D Goodman.

BACKGROUND: The combined injury of traumatic brain injury and hemorrhagic shock has been shown to worsen coagulopathy and systemic inflammation, thereby increasing posttraumatic morbidity and mortality. Aeromedical evacuation to definitive care may exacerbate postinjury morbidity because of the inherent hypobaric hypoxic environment. We hypothesized that blood product resuscitation may mitigate the adverse physiologic effects of postinjury flight.
METHODS: An established porcine model of controlled cortical injury was used to induce traumatic brain injury. Intracerebral monitors were placed to record intracranial pressure, brain tissue oxygenation, and cerebral perfusion. Each of the 42 pigs was hemorrhaged to a goal mean arterial pressure of 40 ± 5 mm Hg for 1 hour. Pigs were grouped according to resuscitation strategy used-Lactated Ringer's (LR) or shed whole blood (WB)-then placed in an altitude chamber for 2 hours at ground, 8,000 ft, or 22,000 ft, and then observed for 4 hours. Hourly blood samples were analyzed for proinflammatory cytokines and lactate. Internal jugular vein blood flow was monitored continuously for microbubble formation with altitude changes.
RESULTS: Cerebral perfusion, tissue oxygenation, and intracranial pressure were unchanged among the six study groups. Venous microbubbles were not observed even with differing altitude or resuscitation strategy. Serum lactate levels from hour 2 of flight to the end of observation were significantly elevated in 22,000 + LR compared with 8,000 + LR and 22,000 + WB. Serum IL-6 levels were significantly elevated in 22,000 + LR compared with 22,000 + WB, 8,000 + LR and ground+LR at hour 1 of observation. Serum tumor necrosis factor-α was significantly elevated at hour 2 of flight in 8,000 + LR versus ground+LR, and in 22,000 + LR vs. 22,000 + WB at hour 1 of observation. Serum IL-1β was significantly elevated hour 1 of flight between 8,000 + LR and ground+LR.
CONCLUSION: Crystalloid resuscitation during aeromedical transport may cause a prolonged lactic acidosis and proinflammatory response that can predispose multiple-injury patients to secondary cellular injury. This physiologic insult may be prevented by using blood product resuscitation strategies.

DOI: https://doi.org/10.1097/TA.0000000000003433
Scand J Trauma Resusc Emerg Med. 2021 Dec 18. 29(1): 171

Intramuscular uptake of tranexamic acid during haemorrhagic shock in a swine model.

Håkon Kvåle Bakke, Ole Martin Fuskevåg, Erik Waage Nielsen, Erik Sveberg Dietrichs.

   BACKGROUND: Tranexamic acid (TXA) reduce mortality in bleeding trauma patients, with greater effect if administered early. Serum concentrations above 10 µg/mL are considered sufficient to inhibit fibrinolysis. Normally administered intravenously (i.v.), TXA can also be administered intramuscularly (i.m.). This could be advantageous in low resource and military settings, if sufficient serum concentrations can be reached in shocked patients with reduced muscular blood perfusion. Accordingly, we aimed to: (1) Determine the impact of shock on the pharmacokinetics of i.m. TXA, and (2) Compare the pharmacokinetics of i.v. versus i.m. TXA in ongoing shock.
MATERIALS AND METHODS: In a prospective experimental study, N = 18 Norwegian landrace pigs (40-50 kg), utilised in a surgical course in haemostatic emergency surgery, were subjected to various abdominal and thoracic trauma. After 1 h of surgery the animals were given 15 mg/kg TXA either i.v. or i.m. A control group without injury, or surgery, received intramuscular TXA. Blood samples were drawn at 0, 5, 15, 25, 35, 45, 60 and 85 min. The samples were centrifuged and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for TXA serum-concentrations.
RESULTS: In shocked pigs, i.m. administration resulted in a mean maximum serum concentration (Cmax) of 20.9 µg/mL, and i.v. administration a Cmax of 48.1 µg/mL. Cmax occurred 15 min after i.m. administration and 5 min after i.v. administration. In non-shocked swine, i.m. administration resulted in a Cmax of 36.9 µg/mL after 15 min. In all groups, mean TXA serum concentrations stayed above 10 µg/mL from administration to end of experiments.
CONCLUSIONS: I.m. administration of TXA in shocked pigs provides serum concentrations associated with inhibition of fibrinolysis. It may be an alternative to i.v. and intraosseous administration during stabilisation and transport of trauma patients to advanced medical care.

Keywords:  Bleeding; Coagulation; Injury; Trauma

DOI:  https://doi.org/10.1186/s13049-021-00983-2
Immunol Res. 2021 Dec 21.

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways.

Matthias Bock, Christian B Bergmann, Sonja Jung, Peter Biberthaler, Laura Heimann, Marc Hanschen.

  CD4+FoxP3+ regulatory T cells (CD4+ Tregs) are known to dampen inflammation following severe trauma. Platelets were shown to augment their posttraumatic activation in burn injury, but the exact mechanisms remain unclear. We hypothesized that platelet activation mechanisms via GPIIb/IIIa, fibrinogen, and PAR4 have an immunological effect and modulate CD4+ Treg activation early after trauma. Therefore, C57Bl/6 N mice were injected with tirofiban (GPIIb/IIIa inhibition), ancrod (fibrinogen splitting enzyme), or tcY-NH2 (selective PAR4 antagonist peptide) before inducing a third-degree burn injury of 25% of the total body surface area. Changes in coagulation, and local and systemic CD4+ Treg activity were assessed via rotational thromboelastometry (ROTEM®) and phospho-flow cytometry 1 h post intervention. The inhibition of GPIIb/IIIa and fibrinogen locally led to a higher basic activity of CD4+ Tregs compared to non-inhibited animals. In contrast, PAR4 disruption on platelets locally led to an increased posttraumatic activation of CD4+ Tregs. Fibrinogen led to complete elimination of coagulation, whereas GPIIb/IIIa or PAR4 inhibition did not. GPIIb/IIIa receptor and fibrinogen inhibition increase CD4+ Tregs activity independently of trauma. Both are crucial for thrombus formation. We suggest platelets trapped in thrombi are unable to interact with CD4+ Tregs but augment their activity when circulating freely. In contrast, PAR4 seems to reduce CD4+ Treg activation following trauma. In summary, GPIIb/IIIa-, PAR4-, and fibrinogen-dependent pathways in platelets modulate CD4+ Treg baseline activity, independently from their hemostatic functionality. PAR4-dependent pathways modulate the posttraumatic interplay of platelets and CD4+ Tregs.

Keywords:  CD4+ regulatory T cells; Fibrinogen; Glycoprotein IIb/IIIa; Protease-activated receptor 4; Thrombocytes; Trauma; αIibβ3

DOI:  https://doi.org/10.1007/s12026-021-09258-5
Front Cell Dev Biol. 2021 ;9 799499

A Novel Insight Into the Fate of Cardiomyocytes in Ischemia-Reperfusion Injury: From Iron Metabolism to Ferroptosis.

Jing-Yan Li, Shuang-Qing Liu, Ren-Qi Yao, Ying-Ping Tian, Yong-Ming Yao.

  Ischemia-reperfusion injury (IRI), critically involved in the pathology of reperfusion therapy for myocardial infarction, is closely related to oxidative stress the inflammatory response, and disturbances in energy metabolism. Emerging evidence shows that metabolic imbalances of iron participate in the pathophysiological process of cardiomyocyte IRI [also termed as myocardial ischemia-reperfusion injury (MIRI)]. Iron is an essential mineral required for vital physiological functions, including cellular respiration, lipid and oxygen metabolism, and protein synthesis. Nevertheless, cardiomyocyte homeostasis and viability are inclined to be jeopardized by iron-induced toxicity under pathological conditions, which is defined as ferroptosis. Upon the occurrence of IRI, excessive iron is transported into cells that drive cardiomyocytes more vulnerable to ferroptosis by the accumulation of reactive oxygen species (ROS) through Fenton reaction and Haber-Weiss reaction. The increased ROS production in ferroptosis correspondingly leads cardiomyocytes to become more sensitive to oxidative stress under the exposure of excess iron. Therefore, ferroptosis might play an important role in the pathogenic progression of MIRI, and precisely targeting ferroptosis mechanisms may be a promising therapeutic option to revert myocardial remodeling. Notably, targeting inhibitors are expected to prevent MIRI deterioration by suppressing cardiomyocyte ferroptosis. Here, we review the pathophysiological alterations from iron homeostasis to ferroptosis together with potential pathways regarding ferroptosis secondary to cardiovascular IRI. We also provide a comprehensive analysis of ferroptosis inhibitors and initiators, as well as regulatory genes involved in the setting of MIRI.

Keywords:  cardiomyocyte; cell death; ferroptosis; iron metabolism; ischemia-reperfusion injury

DOI:  https://doi.org/10.3389/fcell.2021.799499
Crit Care. 2021 Dec 19. 25(1): 440

Dangers of hyperoxia.

Mervyn Singer, Paul J Young, John G Laffey, Pierre Asfar, Fabio Silvio Taccone, Markus B Skrifvars, Christian S Meyhoff, Peter Radermacher.

  Oxygen (O2) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O2, i.e. inspiratory O2 concentrations (FIO2) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO2 > 100 mmHg) and, subsequently, hyperoxia (increased tissue O2 concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O2 toxicity and the potential harms of supplemental O2 in various ICU conditions. The current evidence base suggests that PaO2 > 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an "optimal level" which may vary for given clinical conditions. Since even moderately supra-physiological PaO2 may be associated with deleterious side effects, it seems advisable at present to titrate O2 to maintain PaO2 within the normal range, avoiding both hypoxaemia and excess hyperoxaemia.

Keywords:  ARDS; Acute ischaemic stroke; Cardiopulmonary resuscitation; Hyperoxaemia; Hyperoxia; Intracranial bleeding; Myocardial infarction; Reactive nitrogen species; Reactive oxygen species; Sepsis; Subarachnoidal bleeding; Surgical site infection; Trauma-and-haemorrhage; Traumatic brain injury

DOI:  https://doi.org/10.1186/s13054-021-03815-y
FEBS Lett. 2021 Dec 21.

Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury.

Andreas Herrlich.

  Homeostasis and health of multicellular organisms with multiple organs depends on interorgan communication. Tissue injury in one organ disturbs this homeostasis and can lead to disease in multiple organs, or multiorgan failure. Many routes of interorgan crosstalk during homeostasis are relatively well known, but interorgan crosstalk in disease still lacks understanding. In particular, how tissue injury in one organ can drive injury at remote sites and trigger multiorgan failure with high mortality is poorly understood. As examples, acute kidney injury can trigger acute lung injury and cardiovascular dysfunction; pneumonia, sepsis or liver failure conversely can cause kidney failure; lung transplantation very frequently triggers acute kidney injury. Mechanistically, interorgan crosstalk after tissue injury could involve soluble mediators and their target receptors, cellular mediators, in particular immune cells, as well as newly identified neuro-immune connections. In this review, I will focus the discussion of deleterious interorgan crosstalk and its mechanistic concepts on one example, acute kidney injury-induced remote lung injury.

Keywords:  acute kidney injury; acute lung injury; interorgan communication; multiorgan failure; remote inflammation; respiratory failure; secondary organ complications; systemic inflammation; tissue injury response

DOI:  https://doi.org/10.1002/1873-3468.14262
Antioxidants (Basel). 2021 Dec 07. pii: 1956. [Epub ahead of print]10(12):

Friend or Foe? The Roles of Antioxidants in Acute Lung Injury.

Yang Liu, Shujun Zhou, Du Xiang, Lingao Ju, Dexin Shen, Xinghuan Wang, Yanfeng Wang.

  Acute lung injury (ALI) is an acute hypoxic respiratory insufficiency caused by various intra- and extra-pulmonary injury factors. The oxidative stress caused by excessive reactive oxygen species (ROS) produced in the lungs plays an important role in the pathogenesis of ALI. ROS is a "double-edged sword", which is widely involved in signal transduction and the life process of cells at a physiological concentration. However, excessive ROS can cause mitochondrial oxidative stress, leading to the occurrence of various diseases. It is well-known that antioxidants can alleviate ALI by scavenging ROS. Nevertheless, more and more studies found that antioxidants have no significant effect on severe organ injury, and may even aggravate organ injury and reduce the survival rate of patients. Our study introduces the application of antioxidants in ALI, and explore the mechanisms of antioxidants failure in various diseases including it.

Keywords:  acute lung injury; antioxidants; oxygen radical; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox10121956
Biomedicines. 2021 Dec 03. pii: 1829. [Epub ahead of print]9(12):

Hyperspectral Imaging for the Evaluation of Microcirculatory Tissue Oxygenation and Perfusion Quality in Haemorrhagic Shock: A Porcine Study.

Maximilian Dietrich, Berkin Özdemir, Daniel Gruneberg, Clara Petersen, Alexander Studier-Fischer, Maik von der Forst, Felix C F Schmitt, Mascha O Fiedler, Felix Nickel, Beat Peter Müller-Stich, Thorsten Brenner, Markus A Weigand, Florian Uhle, Karsten Schmidt.

   BACKGROUND: The ultimate goal of haemodynamic therapy is to improve microcirculatory tissue and organ perfusion. Hyperspectral imaging (HSI) has the potential to enable noninvasive microcirculatory monitoring at bedside.
METHODS: HSI (Tivita® Tissue System) measurements of tissue oxygenation, haemoglobin, and water content in the skin (ear) and kidney were evaluated in a double-hit porcine model of major abdominal surgery and haemorrhagic shock. Animals of the control group (n = 7) did not receive any resuscitation regime. The interventional groups were treated exclusively with either crystalloid (n = 8) or continuous norepinephrine infusion (n = 7).
RESULTS: Haemorrhagic shock led to a drop in tissue oxygenation parameters in all groups. These correlated with established indirect markers of tissue oxygenation. Fluid therapy restored tissue oxygenation parameters. Skin and kidney measurements correlated well. High dose norepinephrine therapy deteriorated tissue oxygenation. Tissue water content increased both in the skin and the kidney in response to fluid therapy.
CONCLUSIONS: HSI detected dynamic changes in tissue oxygenation and perfusion quality during shock and was able to indicate resuscitation effectivity. The observed correlation between HSI skin and kidney measurements may offer an estimation of organ oxygenation impairment from skin monitoring. HSI microcirculatory monitoring could open up new opportunities for the guidance of haemodynamic management.

Keywords:  haemodynamic therapy; haemorrhage; hyperspectral imaging; microcirculation; monitoring; resuscitation; shock

DOI:  https://doi.org/10.3390/biomedicines9121829