Can these fourteen signs of sepsis be reduced or
blocked by restoration of blood flow?
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Circulation Complement Coagulation Blood Pressure
Inflammation D.I.C. RBC Deformability Tachycardia
Barrier Function Oxidation Apoptosis Adhesion
Mitochondrion Hypovolemia
Restoration of Circulation
VasoActive Therapy (VAT) uses overlapping neuromuscular stimulation at 32 places distributed on all four extremities. The contraction impulses are sequential, from distal to proximal at quarter-second intervals. This neuro-mechanical circulation increases blood flow toward the heart, thereby increasing venous return, preload, stroke volume, and blood pressure. VAT creates blood flow and shear stress (BF/SS).
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There are two immediate benefits to this: first, the window of opportunity for physicians to treat their patient is expanded by minutes or hours; and secondly, the restored flow helps distribute medicines throughout the body for greater efficacy. Most importantly, shear stress, through mechanotransduction, restarts the autocrine and paracrine processes. Davies, Berk, Pan, Traub and others have cataloged dozens of vasoactive substances that are flow dependent. Under conditions of normal, physiological flow, substances are increased that are mostly anticoagulent, antiinflammatory, vasodilatory, antiapoptotic, antiadhesive, and can change endothelial cells to a quiescent phenotype. Low shear rates, on the other hand, reverse most of these processes.
Davies PF., Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995 Jul;75(3):519-60.
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Reduction of Inflammation
Blood Flow and Shear Stress inhibits the expression of Monocyte Chemoattractant Peptide-1 (MCP-1) and monocyte adhesion induced by cytokines while reducing vascular cell adhesion molecule-1 (VCAM-1). Anti- inflammatory mediators such as NO, Prostacyclin and Krupple-Like Factor 2 are upregulated by shear.
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Pan S, Molecular mechanisms responsible for the atheroprotective effects of laminar shear stress, Antioxid Redox Signal. 2009 Jul;11(7)
Blood shear stress modulates Tumor Necrosis Factor (TNF) effects on EC by inhibiting TNF-mediated activation of MAP kinases.
Berk BC et al, Endothelial atheroprotective and anti-inflammatory mechanisms, Ann N Y Acad Sci. 2001 Dec;947:93-109
Thioredoxin-interacting protein (TXNIP) is a stress-responsive protein that inhibits thioredoxin (TRX) activity. Blood flow inhibited TNF activation of JNK/p38 and VCAM1 expression. Normal flow (12 dyn/cm2) was associated with decreased TXNIP expression and increased TRX activity.
Yamawaki H, et al, Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin interacting protein in endothelial cells, J. Clin. Invest. 115:733–738 (2005).
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Blocking of Complement Activation
Shear stress abrogates the complement-induced proinflammatory response of ECs by upregulation of the complement-inhibitory protein clusterin. Clusterin is a heterodimeric multifunctional glycoprotein capable of interacting with complement components C7, C8, and C9, thereby preventing the formation of the membrane attack complex (MAC). The results of the present study demonstrate that overexpression of clusterin is sufficient to prevent complement-induced activation of ECs. More importantly, clusterin upregulation is necessary for the complement-inhibitory effects of shear stress.
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Urbich C1, Fritzenwanger M, Zeiher AM, Dimmeler S., Laminar shear stress upregulates the complement-inhibitory protein clusterin : a novel potent defense mechanism against complement-induced endothelial cell activation., Circulation. 2000 Feb 1;101(4):352-5
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Blocking formation of complement activation products, especially during the organ failure stage of severe sepsis could be a potentially important therapeutic strategy.
Lupu F, Keshari RS, Lambris JD, Coggeshall KM., Crosstalk between the coagulation and complement systems in sepsis., Thromb Res. 2014 May;133 Suppl 1:S28-31.
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Blocking of Diffuse Intravascular Coagulation
DIC is a double edged problem: simultaneous coagulation and “leaky” vessels. Blood movement from VAT helps reduce blood viscosity and is thrombolytic, plus, shear stress increases thrombomodulin which triggers the protein C anticoagulent cascade. VAT's increased venous return and cardiac output raises pressures on the arterial side of capillaries, restoring pressure gradients.
Ankeny RH, Hinds M, Nerem R, Dynamic Shear Stress Regulation of Inflammatory and Thrombotic Pathways in Baboon Endothelial Outgrowth Cells, Tissue Engineering, Vol 19, 13-14, 2013
Activated Protein C is a physiologic inhibitor of thrombosis, and activation of endogenous Protein C may represent a novel and effective anti-thrombotic strategy.
Hanson SR1, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A., Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates., J Clin Invest. 1993 Oct;92(4):2003-12.
Shear stress improves barrier function by promoting glycocaylx formation, and increasing levels of heparin sulfate and hyaluronan.
Koo et al, Hemodynamic shear stress characteristic of atherosclerosis-resistant regions promotes glycocalyx formation, Am J Physiol Cell Physiol. 2013 Jan 15; 304(2): C137–C146.
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Reduction of Apoptosis
Physiological levels of laminar shear stress completely prevents apoptosis of human endothelial cells. The apoptosis-suppressive effects of shear stress are mediated by upregulation of Cu/Zn SOD and NO synthase. Shear stress-mediated inhibition of endothelial cell apoptosis was associated with complete inhibition of caspase-3-like activity, the central effector arm executing the apoptotic cell death program in endothelial cells. Shear stress-dependent upregulation of Cu/Zn SOD and NO synthase blocks activation of the caspase cascade in response to apoptosis-inducing stimuli.
Dimmeler S, Hermann C, Galle J, Zeiher M, Upregulation of Superoxide Dismutase and Nitric Oxide Synthase Mediates the Apoptosis-Suppressive Effects of Shear Stress on Endothelial Cells, Arterioscler Thromb Vasc Biol. 1999;19:656-664
Laminar shear stress completely inhibits apoptosis of edothelial cells, while increasing substances such as NO, transforming growth factor-b1 and platelet-derived growth factor, while reducing intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, monocyte chemoattractant protein-1 and tissue factor.
Urbich C, Walter D, Zeiher A, Dimmeler S, Laminar Shear Stress Upregulates Integrin Expression. Role in Endothelial Cell Adhesion and Apoptosis, Circ Res. 2000 Oct 13;87(8):683-9.
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Restoration of Barrier Function
Endothelial cells exposed to laminar shear stress express a thick glycocalyx on their surface that plays an important role in reducing vascular permeability.
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Wang G et al, Shear Stress Regulation of Endothelial Glycocalyx Structure Is Determined by Glucobiosynthesis, Arterioscler Thromb Vasc Biol. 2020 Feb;40(2):350-364.
One of the main functions of the glycocalyx is to help reduce vascular permeability. Shear stress increases heparan sulfate and hyaluronic acid which promotes glycocaylx formation.
Koo A et al, Hemodynamic shear stress characteristic of atherosclerosis-resistant regions promotes glycocalyx formation in cultured endothelial cells, Am J Physiol Cell Physiol 304: C137–C146, 2013.
Under shear stress of ~12 dyn/cm2, the glycocalyx was found to be thick and substantially covered the endothelial surface. Regenerating the degraded glycocalyx helps restore endothelial barrier dysfunction.
Harding IC et al, Endothelial barrier reinforcement relies on flow-regulated glycocalyx, a potential therapeutic target, Biorheology. 2019 ; 56(2-3): 131–149.
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Reduction of Inflammatory Adhesion
The major causes of adhesion are Vascular Cellular Adhesion Molecules (VCAM), InterCellular Adhesion Molecules (ICAM), and Monocyte Chemotactic Protein 1 (MCP1) which are reduced through shear stress.
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Endothelial cells under pulsatile flow exhibited significantly higher endothelial nitric oxide synthase (eNOS) activity and lower TNF-a-induced leukocyte adhesion which is consistent with a more quiescent anti-inflammatory and anti-thrombotic phenotype.
Joseph S. Uzarski,, Edward W. Scott,, Peter S. McFetridge, Adaptation of Endothelial Cells to Physiologically-Modeled, Variable Shear Stress, PLoS One. 2013;8(2)
Prolonged pulsatile shear stress induces the AMP-activated protein kinases/poly [ADP ribose] polymerase 1/B-cell lymphoma-6 pathway to inhibit expressions of VCAM-1, MCP-1, and MCP-3.
Jing Zhou, Yi-Shuan Li, Shu Chien, Shear Stress– Initiated Signaling and Its Regulation of Endothelial Function,Arterioscler Thromb Vasc Biol. 2014;34:2191-2198.
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Restoration of Erythrocyte Deformability
Blood-flow-generated shear stress directly improves the deformability of red blood cells through shear stress and hydraulic pressure. The autocrine function of the vascular endothelium plays an important role in regulation of flow mechanics of red blood cells in flowing blood. Two endothelial secretogogues, prostacyclin and nitric oxide, significantly improve deformability of red blood cells and thereby play an important role in regulation of functions of red blood cells in flowing blood.
Korbut RA, Adamek-Guzik T, Madej J, Korbut R., Endothelial secretogogues and deformability of erythrocytes., J Physiol Pharmacol. 2002 Dec;53(4 Pt 1):655-65.
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The ability of the entire RBC to deform is of crucial importance for the maintenance of normal circulation: it allows the passage of erythrocytes through narrow capillaries in the microcirculation and reduces blood viscosity. NO can markedly affect RBC deformability and therefore suggest the regulatory role of NO in maintaining normal RBC deformability.
Bor-Kucukatay M, Wenby RB, Meiselman HJ, Baskurt OK, Effects of nitric oxide on red blood cell deformability., Am J Physiol Heart Circ Physiol. 2003 May;284(5):H1577-84.
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Reduction of Coagulation
Shear stress, through upregulation of thrombomodulin (TM), activates the protein C anticoagulent cascade. TM enhances the rate of protein C activation by thrombin. Activated protein C cleaves and inactivates activated factors V and VIII, thereby exerting a potent negative feedback control on the generation of thrombin.
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Cadroy Y, The Thrombomodulin/Protein C/Protein S Anticoagulant Pathway Modulates the Thrombogenic Properties of the Normal Resting and Stimulated Endothelium, Arterioscler Thromb Vasc Biol.1997 ;17
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Removal of factor Xa by flow is the pre-dominant mechanism of flow influence on the initial stage of blood coagulation. Together with TFPI-induced inhibition of extrinsic tenase complex, these mechanisms make coagulation insensitive to flow at low shear rates and almost preventing coagulation at higher rates.
Shibeko AM, Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa, BMC Systems Biology 2010, 4:5
The expression of tissue factor pathway inhibitor, increased up to 2-fold in ECs under venous flow and up to 3-fold under arterial flow.
Westmuckett AD et al, Fluid flow induces upregulation of synthesis and release of tissue factor pathway inhibitor in vitro., Arterioscler Thromb Vasc Biol. 2000 Nov;20(11)
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Restoration of Mitochondrial Function
We observed significant increases in the expression of key genes related to mitochondrial biogenesis and mitochondrial quality control as well as mtDNA content and mitochondrial mass under shear stress, and mitochondrial respiratory function was enhanced.
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Boa Kim et al, Exercise-Mediated Wall Shear Stress Increases Mitochondrial Biogenesis in Vascular Endothelium, PLoS One, 2014 Nov 6;9(11):e111409
Shear stress exerted by laminar blood flow increases NO bioavailability, while reducing production of Reactive Oxygen Species. Therefore, shear stress safeguards endothelial redox homeostasis and counteracts endothelial dysfunction.
Lee ES et al, Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-β1, Sci Rep, 2017 Feb 17;7:42487.
Shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis. Shear stress, mitigates endothelial dysfunction by promoting mitochondrial biogenesis.
Kim JS, Kim B, Lee H, Thakkar S, Babbitt DM, Eguchi S, Brown MD, Park JY.,Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells. Am J Physiol Heart Circ Physiol. 2015 Aug 1;309(3):H425-33.
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Reduction of Oxidative Stress
An extensive list of genes with antioxidant properties, including NAD(P)H: menadione oxidoreductase, HMOX1, superoxide dismutase 1, superoxide dismutase 2, cyclo-oxygenase 2, (COX2), nitric oxide, thioredoxin reductase, glutathione peroxidase, glutathione-S transferase, g-glutamyl cysteine synthase, microsomal epoxide hydrolase, ferritin (heavy and light chains), glucose-6-phosphate dehydrogenase, cytochrome P450 1A1 and cytochrome P450 1B1, are upregulated by laminar shear stress.
Scott M Wasserman and James N Topper, Adaptation of the endothelium to Fluid Flow: in vitro analyses of gene expression and in vivo implications, Vascular Medicine 2004; 9: 35-45
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Reduction of Distributive Hypovolemia
Blood movement from VAT, by restoring circulation, evens out blood distribution by overcoming the heterogeneous flow patterns found in sepsis. The increased velocity of the blood lowers blood viscosity, plus, it is thrombolytic in nature. Restored cardiac output from BF/SS on the arterial side, raises pressure gradients across capillary beds, improving perfusion. Improved RBC deformability from VAT also serves to improve circulation/perfusion.
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Since the therapy utilizes electrically stimulated muscle contractions, the muscles are experiencing involuntary exercise. According to the Guyton and Hall physiology textbook, this will result in increased blood flow throughout the microcirculation and perfusing muscle tissues within seconds. Over time, this leads to increased vascularization.
John E. Hall PhD, Guyton and Hall Textbook of Medical Physiology, 13th Edition, (Philadelphia: Saunders,2015)
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Resolving Tachycardia
Possible causes for tachycardia in sepsis include low Mean Arterial Pressure (MAP), fever, hypoxia, low pH and calcitonin. Increase BF/SS will raise MAP and increase systemic VO2 through increased blood flow and cardiac output.
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Circulatory collapse is a common feature of sepsis leading to weak venous return. The heart, as a compensating mechanism, responds to arterial baroreceptors by causing tachycardia in an attempt to overcome the blood flow/oxygen deficits the sympathetic nervous system is reporting.
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VAT therapy, essentially a form of neuromechanically assisted circulation, restores blood flow to something approaching “normal” levels and allows the cardiovascular system, including heart rate, to return to normal levels.
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Restoration of blood pressure
Peroneal nerve stimulation resulted in up to 10-fold increase in BF rate.
Brevetti LS, Paek R, Brady SE, Hoffman JI, Sarkar R, Messina LM., Exercise-induced hyperemia unmasks regional blood flow deficit in experimental hindlimb ischemia., J Surg Res. 2001 Jun 1;98(1):21-6.
In a group of 25 patients, a series of 12 treatments using the VasoActiv device, each one lasting 45 minutes, over a four week period resulted in a 479% average increase in TCPO2.
Whitsett T, Unpublished clinical notes, 2010, Oklahoma University Health Sciences Center
Electrical impulses causing muscle contractions can lead to improved circulation and can boost venous return leading to increased preload, stroke volume and cardiac output. Blood pressure is raised as a consequence.
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John E. Hall PhD, Guyton and Hall Textbook of Medical Physiology, 13th Edition, (Philadelphia: Saunders,2015)
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