MUNI MED Microcirculation 1 Faculty of Medicine, Masaryk University Microcirculation Microcirculatory function is the main prerequisite for adequate tissue oxygenation and thus organ function. The microcirculation is formed by the smallest blood vessels (<100 urn diameter), and consists of arterioles, capillaries, and venules. Its purpose 1) provides access for oxygenated blood to the tissues and appropriate return of volume; 2) maintains global tissue flood flow, even in the face of changes in central blood pressure 3) ensures adequate immunological function and, 4) links local blood flow to local metabolic needs The main cell types endothelial cells t*B«i«« smooth muscle cells (mostly in arterioles) circulating blood cells Irom body's Microcirculation The structure and function of the microcirculation is highly heterogeneous in different organ systems Main determinants of capillary blood flow driving pressure, arteriolar tone, hemorheology capillary patency Starling Equation where: Jv = Kf [(Pc - Pj ) - a(TTc - TTj)] Jv Net fluid flux Filtration coefficient Pc Capillary hydrostatic pressure Pi Interstitial hydrostatic pressure o" Reflection coefficient ttc Capillary oncotic pressure TTj Interstitial oncotic pressure and [(Pc - Pi) - c(ttc - TTj)] is the Net driving pressure Transport of substances through capillary membrane Outwardly directed force: Hydrostatic pressure Inwardly direct force: osmosis 10% volume to lymphatics, and eventually returned to venous blood volume returns to capillary Inwardly directed Force: osmosis putwardly directed force: Hydrostatic pressure Arterial end Venous end Bfl Figure 19-21 Starling's law of the capillaries. Ac the arterial end of a capillary' rht outward driving force ul blood pressure is larger [lian che inwardly directed force of osmosis—thus fluid moves out of the vessel. At the venous end of a capillary the inward driving lorce of osmosis is greater than the outwardly directed force of hydrostatic pressure—thus fluid enters the vessel. About 90% ol the lluid leaving the capillary at the arterial end is recovered by the blood hefore it leaves the venous end. The remaining 10'*' is recovered by the venous blood eventually, by way of the lymphatic vessels (sec Chapter 20). At arterial end of capillary the difference in hydrostatic pressures is higher than the difference in osmotic pressures which causes filtration. At arterial end of capillary the difference in hydrostatic pressures is lower than the difference in osmotic pressures which causes reabsorbtion. 3/15/2022 5 Filtration = resorption + lymph flow A. Capillary fluid exchange Regulation of blood supply a) short-term regulation Vasodilatation NO - produced in the endothelium by constitutive (eNOS) and inducible (iNOS) synthase prostacyclins catecholamines histamine bradykinin p02l pCOo ,pH cGMP, cATVTP Vasoconstriction Endothelin ATM ADH Catecholamines Ca2+ Vessel lumen Special mechanisms Kidney Tubuloglomerular feedback Brain Vasodilation as a response to elevated pC02 in CSF Skin Blood flow control is linked to the control of body temperature Lungs hypoxia - vasoconstriction Vu4CI-K+ NB+-/H+ Aiipoliriwiit.' : atp-^aop/amf nos - im (PGE2) ATP-ADP/AMP VawjciHistricliun (L»w)C— ' —1 VMndilaiali.m j Hif-h g-o— n f Large vessels Mainly NO 8 Precapillary sphincters - splanchnic circulation • Under normal circumstances, only some capillaries allow the blood passage • When the precapillary sphincters open, more blood passes into the microcirculation Precapillary 'sphincters Arteriole Sphincters open Sphincters closed Catecholamine-induced Changes in the Splanchnic Circulation Volumes and flows in the splanchnic region (normovolemic healthy male adult) blood volume of approximately 70 ml/kg body weight. splanchnic organs constitute 10% of the body weight, but contain 25% of the total blood volume. nearly two thirds of the splanchnic blood {i.e. > 800 ml) can be autotransfused into the systemic circulation within seconds. liver 300 - 400 ml intestine 300 - 400 ml spleen 100 ml splanchnic vasculature serves as an important blood reservoir for the circulatory system. Anesthesiology® The Journal of the American Society of Anesthesiologists, Inc. From: Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics Anesthes. 2004;100(2):434-439. Distribution of Adrenoceptor Subtypes in the Splanchnic Vasculature Va s c u I a r bed Receptor Pre-portal Hepatic Pre-portal Hepatic subtype arterial arterial venous venous + + + + + + + + + + + Vasoconstriction decreases arterial flow, decreases venous capacitance, impedes venous outflow. Vasodilation increases arterial flow, facilitates venous outflow (see text for details). * refers only to peripheral (Xi-adrenoceptors; activation of central O(i-adrenoceptois decreases sympathoadrenal tone. Date of download: 3/21/2018 Copyright ©2018 American Society of Anesthesiologists. All rights reserved. From: Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics Anesthes. 2004;100(2):434-439. Sympathoadrenal output Date of download: 3/21/2018 Copyright ©2018 American Society of Anesthesiologists. All rights reserved. Regulation of blood supply b) Long-term regulation Days, months or years Mechanisms The blood vessels supplying the tissues increase their a. physical sizes b. Numbers Angiogenesis (buds from existing vessels) vs. vasculogenesis (de novo) 13 Neovascularisation Important for tissues with high metabolic requirements Mechanisms 1. Increase of vascularity Examples: scar tissue tumours Slow process in terminally differentiated tissues 2. Development of collateral circulation from already existing vessels When the flow is blocked, other collateral vessels open Dilation in the acute phase (neurogenic and metabolic factors) Remodelation and enlargement in the long term Comorbidity Genetics T Time Therapy Circulatory shock + inflammation HcsuE-dtaLion based on corrrc-tion (.1 -zypli- lii. In n:j: lyiizi r : -ill:. Liyyij::-- v:::: vn: I.lLiIh". Endothelium ^ynal r.rjnjducLim Coagulation Relation M icrocirculatory dysfunction RBCs ■ ■" 11 -11. ■ 11 - ■; -y Aggregation Oj transport Leukocytes Adhesion Cytokines ROS SMCS Adrenergic signaling "no Coagulation Microvascular ii ■ =i ■ ■ I ■■■ I M icrocirculatory 5 hunting 0,supply demand mismatch Hypoxia i Cellular distress Mitnr.hnnrlri;! Hi bern-dlion Apoptosis f Organ ) 4 failure J 5? •ntcrstitia: fluid - The lymphatic system Venous system Arterial system Arteriole (from heart) Tissue cells Interstitial fluid To venous system Lymphatic capillary 01 Figure 20-1 Role of the lymphatic system in fluid balance. Fluid from plasma flowing through the capillaries moves into interstitial spaces. Although much of this interstitial fluid is either absorbed by tissue cells or reabsorbed by capillaries, some ol the fluid tends to accumulate in the interstitial spaces. As this fluid builds up, it tends to drain into lymphatic vessels that eventually return the fluid to the venous blood. Lymphatic circulation The interstitial fluid enters lymphatic capillaries through loose junctions between endothelial cells. Lymph flow back to the thoracic duct is promoted by contraction of smooth muscle in wall of lymphatic vessels & contraction of surrounding skeletal muscle (lymphatic pump) Lymph carry proteins that cannot pass the capillary wall - necessary for maintaining the circulating protein concentration (failure leads to death within 24 hours) Lymphatic drainage is also the main way of lipid absorption in GIT Pathogens are eliminated in the lymphatic nodes Lymph flow Is increased when the fluid filtration from the capillaries to the interstitium is increased a) Elevated capillary hydrostatic pressure b) Decreased capillary oncotic pressure c) Increased interstitial oncotic pressure d) Increased capillary permeability -Lymphatic pump generates the negative hydrostatic pressure in the interstitium -When the interstitial pressure is permanently elevated to +1 - +2 mmHg, a compression of larger lymphatic vessels may occur 20 Lymphatic pump A. intrinsic Contraction of vessel wall following its dilation Generates pressure between 50- 100 mmHg B. extrinsic Intermittent compression from outside During exercise, the lymphatic flow increases up to 30-fold Oedema Cellular (cytotoxic) oedema - fluid collection in the cells usually caused by ischemia —► ionic pumps failure —► | cellular osmolarity most important inside the skull Interstitial oedema - fluid collection in the interstitium local vs. systemic causes - see further Effusion - fluid collection in body cavities Starling forces Actually pressures, or pressure gradients F = A . K . [(Pv - Pt) - c(ttv - TTt)], where: F... filtration A...filtration area K...membrane permeability coefficient (for water) o... membrane reflection coefficient (for proteins) The pressure gradient is directed outside at the arterial end and inside at the venous end of a capillary Exception: glomerular capillaries (high hydrostatic pressure - cave shock) Pulmonary capillaries - filtration slightly prevails all along the capillary (low both hydrostatic and oncotic pressure gradient) • But the excessive water is either drained by lymphatic vessels or breathed out, the lungs stay „dry" Capillary flow larger hydrostatic pressure tl smallor osmotic pressure capillary wall net flow out Of capillary Into tissues = 10mm smaller hydrostatic pressure U totic larger » A osmotic net flow into capillary = IDitwi The flow from the capillary little exceeds the reabsorption - lymphatic drainage Causes of interstitial oedemas and effusions Higher capillary hydrostatic pressure hypervolemia hyperperfusion i venous return Lower plasma oncotic pressure Increased capillary wall permeability Obstruction of the lymphatic vessels Hypervolemia - etiology 0^ (Poivdipsia) INSl FFK IFNT RENAL 11,0 E\( RETION 1^ . IJjpoprokwimsi H>0 RETENTION Massive Na intake t INSIEEICTENT RENAL Nil EXCRETION' Failing heart Failing kidney (iGFR) TMinmloconicotib I MSflnyf g SIADil 0 INST FFICIENT RENAL Up EXCRETION siADIi :\ hyponatremia hypervolemia normo/hypernatremic hypervolemia Capillary hyperperfusion and oedema Oedema during hypertensive crisis -important in brain circulation Oedema as a side effect of vasodilation treatment Odemas in venous diseases ^hydrostatic pressure at the venous end of a capillary Most often caused by venous valves insufficiency Deep venous thrombosis -asymmetric oedema Leg ulcers - most often of venous origin Increased filtration —> increased capillary permeability —► protein leak —► Jibrin cuff"—> tissue ischemia —> ulcer CVI classification Widmer: 1st stage: oedema 2nd stage: stiff oeadema with hyperpigmentation (hemosiderin) 3. stage: leg ulcer CEAP (clinical-etiology-anatomy-patophysiology) classification -detailed Heart failure and oedema •Left-sided failure • backward • ^hydrostatic pressure in pulmonary capillaries -> pulmonary oedema • Respiratoryfailure, pleural effusion (transudate) • Pulmonary hypertension -> secondary right-sided failure • forward • Systemic hypotensions shock • Organ failure (liver, kidneys, GIT, brain) • Muscular weakness, fatigue, cachexia •Right-sided failure • backward • ^hydrostatic pressure at the venous end of systemic • oedemas and effusions in systemic circulation (incl. pleural effusion) • anasarca (systemic oedema) • hepatomegaly, ascites • forward • isolated is a rarity • leads into 4/left ventricle preload -> left-sided forward failure Pulmonary oedema and pleural effusion Pulmonary oedema: fluid accumulation in the lung tissue („swamp") interstitial alveolar Both fluid filtration and resorption from/to pulmonary circulation Treatment: medication Pleural effusion: fluid between the parietal and visceral pleura (Jake") Fluid is filtrated mainly from the systemic circulation and reabsorbed mainly into the pulmonary circulation Treatment: medication or surgery In transudates, pulmonary oedema is often combined with pleural effusion X-ray Pulmonary oedema Bilateral pleural effusion Exudate vs. transudate Exudate 'hproteins 4/glucose cells present Etiology: 1) inflammation 2) tumour 3) Pulmonary embolism (results from local necrosis) 4) TBC Transudate 4/proteJns l^glucose cells absent Etiology: heart failure hyperhydration hypoproteinemia (liver failure, nephrotic syndrome) Hypoproteinemia Normal blood protein level approx. 62 - 82 g/l Decrease: malnutrition (kwashiorkor) malabsorption liver failure nephrotic syndrome There is no pulmonary oedema (low both hydrostatic and oncotic pressure gradient in pulmonary capillaries)! Inflammation and oedema Mechanisms of endothelial permeability Transcellular transport vesiculo-vacuolar organelles (WO) fenestrations (GIT, kidneys, endocrine glands) - with or without (glomerulus) a membrane Paracellular transport adherent junctions - formed mainly by cadherins dissolve when stimulated by: histamine bradykinin VEGF NO Tight junctions(esp. brain) - form a barrier Vascular mechanisms of inflammation Contraction of arterioles followed by vasodilation and increase in capillary permeability Vasoconstriction: endothelin, TXA2, PAF Vasodilation: iNOS, PGI2, bradykinin Cytokine production Normal Capillaries Lymphatic oedema Result of the impaired lymphatic drainage • Primary lymphatic oedema Idiopathic, a disorder of lymphatic system development Occurs usually during adolescence or early adulthood Sporadic or familiar occurrence • Secondary lymphatic oedema Secondary obstruction of lymphatic vessels (tumour, inflammation, trauma, iatrogenic - surgery radiation therapy, node extirpation) Filariasis in the tropics Oncologic diseases and their treatment in Europe Lymphatic oedema and tumours Mechanic compression of lymphatic vessels by a tumour Interstitial oedema around the tumour (inflammation, VEGF) compression of lymphatic drainage Lymphatic node metastases ^pitting and „non-pitting" oedema In the low-protein oedema (heart failure, liver failure, nephrotic syndrome), a pit remains after pressing by a finger In high-protein oedema (lymphatic oedema, inflammation, chronic oedema), no pit is present Bttora fKMuw to ludiul Ejjxmion na iniri M tjbd muni. Vasospastic disorders Disorders of small arterioles •spasms <-+ vasodilation •| sympathetic activity •Raynaud phenomenon • White: vasoconstriction, lack of blood, cold skin • Blue: | deoxyHb in capillary vasodilation and hypoxia • Red: blood flow restored, pain • Can be provoked by stress or cold Secondary vasospastic disorders Result from other diseases •Atherosclerosis •Connective tissue diseases •Vasculitis •Frostbites •Vibrations •Treatment: reduction of cod and stress, vasodilators Vasculitis • Inflammatory disorders based on immune pathology • Often immune complexes - 111 rol type in Gell and Coombs classification • Affects both microcirculation and larger vessels • Many vascular segments (x atherosclerosis) • Primary x secondary (rheumatoid arthritis, SLE, Sjogren syndrome) • Complications: Vasospasms Development of aneurysms Microthrombi Experiment Murine mesentery Adrenaline —> arterial vasoconstriction (mainly a1 receptors) Histamine —► arterial vasodilation (mainly H1 receptors)