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Φσσιολογία πνεσμονικής κσκλουορίας Ηρακλής Τσαγκάρης Επίκοσρος Καθηγητής Εντατικής Θεραπείας B’ Πανεπιστημιακή Κλινική Εντατικής Θεραπείας Διακλινικό Ιατρείο Πνεσμονικής Υπέρτασης – Νοσοκομείο ΑΤΤΙΚΟΝ Pulmonary Circulation Two Circulations in the Lung • Pulmonary Circulation. – Arises from Right Ventricle. – Receives 100% of blood flow. • Bronchial Circulation. – Arises from the aorta. – Part of systemic circulation. – Receives about 2% of left ventricular output. Pulmonary circulation • Pulmonary artery wall 1/3 as thick as aorta • RV 1/3 as thick as LV • All pulmonary arteries have larger lumen – more compliant – operate under a lower pressure – can accommodate 2/3 of SV from RV • Pulmonary veins shorter but similar compliance compared to systemic veins Total Pulmonary Blood Volume • 450 ml (9% of total blood volume) – reservoir function 1/2 to 2X TPBV – shifts in volume can occur from pulmonary to systemic or visa versa • e.g. mitral stenosis can pulmonary volume 100% • shifts have a greater effect on pulmonary circulation Systemic Bronchial Arteries • Branches off the thoracic aorta which supplies oxygenated blood to the supporting tissue and airways of the lung. (1-2% CO) • Venous drainage is into azygous (1/2) or pulmonary veins (1/2) (short circuit) – drainage into pulmonary veins causes LV output to be slightly higher (1%) than RV output & also dumps some deoxygenated blood into oxygenated pulmonary venous blood Pulmonary lymphatics • Extensive & extends from all the supportive tissue of lungs & courses to the hilum & mainly into the right lymphatic duct – remove plasma filtrate, particulate matter absorbed from alveoli, and escaped protein from the vascular system – helps to maintain negative interstitial pressure which pulls alveolar epithelium against capillary endothelium. “respiratory membrane” Pulmonary Circulation • In series with the systemic circulation. • Receives 100% of cardiac output (3.5L/min/m2). • RBC travels through lung in 4-5 seconds. • 280 billion capillaries, supplying 300 million alveoli. – Surface area for gas exchange = 50 – 100 m2 Alveolar Architecture Alveolar Airspace Alveolar Airspace Functional Anatomy of the Pulmonary Circulation • Thin walled vessels at all levels. • Pulmonary arteries have far less smooth muscle in the wall than systemic arteries. • Consequences of this anatomy- the vessels are: – Distensible. – Compressible. Pulmonary Circulation Pressures Pulmonary Vascular Resistance input pressure - output pressure Vascular Resistance = blood flow PVR = k • mean PA pressure - left atrial pressure cardiac output (index) mean PA pressure - left atrial pressure = 10 mmHg mean aorta pressure - right atrial pressure = 98 mmHg Therefore PVR is 1/10 of SVR Vascular Resistance is Evenly Distributed in the Pulmonary Circulation Reasons Why Pressures Are Different in Pulmonary and Systemic Circulations? • Gravity and Distance: – Distance above or below the heart adds to, or subtracts from, both arterial and venous pressure – Distance between Apex and Base Aorta Systemic 100 mmHg Pulmonary Main PA 15 mmHg Head 50 mmHg Apex 2 mmHg Feet 180 mmHg Base 25 mmHg Reasons Why Pressures Are Different in Pulmonary and Systemic Circulations? • Control of regional perfusion in the systemic circulation: – Large pressure head allows alterations in local vascular resistance to redirect blood flow to areas of increased demand (e.g. to muscles during exercise). – Pulmonary circulation is all performing the same job, no need to redirect flow (exception occurs during hypoxemia). • Consequences of pressure differences: – Left ventricle work load is much greater than right ventricle – Differences in wall thickness indicates differences in work load. Influences on Pulmonary Vascular Resistance Pulmonary vessels have: -Little vascular smooth muscle. -Low intravascular pressure. -High distensiblility and compressiblility. Vessel diameter influenced by extravascular forces: -Gravity -Body position -Lung volume -Alveolar pressures/intrapleural pressures -Intravascular pressures Influences of Pulmonary Vascular Resistance •Transmural pressure = Pressure Inside – Pressure Outside. –Increased transmural pressure-increases vessel diameter. –Decreased transmural pressure-decreased vessel diameter (increase in PVR). –Negative transmural pressure-vessel collapse. Pi Poutside •Different effects of lung volume on alveolar and extraalveolar vessels. Effect of Transmural Pressure on Pulmonary Vessels During Inspiration Resistance Length and Resistance 1/(Radius)4 Effect of Lung Volume on PVR Pulmonary Vascular Resistance During Exercise • During exercise cardiac output increases (e.g. 5-fold), but with little change in mean pulmonary artery pressure – How is this possible? input pressure - output pressure Vascular Resistance = blood flow • Pressure= Flow x Resistance • If pressure does not change, then PVR must decrease with increased blood flow • Passive effect (seen in isolated lung prep) – Recruitment: Opening of previously collapsed capillaries – Distensibility: Increase in diameter of open capillaries. Recruitment and Distention in Response to Increased Pulmonary Artery Pressure Control of Pulmonary Vascular Resistance • Passive Influences on PVR: Influence Effect on PVR Mechanism (above Increase Lengthening and Compression (below Increase Compression of Extraalveolar Vessels Decrease Recruitment and Distension Decrease in Dependent Regions Recruitment and Distension Interstitial Pressure Increase Compression Positive Pressure Ventilation Increase Compression and Derecruitment Lung Volume FRC) Lung Volume FRC) Flow, Pressure Gravity Regional Pulmonary Blood Flow Depends Upon Position Relative to the Heart Main PA Apex Base 15 mmHg 2 mmHg 25 mmHg Gravity, Alveolar Pressure and Blood Flow • Pressure in the pulmonary arterioles depends on both mean pulmonary artery pressure and the vertical position of the vessel in the chest, relative to the heart. • Driving pressure (gradient) for perfusion is different in the 3 lung zones: – Flow in zone may be absent because there is inadequate pressure to overcome alveolar pressure. – Flow in zone 3 is continuous and driven by the pressure in the pulmonary arteriole – pulmonary venous pressure. – Flow in zone 2 may be pulsatile and driven by the pressure in the pulmonary arteriole – alveolar pressure (collapsing the capillaries). Gravity, Alveolar Pressure, and Blood Flow Typically no zone 1 in normal healthy person Large zone 1 in positive pressure ventilation + PEEP Alveolar Dead Space Control of Pulmonary Vascular Resistance • Active Influences on PVR: Increase Decrease Sympathetic Innervation Parasympathetic Innervation -Adrenergic agonists Acetylcholine Thromboxane/PGE2 -Adrenergic Agents Endothelin PGE1 Angiotensin Prostacycline Histamine Nitric oxide Alveolar Hypoxemia Bradykinin Hypoxic Pulmonary Vasoconstriction • Alveolar hypoxia causes active vasoconstriction at level of precapillary arteriole. • Mechanism is not completely understood: – Response occurs locally and does not require innervation. – Mediators have not been identified. – Graded response between pO2 levels of 100 down to 20 mmHg. • Functions to reduce the mismatching of ventilation and perfusion. • Not a strong response due to limited muscle in pulmonary vasculature. • General hypoxemia (high altitude or hypoventilation) can cause extensive pulmonary artery vasoconstriction. Hypoxic pulmonary vasoconstriction Arterioles 30-200μm Barrier Function of Alveolar Wall • Capillary endothelial cells: – permeable to water, small molecules, ions. – barrier to proteins. • Alveolar epithelial cells: – more effective barrier than the endothelial cells. – recently found to pump both salt and water from the alveolar space. Starling’s Equation Q=K[(Pc-Pi) – ( c- i)] Q = flux out of the capillary K = filtration coefficient Pc and Pi = capillary and interstitial hydrostatic pressures c and i = capillary and interstitial osmotic pressures = reflection (sieving) coefficient Pulmonary Capillary dynamics • Starling forces (ultrafiltration) – Capillary hydrostatic P = 7 mmHg. – Interstitial hydrostatic P = -8 mmHg. – Plasma colloid osmotic P = 28 mmHg. – Interstitial colloid osmotic P = 14 mm • • • • Filtration forces = 15 mmHg. Reabsorption forces = 14 mmHg. Net forces favoring filtration = 1 mmHg. Excess fluid removed by lymphatics Normally Starling’s Forces Provide Efficient Protection • Normal fluid flux from the pulmonary capillary bed is approximately 20 ml/hr. – recall that cardiac output through the pulmonary capillaries at rest is ~5 l/min. – < 0.0066% leak. • Abnormal increase in fluid flux can result from: – Increased hydrostatic pressure gradient (cardiogenic pulmonary edema). – Decreased osmotic pressure gradient (cirrhosis, nephrotic syndrome). – Increased protein permeability of the capillary wall (ARDS). Pulmonary Pressures • Pulmonary artery pressure = 25/8 – mean = 15 mmHg • Mean pulmonary capillary P = 7 mmHg. • Major pulmonary veins and left atrium – mean pressure = 2 mmHg. Ορισμοί Ορισμός PAH (2004) • Μέση PAP> 25 mmHg (> 30 mmHg during exercise) Φσσιολογικές τιμές (10-15) • PCWP<15 mmHg (2-12) • PVR > 3 Wood units (2-3) Etiologic classification of pulmonary hypertension • MPA - PCWP = CO * PVR • MPA = CO * + PCWP PVR Pulmonary Hypertension: Define Lesion Post-Capillary PH (PCWP>15 mmHg; PVR nl) Respiratory Diseases VC RA RV PA PV PC Pre-capillary PH PCWP<15 mmHg PVR > 3 Wu LA LV LVEDP Ao Progression of vascular disease Schematic Progression of PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP PVR Right Heart Dysfunction PAP-PCW PVR= CO Time Pathways in the pathogenesis of PH Mechanisms of InflammationMediated Remodeling Kovacs, ERJ, 2012 Kovacs, ERJ, 2012 Kovacs, ERJ, 2012 PH due to left heart disease Venice 2004 Dana Point 2008 The accuracy of Doppler Echocardiography in assessing systolic PAP Arcasoy, AJRCCM, 2003 The accuracy of Doppler Echocardiography in assessing systolic PAP Arcasoy, AJRCCM, 2003 ημεία πνεσμονικής σπέρηαζης MDCTPA Διάμετρος > 29 mm PPV 97%, sens 87%, spec 89%. ΠΡΟΟΧΗ!! Διάμεηρος κύριας πνεσμονικής αρηηρίας < 29 mm ΔΕΝ ΑΠΟΚΛΕΙΕΙ πιθανή παροσζία πνεσμονικής σπέρηαζης. Όηαν η πνεσμονική αρηηρία > 29 mm και ο λόγος διαμέηροσ ημημαηικής αρηηρίας/ βρόγτο είναι > 1 ζε 3 από ηοσς 4 πνεσμονικούς λοβούς, ειδικόηηηα 100% για παροσζία πνεσμονικής σπέρηαζης. Διάμετρος > 29 mm Διάμετρος ΠΑ > διάμετρο ΑΑ Διάμετρος ΠΑ > διάμετρο ΑΑ Πνεσμονική αρηηρία > ανιούζα θωρακική αορηή: PPV 96%, spec 92%, ειδικά ζε αζθενείς < 50 εηών. ημεία πνεσμονικής σπέρηαζης MDCTPA + περικαρδιακή ζσλλογή ΚΑΚΟ προγνωζηικό ζημείο Pulmonary Veno-Occlusive Disease Septal lines Ground glass opacities Mediastinal lymphadenopathy 100% spec, 66% sens Resten et al. AJR 2004;183:6570 56 yo, PVOD Pulmonary Veno-Occlusive Disease •Vasodilators and especially prostanoids must be used with great caution because of the high risk of pulmonary edema. •HRCT is the investigation of choice Galie N, Hoeper MM, Humbert M, et al. Eur Resp J 2009; 34: 1219-1263. Montani Det al. Medicine 2008;87:220-233 Montani D et al. Eur Resp J2009;33:189-200 A. A. Frazier et al. Radiographics 2007;27:867882 Normal PVOD Normal PCH Future in imaging • Pathological remodeling occurs at the level of the pulmonary resistance vessels measuring approximately 100 μm in diameter. • If one were able to visualize these small vessels, recognize occlusions, and ultimately also identify hypertrophy of the smooth muscle cell layer, one might be able to predict the development of pulmonary hypertension at early stages when hemodynamics are still normal. New CTs • The current generation of 64-slice (and higher) multidetector CT (MDCT) scanners allow for better spatial (versus CMR) and temporal (versus older scanners) resolution, shorter scanning times and breath-holds, and electrocardiogram (ECG)-gated acquisition for detailed cardiac structural analysis. Future challenges • Accurate visualization of complex RV anatomies by advanced imaging techniques and precise measurement of blood volumes and flow may obviate invasive procedures in the future (??). Vasoreactivity testing with Epoprostenol Critical pathways in cardiology March 2012 Volume11 (1); 40-2 Arterial or upstream (Rup) and capillary-venou or downstream component: Rup% = 100 x (mPpa – Poccl)/(mPpa – Ppao dPAP-PAOP • • • • Normal value 1-2 mmHg Abnormal level > 5mmHg Prognostic marker >7mmHg Precapillary PH > 10mm Hg W dPAP-PAOP Isolated post capillary PH >15mmHg <7mmHg Combined post and precapillary PH >15mmHg >7mmHg Terminology Πμερμξμξπάθεια και PH: Μηςαμιζμξί Υπξνική αγγειξζύζπαζη Μείωζη ηηπ πμερμξμικήπ αγγειακήπ κξίηηπ Αύνηζη ηηπ καοδιακήπ παοξςήπ και ηηπ γλξιόηηηαπ ηξρ αίμαηξπ Χοόμια ρπξνία: Πειοαμαηικό μξμηέλξ δημιξρογίαπ PH Chen, JAP, 1995 Down regulation of endothelial NO synthase Decreased release of NO Down regulation of voltage gated K channels Increased intracellular free Calcium and smooth muscle contraction Neomuscularization of the arteriole, intimal thickening and medial hypertrophy Hypoxia induced remodeling Stenmark, Cirk Res, 2006 Hypoxia induced remodeling Stenmark, Cirk Res, 2006 Stenmark, Cirk Res, 2006 Upregulated/(downregulated) Suggested classification and management Undelying lung disease mPAP<25mm Hg mPap 2535mmHg mPAP > 35 mmHg COPD with FEV1>60% IPF with FVC > 70% No gross parenchymal or airway abnormalities on CT No PH No PAH treatment recommended Meet criteria for PAH Meet criteria for PAH PAH treatment PAH treatment guidelines may Guidelines may apply apply COPD with FEV1<60% IPF with FVC < 70% Combined pulmonary lesions and emphysema on CT No PH No PAH treatment recommended PH-COPD, PH-ipf, PH-cpfe No data support treatment severePH-COPD, PH-ipf, PH-cpfe Refer to center for individualized care RCTs needed WORLD SYMPOSIUM PH, 28 Feb 2013 Seeger W. PAH treatment bridge to TX