MUNI MED Pulmonary perfusion and diffusion disorders Respiration process • Ventilation • Diffusion • Perfusion umonary gas exchange) Partial pressures Parciální tlaky o2 C02 /O/ \ PH20 PN2 Pa02 PC02 Atmosfér. (%) 20,93 (%) 0,03 (kPa) 0,8 (kPa) 79,04 (kPa) 21,06 (kPa) 0,04 vzduch (suchý) A 0 C 1 HC O Exspir. vzduch 15,1 4,3 b,o 10,i 10,0 D, 16 Alveolárni vzduch Arteriální 13,2 5,1 6,2 76,4 19,8 50 6,3 76,4 8 13,4 5,33 5,2 krev Venózní krev- 14-15 55 6,3 76,4 12,7 5,2 6,13 0,8 Differences between pulmonary and systemic circulation Pulmonary circulation Low pressure Distribution into different segments is regulated uniquely by local metabolic factors (hypoxic vasoconstriction) Total CO is determined by the kidneys and left ventricle (which react primarily to systemic circulation parameters), only resistance is regulated in the lungs Low pressure gradient between pulmonary veins and arteries (sufficient f BP in left atrium is mirrored in the pulmonary trunk) • Systemic circulation • High pressure • Distribution into different segments is regulated metabolically (hypoxic vasodilation) as well as centrally (nervous system, hormones) • Simultaneous regulation of resistance, mechanic function of the heart and circulating volume • Difference between arterial and venous pressures is approx. 100 mmHg, BP in right atrium does not have a direct impact on MAP • Most differences develop during the transition into postnatal circulation Fetal and postnatal circulatory system after birth Perfusion assessment - tota Right ventricular cardiac output: • (EDV-ESV) x HR (estimate - e.g. echocardiography) • termodilution (invasive) - rapid removal of cold marker in high flow (small area under curve) PA catheter 1 The cold injectant is introduced into the right atrium through the proximal injection port of the pul rnonary artery (PA) catheter. X ¥ í 3 The cooled blood then flows into the pulmonary artery, and a thermistor on the catheter registers the change in temperature of the blood. The injectant solution mixes completely with the blood in the right ventricle. Left atrium Left ventri cle Right ventricle Cardiac output Mabon: Area uneef (he tt*e™dilLJton cihvc 6fcaJtattH2lJv Am ink 6* hnrcdtttncne w*ft f« VfM fw( ^ dead space • Physiologically around 1/3 of tidal volume • anatomical VA/ Q equilibrium • VA/Q - dead space • 4^ VA/Q-shunt • VA/Q ~ 1 - no shunt or dead space, or combined shunt and dead space (which is, to a degree, standard) Pressures in pulmonary circulation • Pulmonary wedge pressure • A balloon-tipped catheter is carried by the blood flow into a branch of pulmonary artery, which is occluded this way („wedge") • Pressure measured by the tip of a catheter thus reflects the left atrium pressure and not pulmonary arterial pressure Noninvasive estimation of pulmonary pressures Dynamic pressure (regurgitation jet) static pressure » hydrostatic pressure Sum of Pressures (right atrium) \ (may be ignored) in pulmonary trunk Energy per unit volumejbefore - Energy perunit volunye after F= + 5pvf + pgh1 = P2 + 2PV22+ P9h2 Pressure Energy Kinetic Potential Energy Energy per unit per unit volume Flow velocity Flow velocity -"■yy 1 The often cited example of the Bernoulli Equation or "Bernoulli Effect" is the reduction in pressure which occurs when the fluid speed increases. A2< A1 P2< P, Ü Increased fluid speed, decreased internal pressure. Lower reliability than direct measurement, rather orientational (± 5 mmHg) 2D USG - estimation of right atrial pressure (Pra) • diameter of inferior vena cava (normal 1,5 - 2,5 cm) • change of inferior vena cava diameter during respiration (normal > 50 %) Doppler USG - tricuspid and pulmonary regurgitation (see Bernoulli equation) • Systolic pressure in pulmonary trunk: 4(TRVead)2 + Pra, where TRVend is a flow vefocity of tricuspid regurgitation at the end of the diastole • Diastolic pressure in pulmonary trunk: 4(PRVend)2 + Pra, where PRVend is a flow velocity of pulmonary regurgitation at the end of the diastole • Mean pressure in pulmonary trunk: 4(PRVbd)2 + P where PRVbd is a flow velocity of pulmonary regurgitation at the beginning of the diastole Result in torr; 1 kPa ~ 8 torr (this is why the velocities are multiplied by 4) ra' Pulmonary hypertension • Mean pulmonary pressure> 25 mmHg at rest or > 30 mmHg during effort • precapillary • hypoxic (e.g. COPD, esp. with chronic bronchitis predominance) • restrictive (e.g. ILD, pneumonectomy, severe emphysema) • vascular (e.g. pulmonary embolism, pulmonary arterial hypertension) • postcapillary (e.g. left-sided heart failure) • hyperkinetic (e.g. left-to-right shunts) Pressures and CO in the right heart in pulmonary hypertension Hemodynamic Scenarios: Pulmonary Artery Catheter Right Atrial Pressure (mmHg) Right Ventricular Pressure {mmHg) Mean Pulmonary Artery Pressure (mmHg) Pulmonary Capillary Wedge Pressure (mmHg) Cardiac Index (L/min/m2) Normal 0-8 15-25/0-8 <25 8-12 2.6-4.2 HFrEF, decompensated Pulmonary Arterial HTN Pulmonic Stenosis Tricuspid Stenosis Tricuspid Regurgitation * Left-to-Right Shunt t Right-to-Left Shunt t Tamponade/ Constrictive or Restrictive Cardiomyopathies f 1s <-> • HFrEF: heart failure with reduced EF • Cardiac index: CO per body surface area • In hyperkinetic PH 1^C0 of the right ventricle Pulmonary hypertension - right ventricle r normal L. early pah jL- end-stage pah card i a adaptive remodeling muscle contractility cardiomyocyte size neoangiogenesis metabolic stress inflammation vascular maladaptive remodeling/Failure *metabolic stress inflammation fRV output muscle contractifity — PASMCs V ) adaptive remodeling A cell proliferation 1 apoptosis resistance 1 blood flow adaptive remodeling 1 adventitial tickening Tcell proliferation 1 apoptosis resistance 1 blood flow , • Right ventricle-first concentric hypertrophy, then dilation and ^ RV EF • In advanced stage decreased RV EF during effort instead of the increase • Tricuspid and pulmonary regurgitation • Pulmonary vessels - 1^ wall thickness (which prevents pulmonary edema, but on the other hand f resistance - analogy to systemic hypertension) ECG in right ventricular hypertrophy www.ecg.utah.edu Right-sided axis deviation (+110°) Deep S in left-sided chest leads (correspons with right-sided axis orientation in transversal plane) Dominant R in VI (>0.7 mV) RBBB (incomplete or complete) P pulmonale (>0.25 mV) ST depressions, negative T in right-sided and inferior leads Other causes of right ventricular hypertrophy Inborn defects with left-to-right shunt Valvular diseases Arrhythmogennic cardiomyopathy (ACM, syn. arrhythmogennic right ventricular dysplasia - ARVD) • ECG correlate: £-wave - postexcitation of the right ventricle; VPC shaped as LBBB VENTRICLES FILL VENTRICLES PUMP Fat, fibrous tissue Etiology of pulmonary hypertension (classification) pulmonary arterial hypertension Primary pulmonary hypertension Inborn cardiac defects Left-sided heart failure - pulmonary venous hypertension Pulmonary diseases Pulmonary embolism Other (e.g. sarcoidosis, disorders of hematopoiesis, lymphatic vessels) Pulmonary arterial hypertension • Includes idiopathic hypertension, PAH in inborn cardiac defects, drug-induced PAH (anorectics), persisting PH of newborns or PAH related to connective tissue disorders • Approx. 5 % of all the pulmonary hypertension cases (of which 50 % is idiopathic PAH) • Heritable PAH - 6-10 % of cases - in 75 % mutation of BMPR2 (TGF-ß receptor) • proapoptotic effect on vascular smooth muscle + antiapoptotic effect on endothelium • Low penetrance, BMPR2 mutations or 4/expression frequent also in other types of PAH PAH pathogenesis 1) Vasoconstriction • Endothelial dysfunction • thromboxane A2 > prostacyclin (PGI2) 2) Vascular remodelation 3) microthrombi 4) plexiform lesions (irreversible) ÖMPK.2 hiplrwiuutftLttduy il:!-,TI.ilMiv ALK1 SMADI CAVi SAMJN EiVG SMAD9 tinrimn im'nljl ijk-1-ur.s.: IllJcCliüR ApjwlitLL«ippwMati( Jrugt loiic oil Tunica fldvr.n[iifl I uniLj mi. I■.I l'uniü iininu M*(ILI 3nJ sriiiK>|ll iimvile LeJI hyprrl rophh' 11 ■ I ■ I ■:.11 I: I tn I hTicimtioFJS hi 11 ia! iii ri :-i. ■ --- Reverslljtt Hulmniury arlfrul hyp«t20 % during vasodilation test • Administration of NO in the inhaled air / i.v epoprostenol (synthetic prostacyclin) or adenosine • Good reaction to Ca2+ channel blockers, better prognosis Lung transplantation TO > Y > 30% decrease in PVR (upper median) 1_ < 30% decrease in PVR (lower median) P = 0.039 0 12 3 4 Persons at Risk Follow-up Time (years) Upper 41 35 30 2D 19 Lower 39 25 19 13 12 Malhotra et al. 2011 nborn cardiac defects Cyanotic • transposition of the great vessels • left ventricular hypoplasia • tetralogy of Fallot □f right VEnlride Necyanoticke • aortic stenosis • aortic coarctation • atrial septal defect • patent foramen ovale • ventricular septal defect • persistent ductus arteriosus • bicuspid aortic valve (rather a variant) Pumonary hypertension in: • persistent ductus Botalli (~100 %) • ventricular septal defect (~50 %) • atrial septal defect (~10 %) Pulmonary hypertension in cardiac defects heart defects Uncomplicated Ieft-to-right shunt Mitral stenosis with 'reactive' pulmonary vascular remodeling Left-to-right shunt with reversible pulmonary vascular remodeling Eisenmenger syndrome Eisenmenger syndrome • severe form of pulmonary hypertension in left-to-right shunts • pulmonary pressures ~ MAP • irreversible remodelation of pulmonary vessels Pulmonary hypertension Adventia; proliferation of fibroblasts and macrophages Media; proliferation of smooth muscle celts. • Lefto-to-right shunt -> right-to -> systemic hypoxia Pulmonary embolism tVA/Q Causes: • thromboembolism • fat embolism e.g. fractures) - emboli can bass through bronchopulmonary junctions • air embolism (e.g. venous catheterization) • tumour embolism • complications of pregnancy • amniotic fluid • mola hydatidosa • septic embolism (e.g. cardiac valves) PE consequences • f dead space • shunt (anatomic - blood flow through bronchopulmonary juctions, PFO) • Hyperventilation (stimulation of juxtacapillary J-receptors - subj. dyspnea) • Partially compensates respiratory insufficiency • In milder forms of PE it leads into hyperkapnia and respiratory alkalosis • In severe form hypoxia and hyperkapnia - global resp. insufficiency • Pulmonary hypertension in >50 % obstruction (the same as in pumonary resections) • Cor pulmonale acutum RV dilation, right-sided regugitation, tachycardia, ^troponin, ^natriuretic peptides) • "forward" heart failure -> obstructive shock • Electromechanic disociation in severe embolism (circulatory arrest with normal electrical activity in ECG) • Opening of PFO -> shunt, paradoxical embolism • Subacute massive (succesive) embolism - development during 1-2 weeks Pulmonary embolism and CTEPH • Chronic thrombembolic pulmonary hypertension • follows approx. 1-4 % of pulmonary embolisms, but 25 % CTEPH is without PE history • Consequence of pulmonary embolism • bstruction of pulmonary circulation by unrecanalized thrombi • hyperperfusion in unaffected vessels -> remodeltion with increased vascular resistence (as in PAH) • Progression of dyspnea in a range of months Diffusion - residual volume measurement • Unlike other static parameters, residual volume and related parameters (functional residual capacity and total lung capacity) cannot be directly measured • Options: • Dilution methods (e.g. helium dilution method) • Nitrogen washout test • Whole body plethysmography - RV estimate by the pressure change during expirium Diffusion assessment Transfer factor for CO (TLCO) or diffusing capacity (DLCO) • Can be calculated from decrease of CO concentration (high affinity to Hb) and inert gas concentration (e.g. He - see dilution methods), which accounts for residual volume • Usually single breath method - compares the concentrations of CO and He in the inhaled air and after holding breath, the time of breath holding is other factor in the calculus • Mixture: He 14 %; CO 0,3 %; 02 21 %; N2 rest • Attention for: • Valsalva or Muller manoeuvre • Slow inspiration • Gas leak TLCO and DLCO assessment • DLCO: ml . mirr1. mmHg"1 • TLCO: mmol. mirr1. kPa-1 • 0100 = 1100x2,987 Va = Vi x He/Hee CO^CO^/Hei) kco = ln(C00/COe)/t Kco = kco/Pb DLCO = Vax Kco Va He volume exposed to helium (~TLC) CO, e... concentrations of He and CO at the initial and ending point of breath C00... initial alveolar concentration kco... rate constant for CO removal (i.e. elimination constant) Pb...dry air pressure (barometric - water vapor pressure at 37°C) ~713 mmHg = 95 kPa Kco... CO transfer coefficient Gas concentration (KoF Initial) - 100 - 80 Pulmonary capacity and diffusion in various diseases Abnormal pattern of DLCO,KCO and VA in various disease states: Conditions VA KCO DLCO Incomplete lung expansion (Diaphragm palsy, collapse) TT ■I Loss of lung units (lobectomy, fibrosis) T U Diffuse alveolar damage (ELD) u i ax Emphysema I U Pulmonay vascular disease Normal U u High pulmonary blood volume (Shunt, cardiac failure) Normal T T Alveolar hemorrhage I TTT TT Other causes of pulmonary diffusion changes (Nguyen et alv 2016) Table 1. Conditions and Other Variables Affecting Dlco Measurement Increase Dlco Decrease Dlco Exercise (due to recruitment of capillaries) Postexercise Supine position (due to increased pulmonary capillary blood volume) Standing MOIIer maneuver (Inspiration against closed mouth and nose after forced expiration) Valsalva maneuver Pulmonary hemorrhage Lung resection Polycythemia Pulmonary emphysema (affecting capillary or alveolar bed) Left-to-rig tit shunt (eg, atria! septal defect) Pulmonary vascular disease, including pulmonary arterial hypertension and chronic venous thromboembolism Obesity Interstitial lung diseases Asthma Anemia Chronic bronchitis without major emphysema Evening Morning Drugs (eg, amiodarone, bleomycin, methotrexate) Pregnancy Pulmonary lymphangitic carcinomatosis Dey et alv 2020 TLC0/DLC0 generally assess the area and permeability of alveocapillary barrier Kco/kco also much depends on pulmonary perfusion Lung volumes and diffusion parmeters in restrictive diseases In interstitial lung disease (ILD), there is parallel lowering of vital capacity and residual volume x high in extrapulmonary causes of restriction Generally, TLCO/DLCO is lower in pulmonary restriction or emphysema • It is high in high TLC value because of stretching and thinning of the alveolar membrane Kco (= DLCO/Va) decreases in high volumes (see emphysema) In low volumes, there is a compensation by perfusion and thus high Kco (e.g. extrapulmonary causes of restriction) In ILD, alveolocapillary barrier fibrotization follows - normal value of Kco is actually pathological in low lung volumes dnem- OxsSt reduced capillary blood volume thicker alveolar membrane increased capillary blood volume Lung at FRC Lung at TLC Interstitial lung disease • Concommitant disorder of ventilation (restriction) and diffusion, later perfusion Normal lung Inflammatory ILD pattern Fibrotic ILD pattern Classification of ILD 1) From known causes • silicosis • asbestosis • coal miner lung • farmer's lung - allergy • drug-induced / postradiation ILD 2) Idiopathic • Idiopathic pulmonary fibrosis (IPF) • Cryptogennic fibrotizing alveolitis 3) Granulomatous lesions • sarcoidosis 4) Other Anorganic dust Consequences of interstitial lung disease • Impaired diffusion - combination of shunt and dead space • Pulmonary restriction • Pulmonary hypertension • Hypoxemia leading to respiratory alkalosis (hypoxia in right-to-left shunt and J-receptor stimulation), later hyperkapnia with dead space • Prognosis is the worst in IPF (survival median 3-5 years), better in other causes Pulmonary edema Disorder of diffusion, perfusion, later ventilation (restriction) F = A.K.[(Pc-Pi)-a(rc-ri)] Most often a result of "backward" left-sided heart failure or hypervolemia (1^PC) Pulmonary inflammation (^K and Rarely in hypoproteinemia (rc) • ^ of interstitial fluid leads into ^ lymph flow and 4/ interstitial protein concentration • This maintains the low oncotic pressure gradient Pumonary edema and the main parameters of ventilation, diffusion + perfusion Types of pulmonary edema • Interstitial • Alveolar • Pulmonary edema x pleural effusion • Similarly as in pleural effusion or ascites, exudate and transudate can be distinguished • But the diagnostic proces is more difficult • Most pulmonary edemas are transsudates • Exception: ARDS Adult Respiratory Distress Syndrome (ARDS - „shock lung") • Result of lung inflammation in SIRS, pulmonary infections, aspiration of gastric juice, drowning • Exsudative phase (hours): cytokine release, leukocyte infiltration, pulmonary edema, destruction of type I pneumocytes • Proliferative phase: fibrosis, ^ dead space, proliferation of type II pneumocytes • Reparative phase: ^ inflammation, ^ edema, continuing fibrosis, in most cases permanent restrictive diseases Normal Alveolus tnterstitium Alveolar macrophage Injured Alveolus during the Acute Phase Prorata -rich edema fluid 'Sloughing of bronchial epithelium ,Necrol ic or apoptgiic 1ype) cell * Activated neutrophil loukotrisnss,^ , Oxidants **'r^x sSlÄ Ptoleases * . Red coll -Intact type II call Denuded basement membrane Hyaline membrane Migrating neutrophil jpnxmm Widened, edematous Endothelial b.isi.-mt-nl membrána Platelets Neutrophil Red cell Swollen, injured endothelial calls Fibroblast I Fibroblast Neutrophil Thank you for attention