MUNI MED PATOPHYSIOLOGY OF CIRCULATORY SHOCK Lékařská fakulta Masarykovy univerzity I Shock - definition • Severe tissue hypoperfusion resulting in low supply of oxygen to the organs • Systemic hypotension (of various causes) is present • Inability of circulatory system to supply oxygen + nutrients and to remove metabolites —► organ damage —► failure • P = Q x R Vascular resistance R - systemic resistance (mostly arterioles) - afterload X R [kg.s'.m4]: can be obtained from Hagen-Poiseuill law: R = 8xr|xd/7ix r4,where: r| = viscosity d = length of the segment r = radius Vascular smooth muscle tone Vasodilatation ° NO - produced in the endothelium by constitutive (eNOS) and inducible (iNOS) synthase 0 prostacyclins 0 histamine 0 bradykinin 0 p02, pC02,pH 0 adenosine 0 catecholamines ° cGMRcAMP • Vasoconstriction 0 endothelin ° ATM ° ADH 0 catecholamines ° thromboxane A2 ° Ca2+ Cardiac output • Q~CO = SVxf • CO depends on a) cardiac function b) venous return (—^preload) • depends on circulating volume - physiologically regulated by the kidneys; during the shock, fluid loss can occur by different ways as well SV = EDV (enddiastolic volume) - ESV (endsystolic volume) • EF [%] = SV/EDV • EF don't inform about heart's diastolic function (myocardial relaxation may be assessed by tissue doppler - e.g. E/e') • In practice, CO increases with f only up to approx. 120/min -followed by a decrease caused by short diastole, low EDV and thus SV Cardiac function and venous function Changes of cardiac and venous function curves 101- i i D I ■a O ;\ Ventricular lunctEon curve s ,Volume loading Njf or venoconstriction Ts \ \ - J \. Volume \ depletion or X - venodilatiorK \ Ve nou a relum \ curves ^vA \ i i i i s^ \ s J 1 M 1 \: i -J i 0 2 4 6 8 Venous pressure (mmHg) (a) ID 10r Arteriolar dilation Normal \ . Arterioiar constriction \ 0 2 4 G 8 Venous pressure (mmHg) 10 In high venous (right atrial) pressures, the arteriolar blood passage is not a ..bottleneck", the importance of dilation / constriction for CO is thus smaller Hypervolemia Normal Moderate heart failure 0 2 4 6 8 Venous pressure (mmHg) (c) 0 2 4 6 8 10 Venous pressure (mmHg) „backward" effect + renal fluid retention „forward" effect Preload and afterload in the heart Law of Laplace for wall tension in a hollow sphere: a = , where: P....pressure inside the sphere r....inner radius of the sphere h....sphere wall thickness Preload - wall tension (N.m2 = Pa - force per area) before the systole 0 The main factor is venous return —> filling of cardiac ventricles Afterload - increase in wall tension during the systole 0 The main factor is a peripheral resistence, or pulmonary vascular resistence in the case of the right ventricle Preload is higher in the right ventricle, afterload is highe in the left one Jnterests" of the heart and perfused tissues Systemic hypotension is often associated with lower preload (e.g. severe hemorrhage, severe diarrhea) and/or afterload (e.g. anaphylaxis, sepsis) From the heart's viewpoint, 4/ preload and 4/ afterload are advantageous, regarding the blood supply to key organs they may be linked to circulatory failure caused by circulatory system inability to keep sufficient perfusion pressure (shock states) - the cause is, however, an extracardiac insult -> 4/ preload or 4/ afterload (or both -polytrauma) 0 But: heart must ensure its own perfusion Cardiac causes of shock 0 4/ inotropy 0 4/ lusitropy 0 4/ HR Muscular work of the heart - P-V diagram: Mitral valve opening I LAP>LVP [Mitral valve closure? :'c Lime diagram in the right ventricle P-V diagram and energy consumption • PE: potential energy • SW: stroke work • MV02 ~ (PE + SW) x f 9759 P-V diagram during changes of preload or afterload Endsystolic P-V curve Enddiastolic P-V curve Inotropy and lusitropy 1s inotropy („ability to contract") of the heart - shifts the endsystolic P-V curve up 1s lusitropy („ability to relax") of the heart -shifts the enddiastolic P-V curve down 0 In principle, the relaxation process isATP-dependent as well - as it is enabled by pumping out the cytosolic Ca2+ - which is, however, stable and independent on cycle phase \|/ inotropy or lusitropy decrease an area of P-V diagram (i.e. the cardiac work decreases - compensation by RAAS and SNS linked to an increase of preload and afterload follows similarly to the loss of peripheral resistence or circulating volume) Decreased '/ inotropy compensation Decreased Limit of Frank-Starling mechanism (active muscular force decreases) Period of Ulling 150 200 250 Left ventricular volume (ml) Passive contraction by elastic fibres (relaxation ability decreases) Phases of shock • Compensation of initiating cause • Decompensation • Refractory shock Compensatory mechanisms and their limits Activation of sympathetic nervous system (tens of seconds) p ( Activation of RAAS (cca I hour) •^Vasoconstriction (if possible) - but it leads M^toj^wer blood supply Vasodilatation in some tissues (esp. myocardium) Positively inotropic effect of SNS (if possible) - but at cost of higher metabolic requirements of the heart Increased heart rate - but CO decreases in high HR(>I50 bpm) Keeping circulating volume by lower diuresis - but at cost of acute renal failure Shift to anaerobic metabolism - but at cost of I ATP a | lactate (acidosis) Increased respiratory rate (but shallow breathing due to respiratory muscle hypoperfusion results in f relative dead space) Shift of saturation curve of hemoglobin to right (|2,3-DPG) Hyperglycemia - but there is decreased utilization of Glc in the periphery Tachykardie (> 100/min) Krátká diastola! (> 170/min) J_ 60 80 100 120 140 160 180 200 220 240 Heart rate fmiri'l Decompensated shock i BP I diuresis Brain hypoperfusion - involvment of mental functions Acrocyanosis Tachypnea "Golden hour" Shock at cellular leve Mitochondrial dysfunction (result of hypoxia) - lower production of ATP | ROS production by dysfunctional mitochondria Failure of ion pumps (e.g. Na/K ATP-ase —►fintracelular Ca2+) Activation of Ca2+ -dependent proteases Lysosomal abnormalities - release of lysosomal proteases I intracelular pH, f lactate ° promote hyperpolarization of muscle cells by opening K+ channels —► jCa2+ entry —► jsmooth muscle cell and cardiomyocyte I-,.. Ik ■ ! i ■ Mitochondria ri I OudJliv* phosphoryUaon 4 1 ATP t Anaeiahic glycolysis I- ikn' pump i 1 fnttiie at Cn'"' H.JO, »»N»- IGlycogm tUtfie—»lpH 1 1 SSL 5222 Detachment < fi I..-.. dr pa Ml ion contraction shock C» Vicious circles I)Vasodilatation <-> hypoperfusion 0 Endothelial cells contain two isoforms of nitric oxid synthase - constitutive (eNOS) and inducible (iNOS) ° In lasting hypoxia of endothelial cells there is increased iNOS activity (primarily physiological mechanism) ° f NO increases vasodilation and hypoperfusion ° Lactate acidosis —> hypotension (lactate - prognostic factor) 2) Myocardial hypoxia <-> lower contractility ° Lower myocardial perfusion leads into jCO, which further reduces coronary flow ° Myocardium does not benefit from the shift of Hb saturation curve -efficiency of 02 extraction is already at its maximum 3) Brain hypoperfusion <-> jSNS activity ° Lower perfusion of vasomotor centre leads first into SNS hyperactivity, which is then followed by its supression ° That leads into jbrain perfusion Refractory Other vicious circles in refractory shock *SIRS (systemic inflammation) *DIC (systemic activation of coagulation) Vicious cycle of shock Decreased cardiac ^^^^^^--^^^^ Ivgnous Melabdic I ntrac Gil uiar! Corofiary return acidosis fluid toss perfusion Parenchymal cell injury Cellular / aggregation \ Endothelial activation/ microcirculatory damage Soura: Briinicardi FC, Andersen DK, BillierTR, Dunn DL, HunterJG, Matthews JB, PollDdi REi Sthttrti1? Printiples of Surpryj Stfrfdition: httpiaocessmEdicineicarn Copyright1 © The McGraw-Hill Companies, [ne, All rights reserved. Systemic Inflammatory Response Syndrome (SIRS) Systemic activation of immune mechanisms SIRS may induce the shock + multiorgan failure on its own (vasodilation, of vascular permeability) Causes: ° infections (sepsis) • during the shock, it can be caused by the damage of intestinal barrier caused by GIT hypoperfusion ° shock caused by non-infectious causes (diffuse tissue damage in hypoxia) ° non-compatible blood transfusions ° radiation syndrome (esp. GIT form) Vascular reaction in SIRS Disseminated intravascular coagulopathy (DIC) Systemic exposure to thrombin Two phases: Formation of microtrombi (with local ischemia) Bleeding as a result of consummation of coagulation factors Consequence of the vessel wall damage Moreover, slower blood flow contributes to the extent of coagulation reactions DIC is especially frequent in septic shock igns of shock (benchmark) systolic BP < 90 mmHg mean BP < 65 mmHg lactate > 4 mmol/l diuresis < 0.5 ml/kg/h often: ° CI (= CO/body surface area) < 1.8 (not in septic shock) ° HR > 100/min (not in shock with bradycardia, neurogenic shock) Forms of shock a) Hypovolemic ("cold and dry") shock - low circulating volume, low preload b) Distributive ("warm and dry") shock - low resistance, low afterload, CO might be increased c) Cardiogennic ("cold and wet") shock - low CO in bad cardiac function, fluid congestion d) Obstructive shock - low preload of one ventricle in normovolemia and subsequent lowering of CO + congestion - pathophysiology similar to cardiogennic shock (but congestion occurs in one half of the circulation) Cardiac and venous function in shock Q [dm3.min1] vasodilation heartfailure P [mmHg] in right atrium Type of shock CO SVR PWP CVP Hypovolemic 4 t 1 1 Cardiogenic 1 t t t Distributive t 11 1 1 Hypovolemic shock: compensation by the vasoconstriction and cardiac mechanisms (but: CO is limited by low venous return) Distributive shock: compensation by cardiac mechanisms (vasoconstriction is usually impossible) Cardiogennic (and obstructive) shock: compensation by vasoconstriction SVR = [(MAP - CVP)/CO] x 80 Hypovolemic shock - causes • Acute bleeding • Burns, trauma 0 Combination of hypovolemia and vasodilation • Rapid development of ascites • Acute pancreatitis • Severe dehydratation ° Vomiting, diarrhoea 0 Excessive diuresis (e.g. in diabetes insipidus) Acute blood loss • Circulatory disorder (SBP < 100 mmHg, HR > 100/min) following the loss of 15% of circulating volume, shock in 30% of circulating volume • Immediate priorities are to maintain the tissue perfusion (crystalloids, colloids) and to stop bleeding (if possible), then blood derivates (erythrocytes + plasma + thrombocytes) Distributive shock - causes • Anafylactic shock Anafylactoid shock ° Mediators of mast cells, but without IgE ° E.g. snake venoms, radiocontrasts • Septic shock ° Role of bacterial lipopolysaccharides ° Bacterial toxins ° IL-l,TNF-a - stimulate synthesis of PGE2 and NO Neurogennic shock ° Vasodilatation as a result of vasomotoric centre (or its efferent pahways) impairment Development of anaphylactic reaction Sensibilization of Th- and B-cells and IgE production Opsonization of basophils a mastocytes ° IgE binds to FcsR (I a II) IgE-mediated degranulation of the mast cell and basophils following the repeated contact with an antigen ° mediator release primary (stored)- HISTAMIN (dominantly H, receptors) secondary (newly formed) - PG, LTA, PAF, bradykinin, cytokines,... ° efects vazodilatation, SMC contraction (incl. bronchoconstriction), Tcapillary permeability, chemotaxis, Tmucus secretion, platelet aggregation Anaphylactic and anaphylactoid reaction Anaphylaxis Severe, systemic, potentially life-threatening reaction following systemic exposition to an allergen ° Medication, food, insects, allergen extracts, latex ° Manifestation mucous membrane, derm: erythema, exanthema, pruritus, oedema resp. system: acute rhinitis, nasal obstruction, sneezing, irritation to cough, breathing problems, foreign body sensation in throat GIT: vomitus, colic, diarrhoea CV system: palpitation, tachycardia, hypotension, arrhythmia urogenital system: urine incontinence CNS: consciousness disorders, spasms ° Anaphylactoid reaction: Participation of mast cell mediators, but without IgE IgG, immune complexes, anaphylatoxins (C3a, C5a), myorelaxants, opiates, contrast matters, snake venoms... SIRS and sepsis SEPSIS STEPS SEPSIS 2 SIRS + Confirmed or suspected infection SEPSIS Sepsis + Signs of End Organ Damage Hypotension (SEP <90) Lactate >4 mmol Severe Sepsis with persistent: Signs of End Organ Damage Hypotension (SBP <90) Lactate >i Slides Courtesy of CurtisMerxitt, D.O. https://upload.wikimedia.org/wiki pedia/commons/a/ad/Sepsis_Steps.png Cardiogennic shock - causes Myocardial infarction Arrhythmias • Valvular disease (e.g. rupture of papillary muscles) Decompensation of heart failure in dilated/restrictive cardiomyopathy, amyloidosis • Overload by catecholamines ("tako-tsubo syndrome" - apical akinesia + basal hyperkinesia) Rupture of ventricular septum Obstructive shock - e.g. cardiac tamponade, massive pulmonary embolism, aortic dissection „Backward" acute heart failure - X-ray Pulmonary oedema Bilateral pleural effusion Organ complications in shock • Lungs =^o ARDS • Liver ° necrosis of hepatocytes • GIT ° stress ulcer ° Damage of intestinal mucosa by ischemic necrosis • Kidneys ° Acute renal failure in vasoconstriction of a. afferens ° Acute tubular necrosis during ischemia sepsis Adult Respiratory D „shock lung") istress Syndrome (ARDS - 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, f dead space, proliferation of type II pneumocytes Reparative phase: j inflammation, j edema, continuing fibrosis, in most cases permanent restrictive diseases Norma! Alveolus Alveolar air space Type I Mil Epithelial basomont membrane Inters! ilium Injured Alveolus during the Acute Phase Proiain-rich edema fluid Sloughing of bronchial epithelium Necroi if or apo ptoitc lype I cell Fted cell Intact type H call Endothelial cell Endothelial^ l:.!Si-i'iflll membrane Platelets Neutrophil Red cell Swollen, injured endothelial rails Fibrobiasl FJbrobls&l Neutrophil Multiorgan dysfunction syndrome (MODS) • Functional disorder of more organs at once (lungs, liver, GIT, kidneys, brain, heart) • It can develop after initial insult (days or weeks) • Hypermetabolism, catabolic stress • Can both preceed or result from SIRS (primary vs. secondary MODS) • Dysfunction —► failure Persistent MODS as an adaptation? n|/ mitochondria in tissues Analogy of hibernating myocardium (here, also 4/ of contractile apparatus and energy consumption) Gene expression similar to hibernating animals Later functional improvement is possible General principles of treatment • Treatment of underlying cause • Positively inotropic drugs, vasopressors (e.g. catecholamines - but: they can worsen the situation in obstructive shock) • Colloid solutions, crystalloid solutions (but: there is a risk of oedema in cardiogenic shock) • °2 • i.v. corticoids (anaphylaxis, SIRS?) • ATB (septic shock) • Mechanic circulation support (cardiogenic shock) • Anti-shock position (?) Crystalloid x colloid solutions • Crystalloid - ionic solutions (best normochloremic) ° They do not induce allergic reactions or alter coagulation • Colloids - high molecular weight compounds (hydroxyethylstarch, gelatine, albumin) ° Fluid distribution points more to intravascular compartment But less than is expected theoretically - damaged glycocalyx -defines water reabsorption Classic Starling equation Colloid osmotic pressure 1 Revised Starling equation L2. t O Colloid osmotic pressure Ml. ujmu milimiLl Gtyrcealyx. sub glycoralY* space ig.P Endothelium Mechanical circulatory support A B CD ECMO: Kaplan-Meier curves www.jtcvs.org/article/S0022-5223(18)30906-1/fulltext Trendelenburg („anti-shock") position 15-30° 1^ Venous return After collapse Inefficient in the long term Central venous catheter insertion (circulatory support administration) Worsens pulmonary ventilation Cave cardiogenic shock, bleeding, t ICP 80494573