Septic Shock Definition & Epidemiology PDF

Septic Shock definition Sepsis is A life-threatening organ dysfunction caused by a dysregulated host response to infection (SOFA score of ≥2) associated with in-hospital mortality >10% Septic Shock is a subset of sepsis with profound circulatory, cellular, and metabolic abnormalities with higher m...

Septic Shock definition Sepsis is A life-threatening organ dysfunction caused by a dysregulated host response to infection (SOFA score of ≥2) associated with in-hospital mortality >10% Septic Shock is a subset of sepsis with profound circulatory, cellular, and metabolic abnormalities with higher mortality. Vasopressor requirement (MAP ≥ 65 mmHg) and serum lactate level > 2 mmol/L in the absence of hypovolemia, associated with in-hospital mortality > 40% 2016 SEPSIS—3 Singer et al. Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. © AOP Health 1 Septic Shock epidemiology Sepsis incidence is 288 per 100,000 person-years, and hospital mortality is 17–26%. (data from high-income countries) sepsis incidence maybe high as 4000 per 100,000 person-years with a mortality >50% (data from lower socio-demographic areas) -It affects between 47 and 50 million people every year, at least 11 million die – one death every 2.8 seconds. -20% of all deaths worldwide are associated with sepsis. -Depending on country, mortality varies between 15% and more than 50 %. Fleischmann, M.C.; International Forum of Acute Care Trialists. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am. J. Respir. Crit. Care Med. 2016, 193, 259–272 Rudd, K.E.; et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet 2020, 395, 200–211. https://www.worldsepsisday.org/sepsis © AOP Health 2  Septic Shock physiopathology Infection Severe sepsis = infection + organ dysfunction Severe Hypovolemia hypotension Vasoplegia Shock Cardiac Dysfonction © AOP Health 3  Septic Shock physiopathology © AOP Health 4 Septic Shock physiopathology vascular inflammation especially at 5 endothelium yields to a Vasoplegia and fluid leakage which constitute the distributive shock. Septic Shock is the exemple of distributive shock the most frequently encountered in ICU. © AOP Health 5  Septic Shock physiopathology La réponse immunitaire dans le sepsis et le choc septique conduit à l'altération des fonctions de l'organe − Activation initiale des monocytes / macrophages et des granulocytes neutrophiles  Libération de médiateurs pro-inflammatoires (cytokines) tels que le TNF (facteur de nécrose tumorale), l'interleukine et l'interféron − Activation du système de coagulation (en activant le facteur tissulaire) − Inhibition d'anticoagulants physiologiques (par exemple antithrombine III)  Coagulation intravasculaire disséminée − Dommages des cellules endothéliales − Troubles de la microcirculation  Passage du liquide intravasculaire dans l'espace interstitiel 6  Déplétion du volume intravasculaire prononcée − Formation d'oxyde d'azote (NO) (vasodilatateur puissant)  Hypotension − Fonction cardiaque altérée  Fraction d'éjection réduite − Dysfonction endocrinienne  Échec relatif du cortex surrénalien (cortisol )  Déplétion de Vasopressin et  de la sécrétion d'insuline © AOP Health 6  Different categories of shock Hemodynamic Shock is defined as acute circulatory insufficiency that impact significantly oxygenation and metabolism of tissues and organs. Shock is associated with: hypotension non spontaneously reversible Tachycardia (usually) Often with tachypnea, oliguria and cognitive 7 dysfonction + biological disturbance : lactic acidosis, reflecting cellular hypoxia 4 types of shock: − Hypovolemic shock (ex.hemorrage) − cardiogenic shock − distributive shock (ex. septic, anaphylaxis) Fluid, Hypovolemia, Pump, Obstructibe − Obstructive shock (ex. tamponade) Leak Volume failure Obstacle © AOP Health 7 Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013 Oct 31;369(18):1726-34  Different categories of shock Initial evaluation of shock: As shown by the algorithm on previous slide for evaluating patients in shock, The figure belows represents schematically the 4 principal types of shock, Septic Shock is distributive as it combines vasoplegia + increased vascular permeability. 8 It belongs to vasoplegic shock categories. Vasoplegia = state of permanent dilatation of arterioles associated with decreased vascular tone © AOP Health Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013 Oct 31;369(18):1726-34 8 9 Vasoplegic shock and inflammation Bleeding Infection Trauma Burn Surgery (cardiac) Post cardiac arrest Sepsis and Vasoplegic septic shock Systemic inflammatory shock Response Syndrome © AOP Health 9 https://www.nature.com/scitable/content/pamps-and-damps-in-the-inflammatory-response-14464749  Septic shock - Diagnosis Hemodynamic and organ perfusion  Hypotension : MAP measurement (not SAP) < 65mmHg; => DAP can help to diagnose vasoplegia  Evaluation of tissues perfusion : lactate > 2 mmol/L + mottling score or Capillary Refill Time … Organe failure: in order to complete organ failure evaluation, SOFA score, listing all of items evaluating different organes a,nd vital function is calculated : 10  Lung function: PaO2 /FiO2 mmHg  Coagulation/Hemostasis : Platelets An drop of >2 in SOFA score  Liver function : bilirubine qualifies for sepsis  Cardiovascular function : hypotension  Cognitive (CNS) function : score de Glasgow  Renal function : creatinine Ratio PaO2 /FiO2 = ratio of partial arterial pressure of oxygen and fraction of oxygen inspired  compares level of oxygen actually in blood and concentration pof oxygen in inspired air. Singer M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 © AOP Health 10  Septic shock - Diagnosis Score SOFA : Sequential Organ Failure Assessment 11 © AOP Health SOFA Score > 9 is usually associated with a mortality of 40 to 50% 11 Vasopressin depletion in septic shock Levels of Vasopressin during late phase are lower than during early phase of septic shock. Vasopressin depletion may contribute to vasoplegic shock © AOP Health Mutlu et al. Intensive Care Med (2004) 30:1276–1291 12 Vasopressin depletion in septic shock Levels of Vasopressin are initially high and decrease rapidly to a lower level during late phase Matériel Médical et Scientifique – Confidentiel – Non reproductible © AOP Health Sharshar et al. Crit Care Med 2003; 31:1752–1758 13 Vasopressin depletion in septic shock: Effect of Vasopressin treatment Levels of Vasopressin are lower in septic shock as compared with cardiogenic shock Exogenous vasopressin administration to compensate depletion restore blood pressure Matériel Médical et Scientifique – Confidentiel – Non reproductible © AOP Health Landry et al. Circulation. 1997 Mar 4;95(5):1122-5. 14  Vasoplegia in post-cardiac surgery: physiopathology Les mécanismes aboutissant à une vasoplégie sont similaires, les médiateurs pro- inflammatoires à l’origine du SIRS diffèrent, mais les voies physiopathologiques sont ensuite communes. © AOP Health Lambden et al. Critical Care (2018) 22:174 15 https://doi.org/10.1186/s13054-018-2102-1 Omar et al. Am J Med Sci 2015;349(1):80–88 Vasoplegia in post-cardiac surgery : incidence Incidence of vasoplegioc shock ranges from 15 to 30% OHT, orthotropic heart transplant © AOP Health 16 Omar et al. Am J Med Sci 2015;349(1):80–88 Vasoplegia in post-cardiac surgery : Vasopressin depletion  Patients who develop vasoplegic shock showed significant lower AVP levels at day 2 and higher at day 5, 6 and 7 © AOP Health 17 Kunkes JH, Baker WL, Hammond JA, Gluck J. Vasopressin therapy in cardiac surgery. J Card Surg. 2019 Jan;34(1):20-27. Vasoplegia in post-cardiac surgery : Vasopressin treatment On initiation of normothermic cardiopulmonary bypass (CPB) and non- pulsatile blood flow, mean arterial pressure (MAP) fell to the 20–30 mm Hg range response to phenylephrine was insignificant despite doses up to 2 µg. Kg- 1. min-1 and several 100–200 µg boluses. infusion of norepinephrine was then commenced, initially at 5 µg.min-1 then progressively increased up to 25 µg.min-1 without significant response. arterial blood gases analysis (ABG) = low haematocrit of 14.1; 600 mls of packed red blood cells was transfused into the CPB pump (the haematocrit subsequently increased to 18.3).  Refractory hypotension diagnosed = trial of vasopressin-2 units was administered  The MAP promptly increased to 82 mmHg and stabilized in the 80–85 mmHg range.  phenylephrine infusion discontinued and norepinephrine infusion tapered. Subsequently, only one other bolus of vasopressin 0.5 unit was required to maintain the BP in the targeted range.  Like in septic shock, Exogenous vasopressin administration to compensate depletion restore blood pressure © AOP Health McGaw C et al. West Indian Med J 2007; 56 (6): 550 18  Complications of septic shock Systemic organ failure 19 Arrhythmias ARDS © AOP Health http://www.derangedphysiology.com/php/Shock-and-hemodynamic- 19 support/images/septic%20shock%20cascade.JPG  Septic Shock from physiopathology to management Anti-infective agents Infection = vasopressors = infection + organ dysfunction Severe sepsis Severe Hypovolemia hypotension Vasoplegia Shock Cardiac = fluids Dysfonction = inotropes © AOP Health 20  Therapeutic strategy for management of septic shock : organ support Ventilatory support : intubation, ventilation invasive ou non-invasive, ECCOR* Renal support : hemofiltration, hemodialysis Cardiovascular support: fluid, vasopressors, inotropes +/- extracorporeal membrane oxygenation (ECMO) Fever management (cooling), Cerebral œdema, coagulation etc... 21 Quenot JP, et al. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013 Apr 25;17(2):R65. Vincent JL et al. Sepsis in European intensive care units: Results of the SOAP © AOP Health study* Critical Care Medicine 2006 - Volume 34 (2): 344-353 * ECCOR = épuration extracorporelle du CO2 21 Septic Shock from physiopathology to management © AOP Health 22 Vasopressors and Fluids: When to start? Although it is never good to initiate vasopressors to a patient that is still with hypovolemia without having started vascular filling with fluids (risk of tissue ischemia such in guts) but… New data advocates for a combined approach with initiating both fluids and vasopressors this tends to decrease the total volume of fluid administered and also reduce length of ICU stay, and maybe decrease mortality, especially is the vasopressors are given in a multimodal approach. 26 This trend is supportive of early vasopressin introduction This is part of “multimodal approach” © AOP Health Ospina-Tascón et al. Critical Care (2020) 24:52 26  Mechanism of Vasomotricity of smooth vascular cell Vasoplegia and vasocontriction at vascular cells level vasoconstrictors such angiotensine II or norepinephrine induce an increase of calcium flow vasodilators such natriuretic in the cell, that activate atrial peptide or nitric oxide myosine kinase, which in activate myosine phosphatase turn will phosphorylate and, which induce myosine myosine and trigger dephosphorylation, and vasoconstriction trigger vasorelaxation. © AOP Health 27 27 Effect of adrenergic vasopressors: loss of efficacy  Adrenergic receptor uncoupling/ desensitization due to cytokines, inflammation, excess of NO and acidosis Desensitization of alpha-1 receptor- mediated contraction in animal model does not appear to be mediated by changes in receptor number or affinity but may involve alterations in receptor coupling. Lurie et al. J Pharmacol Exp Ther. 1985 Jul;234(1):147-52. Carrier et al,. Blood Vessels (1978) 15 (4): 247–258. Kiuchi et al. Circulation Research 1992;71:1185-1199 © AOP Health 28  Vasopressors: When to stop? … or When to introduce another agent? Obviously, going with a sole As vasoplegic shock vasopressor agent and becomes or isalready continue to escalate dose to resistent or refractory try keep patient in control is to catecholamines, not the optimal option necessitating higher dose to maintain effects, clinicians are obliged to NE dose* > 0,5 mcg/kg/min are escalate norepinephrine associated with 90% mortality dose *NE tartrate in publication © AOP Health 29 Martin C. & al. «Norepinephrine: not too much, not too long » SHOCK, Vol. 44, No. 4, pp. 305–309, 2015 Vasopressors: When to stop increasing dose? … or When to introduce another agent? Sato et al. The Relationship Between Norepinephrine Equivalent Dose of Vasopressors Within 24 Hours From The odds of in-hospital mortality increased 20.7% for every 10 μg/min the Onset of Septic Shock and In-Hospital Mortality Rate increase in norepinephrine-equivalent dose under 60 μg/min at the time of vasopressin initiation (adjusted OR, 1.21 [95% CI, 1.09–1.34]) Sacha GL, Kiser TH, Wright GC, Vandivier RW, Moss M, Burnham EL, Ho PM, Reynolds PM, Bauer SR. © AOP Health Association Between Vasopressin Rebranding and Utilization in Patients With Septic Shock. 30 Crit Care Med. 2022 Apr 1;50(4):644-654. 03.09.2024 Mechanism of action of vasopressors: potential synergies 31 La vasoconstriction est médiée via le signal de transduction IP3 (inositol phosphate 3). Les protéines Gq activent la contraction des muscles lisses par la voie IP3, après avoir été stimulée par l’activation des récepteurs V1a, AT1 (activés par la Vasopressin ou l’angiotensin II, respectivement), ou par l’activation des récepteurs α1 (activates par la NE, Epi, et la phenylephrine). La protéine Gq active la phospholipase C qui induit la formation d’inositol 3 phosphate et de diacyl-glycerol (DAG). Le DAG stimule au niveau de la membrane la rentrée de calcium dans la cellule tandis que l’IP3 stimule les canaux calciques du reticulum endoplasmique. La liberation de calcium stimule la calmoduline (CM) et la voie JAK2. Le complexe calcium/CM se lie à la myosine-kinase qui avec l’addition d’ATP va phosphoryler les chaines légères de myosine et provoquer la vasoconstriction. Parallèlement, l’activation de la voie JAK2, sensibilise la calmoduline via les ROS et empêche la vasorelaxation, via la stimulation de la rhodokinase de se faire pendant cette phase. [Figure created with Motifolio Toolkit (Ellicott City, MD).] AT1 indicates angiotensin-type 1 receptor; ATP, adenosine triphosphate; CM, calmodulin; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol triphosphate; JAK2, Janus kinase 2; MLCK, myosin light-chain kinase; MLC, myosin light chain; MLCP, myosin light chain phosphatase; NE, norepinephrine; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; ROS, reactive oxygen species; V1a, vasopressin-type 1a receptor. © AOP Health 31 Chow JH et al. Anesth Analg 2020 Jan;130(1):15-30. doi: 10.1213/ANE.0000000000004343  Vasoplegia : mechanism of action of Vasopressin synergies Hypoxia, high lactate and mitochondrial dysfunction triggers ATP drop -Excess of NO -Resistance and refractoriness to catecholamines Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K+-channel activities of cultured smooth muscle cells from porcine coronary artery. Am J Physiol 1992;263:H491-H496. © AOP Health 32 32 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001; 345: 588–95. Effect of vasopressors on renal arteries and during acidosis Desensitization of alpha1 adrenergic receptors in case of acidosis/hypoxia  need to increase norepinephrine dose to maintain vasopressor effect Vasopressin: vasopressor effect maintained in case of acidosis (1/3 of responders in case of acidosis wit same AVP dose, 2/3 of responders if no acidosis – Bauer et al.? 2023) Norepinephrine: vasoconstrictive effect on both afferent and efferent renal arterioles Vasopressin: vasoconstrictive effect on efferent renal arterioles = maintain glomerular filtration 33 © AOP Health Mutlu et al. 2004 33  Septic shock: Summary  Septic shock is a serious condition associated with very high mortality (30% to more 50%)  Septic shock wis a syndrome associating infection, organ failure and severe hypotension necessitating vasopressor support.  Septic shock is a distributive shock that results from hypovolemia, vasoplegia and some degree of cardiac dysfunction.  Vasoplegia stems from vascular inflammation and adrenergic receptors desensitization principally to excess of NO and acidosis.  Endogenous vasopressors response to shock involves catecholamines, vasopressin and renine-angiotensin system.  Vasopressin levels are depleted in the late stage of septic shock.  Vasopressin can take-over in non-catecholamine responding cells with maintained activity in case of acidosis. © AOP Health 34