1 Sepsis and MODS MUDr. MSc. Michal Šitina, PhD. Department of pathological physiology, MUNI Department of anaesthesia and intensive care medicine, FNUSA Biostatistics, ICRC-FNUSA 2 Contents of seminar 1. Sepsis and MODS 2. Meningococcal sepsis 3. Sepsis-like disorders (SIRS) 3 Paradoxes of sepsis • severe and very frequent disorder, meets physicians of most specialities, but rather marginal in the curriculum of medical faculties • cause of 25 % deaths, bacterial infection, although we have ATB 4 Sepsis „intuitively“ local reaction • erythema • swelling • dysfunction • fever systemic reaction • vasoplegia, shock • anasarka, hypovolemia • MODS • cytokine storm 5 Definition of sepsis Bone (1992) • SIRS ▪ T > 38°C or < 36°C ▪ HR > 90/min ▪ BR > 20/min or pCO2 < 4.3 ▪ Leu > 12 or < 4 • sepsis = infekce + SIRS • severe sepsis = sepse s orgánovou dysfunkcí • septic shock = těžká sepse vyžadující katecholaminy Consensual conference (2016) • sepsis = life threatening new organ dysfunction due to systemic reaction to infection • septic shock = sepsis with need of catecholamines AND increased lactate 6 • man 71 yo, anamn. hypertension and nephrolithiasis • brought to ER because of progressive weakness and back pain for 3 days, sleepy, desoriented • initially BP 90/50 (chronically 150/90), SR 125/min, clinical signs of dehydration, T 38.4, mild dyspnea, positive tapotement on the left side • laboratory • urea 25 (normal < 8), crea 264 (normal < 100), K 5.2 • pH 7.22, BE -13, pCO2 3.5 (normal > 4.6), SaO2 94% • lactate 4.5 (normal < 2) • leu 19, CRP 240 (normal < 2), leu in urine 4+ • abdominal US – dilated renal pelvis Dg.: Sepsis by obstructive pyelonephritis How does a septic patient look like? • crystalloids 1000 ml, but BP decreased to 70/40, NA administered, lactate 5, further 2 l of fluids • worsening of dyspnea, SaO2 90%, with 4 l O2 96 % • empirical administration of cefotaxim, urological consult. • performed nephrostomy of left kidney, drainage of pulurent urine • oliguria 30 ml/hod, further fluids • on the nest day urea 30, crea 230, lactate 2.1, normal diuresis, no NA necessary, leu 12, CRP 234 • gradual stabilisation, E. coli sensitive to cefotaxime in urine culture • later ureterocystoscopy with of concrement removal in plan Dg.: Septic shock with failure of circulation, kidneys and CNS 7 • no clear-cut relation between „size of infection“ and sepsis • focal dental infection with sepsis • severe cholecystitis without sepsis • various bacteria and site of infection cause similar sepsis • usual bacteria sufficient, no „superbacteria“ necessary • genetic base of tendency to react with sepsis • etiology • bacterial infection • candidosis, aspergillosis, other mycoses usually without sepsis • less often viruses or TBC (miliary form, or TBC pneumonia) Sepsis versus infection Sepsis versus MODS • sepsis is illness • MODS = multiple organ dysfunction syndrom • belongs to the picture of sepsis, but not just sepsis • polytrauma • cardiogenic shock by myocardial infarction • … 8 • disorder highly complex and multisystemic, no one elegant explanation • exaggerated imunne response to usual infectious agens?? • corticosteroids • immunosupressive drugs • anti-cytokine antibodies (e.g. antiTNF-a) • high-volume dialysis eliminating cytokines • activated protein C • AT-III Immune system in sepsis 9 • low peripheral resistance (NO) - vasoplegia • Leaky endothelium (damaged glycocalyx) – albumin in interstitium, lack of oncotic gradient • fluid loss into interstitium – hypovolemia • edema, anasarka • !!! edemas do not exclude hypovolemia • change in cardiac output • decreased • hypovolemia • septick cardiomyopathy – both left and right ventricles involved • increased • hyperdynamic shock – e..g CO above 9 l/min, but increased lactate ➢ problem in microcirkulaci?? Cardiovascular system in sepsis 10 • increased lactate vs. increased cardiac output + high central venous saturation ➢ problem in microcirkulaci • microthrombi – activated coagulation, DIC • functional shortcuts • Interstitial edema with diffusion impairment • mitochondrial dysfunction Mikrocirculation in sepsis 11 Relationship of oxygen supply-demand in sepsis 12 • inflammation end coagulation are interconnected • low grade DIC • more thrombotisation • mikrothrombi • thrombocytopenia (vs. heparine induced trombocytopenia) • massive DIC with consumed factors and bleeding is rare • special is meningococcal sepsis ➢ Purpura fulminans Coagulopathy in sepsis 13 • G- diplococcus • most often associated with PF • often even without DIC • many factors • AT-III and protein C deficit • meningococcal endotoxin is more prothrombotic than with other bacteria • Shwartzman reaction • adhesion of meningococci to human endothelium Meningococcal sepsis and purpura fulminans Melican K,(2013) PLoS Pathog 9(1): e1003139 14 Kidneys in sepsis • significant mortality association and causality of AKI (acute kidney injury) • oliguria is one of first symptoms • functional, often full recovery, but slowly • after improvement/partial reparation often non-oliguric renal failure, recovery of tubular functions is slower • Pathogenesis • mechanism is NOT ischaemic tubular necrosis - no necrosis on histology • minimal changes identified early post mortem • alteration of microcirculation (glomerulus, peritubular capillaries) • metabolic „shutdown“ of tubular cells • Note: initially often hyperfiltration – high dose of ATB necessary 15 • ARDS • non-cardiac pulmonary edema • diffuse lung involvement • many other causes than sepsis/SIRS (e.g. COVID-19) • shock lung after non-pulmonary trauma – so was ARDS discovered • often combined with primary pneumonia • community bacteria – pneumococcus, hemophilus, staphylococcus, E.coli … • often secondary pneumonia due to the immunodeficiency • nosocomial bacteria – PSAE, KLPN, acinetobacter, enterobacter, aspergillus, HSV reactivation • weakness of respiratory muscles, extubation impossible • tracheostomy • danger of re-infection Respiratory system in sepsis 16 Metabolism in sepsis • Low T3 syndrome – conversion of T4 to rT3, low T3, normal TSH • catabolism, severe proteolysis • snaha zajistit AA a glukozu pro imunitní systém (cytokiny, adrenalinu, kortikoidy) • inzulinorezistence - hyperglykémie • Up to 250 g protein/day = 1 kg musles/day • hypoalbuminemia – positive acute phase protein – high turnover, low level • high need of cortisol, sometimes substitution necessary fpr relative hypocorticalism (CAVE: chronic hypocorticalism or longterm use of corticosteroids) • Muscles • ICU acquired weakness • sarcopenia (atrophy, proteolysis) • Critical illness polyneuromyopathy (CIP, CIM) 17 Other systems in sepsis • GIT • disordered continuity of microvilli • translocation of bacteria - second hit, motor of MODS • enteral feeding for nutrition of microvilli („trophical nutrition“) • selective decontamination did not bring any significant effect • liver – cholestasis, higher transaminase, usually unimportant • Brain • septic encefalopathy • delirium up to coma – more expressed at older patients • sometimes admitted as neurological disorder (apoplex?, but normal brain CT) 18 Principles of sepsis treatment • source elimination – ATB, surgery, as fast as possible • blood culture, microbiology – targeted ATB • circulatory optimization • fluids, NA, vasopressin, corticosteroids • symptomatic treatment of other problems • cardiac dysfunction – dobutamine, levosimendan • MV • dialysis • enteral/parenteral nutrition • RHB • correction of metabolic abnormalities • treatment of DIC – heparine, fibrinogen substitution, AT3 substitution, thrombocytes 19 Sepsis-like disorders – SIRS, SIRS shock • non-infectious antigens start the same immune response (SIRS) as by sepsis • tissue damage results in release of DAMPs (HMGB1, protein S100, ATP, DNA, RNA) • both PAMPs and DAMPs bind to the same receptors of immune cells callled PRR (pattern recognition receptors, e.g. Toll-like receptors) • cause is different, but systemic response incl. MODS is the same • similar clinical signs, can be difficult to distinguish 20 Sepsis-like disorders • acute pancreatitis • status after CPR • major trauma • severe burns • large operations • massive transfusion (TRALI) • ischemic-reperfusion damage • anaphylaxis? • all other shocks – SIRS is secondary • massive bleeding • cardiogenic shock • massive pulmonary embolism • ... • instestinal ischemia • Endotoxin shock • worsening after ATB initiation • Jarisch-Herxheimer reaction (syphylis treatment) 21 MODS as adaptation? • MODS, but • bez dramatic pathology on section, early post-mortem histology almost normal • usually full recovery of function • usually adequate oxygen supply ➢ adaptation, metabolic shutdown, similar to hibernation • hibernating myocardium known from cardiology • but hibernation proved also in septic cardiomyopathy (expression of similar genes as in hibernatng animals) • low T3 syndrome • decrease in number of mitochondria 22 Problems of sepsis research 23 Individualisation 24 Summary • life threatening new organ dysfunction due to infection • „local inflammation everywhere“ • multiple organ dysfunction • circulatory failure • acute kidney injury • ARDS • DIC • GIT – motor of sepsis • metabolism – catabolism and CIPNM • meningococci – pronounced ability to activate thrombosis • very similar to other systemic conditions - SIRS