Sepsis and Multiple Organ Failure. J.G. van der Hoeven Radboud University Nijmegen Medical Centre

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1 Sepsis and Multiple Organ Failure J.G. van der Hoeven Radboud University Nijmegen Medical Centre

2 Sepsis - initiation Microorganism Tissue Damage Pathogen Associated Molecular Pattern (PAMP) Pattern Recognition Receptor (PRR) = Damage Associated Molecular Patterns = (DAMP) Alarmins Pattern Recognition Receptor (PRR) Immune cell Immune cell Inflammatory Response

3 Activation of endothelium + PMN migration Activation of coagulation Pro-inflammatory cytokines/chemokines C5a Induction of late cytokines HMGB-1 and MIF Mortality (%) apc N = ,4 24,2 Placebo 34,1 32,7 + + IL-17 cytokine family 0 Mortality D28 Mortality D 90 Ranieri VM. N Engl J Med 2012 Adaptive immune response

4 Microcirculatory shunting Mitochondrial dysfunction Systolic and diastolic myocardial dysfunction Excessive vasodilation Venous pooling Increased endothelial permeability

5 Vasodilatation in Sepsis Septic shock with lactate acidosis ino synthase ATP, H +, Lactate vascular smooth muscle Vasopressin secretion NO Open KCa Open KATP Vasopressin stores cgmp Cytoplasmic Calcium Vasopressin plasma Phosphorylated myosin Vasodilatation

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7 IFN-Υ ± IL-10 IDO activity Tryptophan & kynurenine Lymphocyte apoptosis Increased KT ratio plasma Microvascular reactivity IL-6 e NO N = 80 Darcey CJ. PLOSone 2011;6:e21185

8 INOTROPIC DOSE IDO ACTIVITY N = 16 Changsirivathanathamrong D. Crit Care Med 2011;39:

9 Changsirivathanathamrong D. Crit Care Med 2011;39:

10 Treatment Early antibiotics and source control Volume therapy Increasing afterload with NE / vasopressin Inotropic agents Standard ICU treatment

11 HES 130/0.42 versus Ringer s acetate Adult patients with severe sepsis MC (N = 26), blinded, stratified clinical trial HES 130/0.42 vs Ringer s acetate Daily maximum dose 33 ml/kg IBW Primary outcome composite death/dialysis dependence at D90 Perner A. N Engl J Med 2012;367:

12 HES 130/0.42 versus Ringer s acetate Ringer s HES 130/ P = 0.03 P = 0.03 P = 0.09 P = Death/DD Day 90 Death Day 90 Severe bleeding RRT No differences in total amount of fluid needed Perner A. N Engl J Med 2012;367:

13 HES 130/0.4 versus NaCl 0.9% CHEST trial Myburgh JA. N Engl J Med 2012;367:

14 AKI and HES 130/0.4 Placebo HES 130/ ,8 P = 0.04 RRT 7 Myburgh JA. N Engl J Med 2012;367:

15 Lactate driven therapy Mortality (%) Control Lactate driven P = ,5 33,9 N = 348 After correction for risk factors mortality lower in lactate group (HR 0.61, p = 0.006) Duration MV, duration ICU stay, lower SOFA score 0 Admission lactate 3 mmol/l Goal: lactate 20% in 2 hrs Jansen TC. Am J Respir Crit Care Med 2010, 182:

16 Death Pro- inflammatory response A Homeostasis Anti- inflammatory response Pro- inflammatory response Homeostasis Anti- inflammatory response Time (days) Time (days) B Pro- inflammation Anti- inflammation Bacterial load Pro- inflammatory response C Death Death Homeostasis Anti- inflammatory response Time (days)

17 Immunoparalysis Monocyte Class II MHC expression LPS-induced cytokine production Lymphocyte apoptosis T-reg dominant adaptive immune response Changes in lymphocyte phenotype % cytokine reduction after LPS stimulation TNF-α IL-1β IL-12 IF-ϒ

18 Draisma A. Crit Care Med 2009;37:

19 Immunoparalysis Spleen of septic and control patients

20 HLA-DR expression in patients with sepsis Monneret G. Intensive Care Med 2006;32:

21 IFNγ secretion Boomer JS. Crit Care 2012;16:R112

22 Clinical evidence Low virulence bacterial infections CMV HS Aspergillus

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25 Leentjes J. Am J Respir Crit Care Med 2012;186:

26 GM-CSF treatment in PRCT N = 38 sepsis Meisel C. Am J Respir Crit Care Med 2009;180:

27 HLA-DR Interleukin-10 Interleukin-6 Interleukin-8 TNF-α Decreased time on MV Improvement in APACHE II score Decrease in LOS (NS) Meisel C. Am J Respir Crit Care Med 2009;180:

28 Important questions remain What should we administer? When should we administer? Which markers should we use?

29 What can be done? HLA-DR expression Cytokine production after ex-vivo stimulation Skrupky LP. Anesthesiology 2011;115:

30 PD-1 Negative costimulatory molecule on Tcells Skrupky LP. Anesthesiology 2011;115:

31 Conclusions Hemodynamic instability in sepsis is multifactorial Starch products should be avoided Sepsis induced immunoparalysis may result in severe opportunistic infections Immunoparalysis may be reversed with IFN-γ, GM-CSF and IL-7