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Sepsis: Evolving Concepts John C. Marshall, MD FRCSC St. Michael’s Hospital University of Toronto Sepsis Pepsis Hippocrates 460 – 370 BC Fermentation caused by living organisms Germ theory of disease Louis Pasteur 1822 - 1895 Consequences • Public health • Immunization • Sterilization • Antibiotics Susceptibility to LPS is Transferred with Bone Marrow Cells C3H HeJ C3H HeN (Resistant) (Sensitive) - Michalek, J.Infect.Dis. 141:55, 1980 Susceptibility to LPS is Transferred with Bone Marrow Cells C3H HeJ (Resistant) C3H HeN IRRADIATION (Sensitive) CROSSOVER BONE MARROW TRANSPLANT + LPS - Michalek, J.Infect.Dis. 141:55, 1980 Susceptibility to LPS is Transferred with Bone Marrow Cells C3H HeJ C3H HeN (Resistant) IRRADIATION (Sensitive) CROSSOVER BONE MARROW TRANSPLANT + LPS HeJ Marrow Live HeN Marrow Die - Michalek, J.Infect.Dis. 141:55, 1980 “Passive immunization against tumor necrosis factor/cachectin protects mice from the lethal effects of endotoxin.” Bruce Beutler Beutler, Milsark, & Cerami Science 229:869, 1985 Consequences • New diseases • New therapeutic targets • Response is the disease • Not unique to infection ACCP/SCCM Consensus Conference 1991 Infection Sepsis Trauma SIRS Burns Pancreatitis Systemic Inflammatory Response Syndrome Rates of Sepsis, U.S. 1979 - 2001 - Martin, N Engl J Med 348:1546, 2003 - Crit Care Med 32:858, 2004 - Crit Care Med 36:296, 2008 <8 Fluids CVP >8 Mean Arterial Pressure <65 Pressors > 65 ScvO2 Transfusion, Inotropes > 70 Goals achieved The Impact of Goal-Directed Therapy NNT to prevent 1 death = 6-8 Mortality (%) 60 50 Standard Therapy Goal-directed 40 30 20 10 0 Hospital Mortality 28 Day Mortality 60 Day Mortality Rivers E, et al. N Engl J Med 2001;345:1368 100 (95% CI) Odds Ratio for Death Impact of Delayed Antibiotic Therapy on Clinical Outcome 10 1 Time from Onset of Hypotension (Hours) -Kumar, Crit Care Med 34:1589, 2006 Impact of Source Control in 1170 Patients with Sepsis 28 Day Mortality Adequate Inadequate 31.4% (303/964) 42.7% (88/206) Odds Ratio 0.61 (0.45-0.83) p. 0.003 Despite conventional treatment, 30 to 40% of septic patients die of a process characterized by persistent inflammation and non-resolving organ dysfunction. Lipopolysaccharide (LPS) Susceptibility to LPS is Transferred with Bone Marrow Cells C3H HeJ C3H HeN (Resistant) IRRADIATION (Sensitive) CROSSOVER BONE MARROW TRANSPLANT + LPS HeJ Marrow Live HeN Marrow Die - Michalek, J.Infect.Dis. 141:55, 1980 Toll-like Receptors TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 Lipoteichoic acid, bacterial lipoprotein, Injured tissue Double-stranded RNA Endotoxin, elastase, heparan, HSP60, oxidized phospholipids Flagellin Mycoplasma lipopeptide Imiquod, viral DNA Viral DNA, single-strand RNA Bacterial DNA Clearance of Candida is Impaired in TLR4 Mutant C3H/HeJ Mice Log cfu/Gm kidney PMN/Mouse (X 106) 8 10 8 * 6 4 C3H HeN C3H/HeJ * 6 * 4 2 0 Day 1 C3H/HeN C3H HeJ Day 7 2 0 Baseline 4 Hours - Netea, J Infect Dis 185:1483, 2002 Mediators of Lethality in Murine Endotoxemia Cytokines IL-1, IL-12, IL-18, IL-27, TNF, IFN, TGFβ, LIF,MIF, GCSF, HMGB-1, MIP-1α, MFP-14, LBP, PTH-RP IL-1ra, IL-4, IL-10, IL-13, IFNα, HGF, LIF, CRP, MCP-1, BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin Receptors TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr, CD11a, CD14 VIPr, Adenosine A3r Non-proteins Signal transduction Coagulation Factors PAF, PLA2 Vitamin B12, Vitamin D3 hck, COX-2, p38, jnk, NFκB, iNOS, caspase-3 Stat4, Stat6, IκB, HSP70, hemoxygenase PAI 1, Tissue Factor TFPI, APC - Marshall Nature Rev Drug Disc 2:391, 2003 LPS challenge in human volunteers causes altered expression of 3714 distinct genes. - Calvano, Nature 437:1032, 2005 Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Therapies Targeting Endotoxin TLR4 Antagonists E5564 (Eisai) Others CD14 Antagonists IC14 Anti-LPS Strategies Antibodies: J5, HA-1A, E5 rBPI21 Polymyxin B dextran HDL, taurolidine Alkaline phosphatase Lipid emulsion Extracorporeal removal Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Neutralization of Pro-Inflammatory Cytokines in Sepsis Interleukin-1 Receptor Antagonist 3 Studies; 1688 patients 28 Day Mortality Odds Ratio: 0.80 (0.65-0.99) p=0.04 Neutralization of Pro-Inflammatory Cytokines in Sepsis Anti-TNF Antibodies 8 Studies; 6500 patients 28 Day Mortality Odds Ratio: 0.93 (0.87-0.99) p=0.02 Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Recombinant PAF Acetylhydrolase Phase II Trial (N = 240) 28 Day Mortality (%) Placebo Treated p. 28.4 14.5 0.03 Severe Sepsis 44.2 21.4 0.03 Trauma 10.5 5.9 NS Overall - Shuster, Crit Care Med 31:1612, 2003 Effects of L-NMMA on Survival in Septic Shock Percent Surviving 100 80 Placebo 60 40 L-NMMA p<0.001 Wilcoxon 20 0 0 7 14 21 28 Day of Study - Lopez, Crit Care Med 32:21, 2004 rhAPC Reduces Mortality in Sepsis -Bernard et al; NEJM 344:649, 2001 Endotoxin TLR4 MyD88 CD14 IRAK TRAF2 MAP Kinases: Erk, p38, Jnk PI3 Kinase NFkB Pro-inflammatory genes: IL-1, TNF Tissue ischemia, Cell necrosis, Apoptosis PAF, Nitric oxide, Coagulation Corticosteroids in Septic Shock: A Meta-analysis Annane D BMJ 2004;329:480 Adjuvant Therapy in Sepsis Anti-endotoxin Therapy 9 trials; 3057 Patients Anti-TNF Antibodies 10 Trials; 6821 Patients IL-1ra 3 Trials; 1688 Patients Intravenous immune globulin 20 Trials; 2621 Patients Activated Protein C; All Patients 2 Trials 4303 Patients Activated Protein C; Patients with MOF 2 Trials; 2133 Patients 0.6 0.7 0.8 0.9 Experimental Agent Better 1.0 1.1 1.2 1.3 Placebo Better - Marshall, J Leukoc Biol 83:471, 2008 But … • Impact is modest • Indications for use poorly defined Dose-dependent Effects of L-NMMA on Survival All doses <5 mg/kg/hr > 5mg/kg/hr 0 1 2 3 4 5 6 Study Drug Better - Lopez, Crit Care Med 32:21, 2004 TNF Levels Following Infusion 8 7 TNF (ng/ml) 6 TNF MAb Placebo 5 4 3 2 1 0 Pre 2 24 Hours Post-Infusion 72 Sepsis Syndrome (Bone et al; 1987) Suspected or proven infection, in association with: • • • • Tachycardia Tachypnea Hyper- or hypothermia Dysfunction of one or more organs Sepsis Syndrome • 24 year old man with penetrating injury to colon • 86 year old woman with CHF and Enterococcal UTI • 51 year old man with COPD exacerbation; Candida in sputum The PIRO Concept • Predisposition • Insult • Response • Organ dysfunction - Crit Care Med 31:1250, 2003 Cancer staging stratifies by: • Prognosis • Potential to respond to treatment Insult Inflammatory Response Infection Adaptive Injurious Injury, Ischemia Organ Dysfunction Inflammation Iatrogenic Risk of Death: Cause of Death of Biologic Parent All causes Natural causes Infection Cardiovascular Cancer RR 95% CI 1.71 1.98 5.81 4.52 1.19 1.14 – 2.57 1.25 – 3.12 2.47 – 13.7 1.32 – 15.4 0.16 – 8.99 - Sorensen et al N Engl J Med 318:727, 1988 Tumor Necrosis Factor α G A; -308 (Promoter) Author Disease Cases Controls p. Nadel Meningococcemia (deaths) 0.56 0.29 0.03 Mira Septic shock (deaths) 0.52 0.24 0.008 Tang Septic shock (deaths) 0.40 0.08 <0.05 Mean Change in DAS28 The TNF -308A/G Polymorphism Modifies the Response to Anti-TNF Therapy GG GA AA 1 *p=0.001 0 -1 -2 * -3 -4 Etanercept (N=455) Infliximab (N=453) - Maxwell, Hum Mol Genet 17:3532, 2008 Influence of Infectious Challenge on Response to Neutralization of TNFα LPS N=256 E. coli N=56 CLP N=23 S. aureus N=14 Grp. B Strep. N=10 S. pneumoniae N=21 -40 -20 0 20 40 60 Absolute Risk Reduction (%) - Lorente & Marshall, Shock 24 (Suppl):107, 2005 Salmonella N=11 Candida N=14 Listeria N=10 M. tuberculosis N=11 -40 -30 -20 -10 0 10 20 30 Absolute Risk Reduction (%) - Lorente & Marshall, Shock 24 (Suppl):107, 2005 Impact of Infection-Related Variables on ICU Outcome Infectious Focus N OR for Mortality 95% CI Intra-abdominal 31 1.38 0.56-3.40 Pneumonia 30 1.82 0.74-4.47 Bacteremia 57 1.83 0.79-4.26 Urinary Tract 23 0.49 0.15-1.60 Impact of Source Control in Patients with Low IL-6 Levels Source Control Adequate Mortality 126 (23.1%) (N=545) Inadequate 48 (39.7%)* (N=121) * p<0.001 Impact of Source Control in Patients with High IL-6 Levels Source Control Adequate Mortality 177 (42.3%) (N=419) Inadequate 40 (47.1%)* (N=85) * p=0.49 Impact of Organ Dysfunction on Response to Antibiotics ICU Mortality Adequate Inadequate p. LOD > 4 (N=72) 21/36 (59%) 20/36 (56%) 0.81 LOD < 4 (N=70) 2/27 (7%) 16/43 (37%) 0.006 - Clec’h, Intensive Care Med 30:1327, 2004 28 Day Mortality (Per cent) Anti-TNF is Most Efficacious in Patients without Organ Dysfunction 100 * p=0.003; OR 0.51 (0.32-0.80) 80 Placebo Afelimomab 60 40 20 * 0 0-4 5-8 9-12 13-16 17-20 21-24 Baseline MOD Score Response to Drotrecogin α as a Function of Number of Organ Failures 1690 All patients 418 One OF 543 2 OF 432 3 OF 235 4 OF 61 .5 5 OF .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4 Conclusions • Improved understanding of biology of response to injury • Can be translated into effective new therapies • The obstacle is our intrinsic conceptual conservatism Thank you!