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Sepsis: still misunderstood after all these years... Naeem Ali, MD Assistant Professor Director, Medical Intensive Care Unit The Ohio State University Medical Center 2008 Ann Surg. 1886 April; 3(4): 321–333. Objectives 1. To identify the severe sepsis syndrome 2. To prioritize treatments for patients with septic shock 3. To understand the current controversies and upcoming studies in severe sepsis • What is sepsis? • How common is sepsis? • What causes sepsis? • How do you treat sepsis? Recognition 6 hours Resuscitation Initial Management 24 hours Maintenance Hospitalization Recovery Pre and post-discharge What is sepsis? I shall not today attempt further to define the kinds of material…[b]ut I know it when I see it… •Justice Potter Stewart, 1964 RECOGNITION • 84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound • Presents to the ED from his residence with altered mental status, fever and smelly urine • Temp 102.3 P 118 R 32 BP 78/34 • 84% SPO2 Karol Wojtyla (1920-2005) Sepsis: Defining a Disease Continuum SIRS = Systemic Inflammatory Response Syndrome Infection/ Trauma SIRS Sepsis Severe Sepsis A clinical response arising from a nonspecific insult, including 2 of the following: • • • • Temperature 38oC or 36oC HR 90 beats/min Respirations 20/min WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81 ? Sepsis: Defining a Disease Continuum SIRS = Systemic Inflammatory Response Syndrome Infection/ Trauma SIRS Sepsis Severe Sepsis SIRS with a presumed or confirmed infectious process Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81 • 84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound • Presents to the ED from his residence with altered mental status, fever and smelly urine • Temp 102.3 P 118 R 32 BP 78/34 • 84% SPO2 Does he have sepsis? Is he sick or not sick? Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe Sepsis Sepsis with 1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Metabolic acidosis Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207 Neurologic Altered Consciousness Confusion Psychosis Tachycardia Hypotension Altered CVP Altered PAOP Cardiovascular Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2 300 Respiratory Jaundice Enzymes Albumin PT Hepatic Oliguria Anuria Creatinine Renal Platelets PT/APTT Protein C D-dimer Coagulation Sepsis: Timing of Organ Failures Wheeler et al. NEJM 1999; 340: 207-14 Mortality increases with increasing organ failure Hebert et al. Chest 1993;104:230-5 Neurologic Altered Consciousness Confusion Psychosis Sepsis: Tachycardia Hypotension Altered CVP Altered PAOP Defining a Disease Continuum Infection/ SIRS Tachypnea Trauma PaO <70 mm Hg 2 SaO2 <90% PaO2/FiO2 300 Respiratory Jaundice Enzymes Albumin PT Hepatic Cardiovascular Sepsis Severe Sepsis Oliguria Anuria Creatinine Sepsis withRenal 1 sign of organ failure Cardiovascular (refractory hypotension) Platelets Renal PT/APTT Respiratory Protein C Hepatic D-dimer Hematologic CNS Metabolic acidosis Coagulation Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207 Mortality Increases in Septic Shock Patients Incidence Mortality Sepsis 400,000 7-17% Severe Sepsis 300,000 20-53% Septic Shock 53-63% Balk, R.A. Crit Care Clin 2000;337:52 How sick is he? • • • • • • • WBC 30K with 20% bands Shock ABG 7.20/28/42/15 on 100% FiO2 Platelets normal, INR 1.7 LFTs normal BUN 32, Creatinine 1.9 Delirious This seems kind of bad. Glad it doesn’t happen much RECOGNITION http://www.cnn.com/2004/SHOWBIZ/Movies/10/11 /obit.reeve/index.html Accessed 8/23/05 1,800 600 Severe Sepsis Cases US Population 500 1,400 1,200 400 1,000 300 800 2001 2025 At LEAST the 10th Leading Cause of Death Rate per 100,000 Population Year Angus DC, et al. JAMA 2000;284:2762-70. Angus DC, et al. Crit Care Med 2001;29:1303-10. 300 Total US Population (million) Sepsis Cases (x103) 1,600 Severe Sepsis is common and increasing in incidence 2050 Incidence Mortality 250 200 150 100 50 0Severe Sepsis Stroke Breast CA Lung CA Severe Sepsis Stroke Breast Cancer Lung Cancer *Calculated data based on information compiled from the American Heart Association, American Cancer Society, National Center for Health Statistics and the US Census Bureau (1995-1999) Mortality rate is decreasing but more are dying overall • 1979 – 1984 – 27.8% – 43,579 – 21.9/100,000 population MORTALITY • 1995 – 2000 – 17.9% – 120,491 – 43.9/100,000 population • Mortality dropped most with Gram+ infections Martin et al, NEJM 2003:348;1546-54. 215,000 deaths a year in US ~590 Deaths Every day Severe Sepsis Costs a Lot Average per-patient cost Total national cost Age •Average LOS 19.6 days •Average cost $22,100/case •Total national hospital cost was $16.7 BILLION •52.3% of costs in those >64 years •30.8% total costs in those >74 years Angus et al, Crit Care Med 2001; 29: 1303-10 OSUMC-Specific Data: January 1995 – August 26, 2006 • ICD9 codes for sepsis – NPV 80%, PPV 90% • 12,518 admissions – 2.9 admissions/day • 2856 deaths (23%) – One death every 1.5 days • Average hospital LOS 17.5 days – 219,246 hospital days – 18,807 hospital days/yr • 4725 with ICU stay (37.7%) – Average ICU LOS 11.7 days – 4742 ICU days/yr – 13 ICU beds with septic patients/day • Total charges of $1,028,675,176.43 • Yearly charge of $88,241,231.35 • Average charge of $82,175.68 This doesn’t sound that great Maybe we should figure out what causes this Risk factors and Pathogenesis The Pathogenesis of Sepsis Infectious Agents •Endotoxin/LPS •Lipopeptides •Lipoteichoic acid •DNA •Flagellin Response to Stimulus •Inflammation •Immunosuppression •Coagulopathy •Mitochondrial dysfunction Susceptible Host •Co-morbidities •Age •Genetic polymorphisms A Theoretical Picture of Sepsis Infection Inflammation Organ Failure Cellular Failure Infection factors Host factors Cytokines Dysregulated Coagulation Poor Perfusion Apoptosis Mitochondrial Dysfunction Metabolic Derangement MOSF Death Microvascular Blood Flow Normal Septic shock De Backer et al, AJRCCM 2002; 166:98-104. Organisms Found in Sepsis Gram negative bacteria Gram positive bacteria Fungi Only about 30% have a positive blood culture Martin et al, NEJM 2003:348;1546-54. Sites of Infection in Severe Sepsis Other/Unknown Endocarditis Central nervous system Wound/soft tissue Device-related Abdominal Genitourinary Primary Bacteremia Respiratory 0 5 10 15 20 25 Angus et al, Crit Care Med 2001; 29: 1303-10 30 35 40 Extremes of age are associated with higher incidence Cases OR if >65 is 13! Incidence AGE Angus et al, Crit Care Med 2001; 29: 1303-10 Population-Adjusted Incidence of Sepsis, According to Sex, 1979-2000 MEN (OR 1.3) WOMEN 38.8% sever e sepsis 659,935 cases 240.4 cases/100K Martin, G. S. et al. N Engl J Med 2003;348:1546-1554 Race is associated with Incidence of Sepsis Black Other OR 1.9 White Martin et al N Engl J Med 2003;348:1546-1554 Highest incidence Youngest age at onset Highest mortality was among African-American men Important Patient-Related Factors CO-MORBIDITIES •Immunosuppression •AIDS (OR 5.1) •Cancer •Any (OR 2.8) •Solid (OR 1.8) •Liquid (OR 15.7) GENETIC PRE-DISPOSITION •Innate immune system •Cytokine genes •Other polymorphisms •Cirrhosis (OR 2.6) •Alcohol dependence (OR 1.5) •Chronic catheters (OR 64) •TRANSFUSIONS (OR 6.0) •Diabetes All right, all right, I get it. But isn’t that guy dying on us? Shouldn’t we do something about that? TREATMENT Treatment of Inflammation Failed Strategies • • • • • • • • • High-dose corticosteroids PLA2 inhibitors Pentoxifylline Prostaglandin E1 Ketoconazole Anti-endotoxin antibodies Anti-TNF antibodies Interleukin-1 receptor antagonist Tissue factor pathway inhibitor American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians Canadian Critical Care Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine European Respiratory Society International Sepsis Forum Japanese Association for Acute Medicine Japanese Association of Intensive Care Medicine Society of Critical Care Medicine Society of Hospital Medicine Surgical Infection Society World Federation of Societies of Intensive and Critical Care Medicine German Sepsis Society Latin America Sepsis Institute RESUSCITATION PHASE GOAL: Keep him alive for 24 hours • A – Airway – Intubation Treat the Infection • B – Breathing – Mechanical ventilation • C – Circulation – IV access – Goal directed therapy – Steroids Antibiotics – Go BIG early •Every hour in delay of appropriate atbx = 7.6% lower survival •Median time to appropriate atbx = 6h Kumar et al. Crit Care Med 2006; 34: 1589-96. Surviving Sepsis Campaign Level 1 Recs re ATBX • Get cxs before atbx if WON’T DELAY ATBX • ≥2 blood cxs (≥1 peripheral, 1 from each CVC), other sites as indicated • Begin IV atbx ASAP and ALWAYS within 1h of recognizing severe sepsis/septic shock • Use broad-spectrum atbx, ≥1 agents with activity against likely bugs and penetration into site • Reassess choices daily • Duration can probably be 7-10d • Stop atbx if not infected How do you know when you’ve addressed “C” in ABCs? Early Goal-Directed Therapy CVP: central venous pressure MAP: mean arterial pressure ScvO2: central venous oxygen saturation N Engl J Med 2001;345:1368 Early Goal-Directed Therapy Results 60 50 28-day Mortality 49.2% 40 P = 0.01* 33.3% 30 20 10 0 Standard Therapy n=133 N Engl J Med 2001;345:1368-77. EGDT n=130 Limitations • Single center and a single group of investigators – Is it generalizable? • Is the whole protocol necessary? – Blood? – Inotropes? – Continuous ScvO2 monitoring? ProCESS Study Design • Three Arms – Usual Care Arm – Early Goal-Directed Therapy (EGDT) Arm – Protocolized Standard Care (PSC) Arm • 24 Centers, 1935 Subjects – 645 in each arm ProCESS Objectives • Aim 1: Clinical Efficacy – Is any protocolized care superior to usual care? – Is EGDT arm superior to PSC arm? • Aim 2: Mechanisms of Action – – – – Inflammation Cellular hypoxia Oxidative stress Coagulation / thrombosis • Aim 3: Costs and Cost-effectiveness A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit •N=6997 •Randomized to NS or 4% albumin for any resuscitation •In patients with severe sepsis: •30.7% mortality with albumin •35.3% mortality with NS NEJM 2004; 350: 2247-56 Vasopressors In Septic Shock Heart Rate Contractility Vasoconstrict Dopamine Low dose 0 0 1- Med dose 2+ 2+ 0 Hi dose 2+ 2+ 3+ Dobutamine 1+ 4+ 1- Norepinephrine 2+ 2+ 4+ Phenylephrine 2- 0 4+ Epinephrine 4+ 4+ 4+ Vasopressin 1- 1- 4+ Original Article Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock James A. Russell, M.D., Keith R. Walley, M.D., Joel Singer, Ph.D., Anthony C. Gordon, M.B., B.S., M.D., Paul C. Hébert, M.D., D. James Cooper, B.M., B.S., M.D., Cheryl L. Holmes, M.D., Sangeeta Mehta, M.D., John T. Granton, M.D., Michelle M. Storms, B.Sc.N., Deborah J. Cook, M.D., Jeffrey J. Presneill, M.B., B.S., Ph.D., Dieter Ayers, M.Sc., for the VASST Investigators N Engl J Med Volume 358(9):877-887 February 28, 2008 Study Overview • In a multicenter trial, 778 patients with septic shock who were being treated with catecholamine vasopressors were randomly assigned to either norepinephrine or vasopressin in addition to open-label vasopressors Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion Russell JA et al. N Engl J Med 2008;358:877-887 Rates and Risks of Death from Any Cause According to the Severity of Shock Russell JA et al. N Engl J Med 2008;358:877-887 Surviving Sepsis Campaign Level 1 Recs re Resuscitation and Pressors • Begin resuscitation immediately if low bp or lactate >4 • Goals include: – CVP 8-12 (higher if on vent) – MAP ≥65 – UO ≥0.5mL/kg/h – CvO2 ≥70% or SvO2 ≥65% • Use crystalloids or colloids • Give “fluid challenge” and monitor response – at least 1L crystalloid or 300mL colloid over 30min • Reduce fluid administration if filling pressures rise without hemodynamic improvement • Norepi or dopa are initial pressors of choice • DON’T use “renal dose” dopamine • Insert an a-line in those on pressors • Use dobutamine in patients with myocardial dysfxn (elevated filling pressures, low CO) • Do not increase CI to supranormal levels Corticosteroids Steroids Placebo N=300 •Sick •Sbp<90 for 1h despite vasopressors •Mechanical ventilation •Another organ failure •Treated within 8h •77% unresponsive to ACTH •ACTH unresponsiveness predicted benefit Annane, D. JAMA, 2002; 288 (7): 868. Not steroids again…. N=499 •Less Sick Sprung. NEJM, 2008; 358: 111. •Sbp<90 or vasopressors despite fluids •Hypoperfusion or OF due to sepsis •Treated within 72h (77% within 12h) •47% unresponsive to ACTH •ACTH unresponsiveness did NOT predict benefit •25% had misclassification of ACTH response Surviving Sepsis Campaign Level 1 Recs re Steroids • Use hydrocortisone dose ≤300mg/d • Do not use steroids without shock LEVEL 2 • Consider steroids if hypotension poorly responsive to fluids and pressors • ACTH stim test DOES NOT identify those who will benefit from steroids • Fludrocortisone may be included • Steroids may be weaned INITIAL MANAGEMENT PHASE GOAL: Let’s get him better • Supportive care – Identify organ failures – Customize antibiotics based on cultures/sensitivities – Additional diagnostic testing – Goals of care discussions • Specific care – Drotrecogin alfa (activated) [Xigris®] – Lung protective ventilation – Conservative fluid management APC Links Coagulation & Inflammation Coagulation cascade Inflammation N Engl J Med 2001;344:699-709. Inhibition of fibrinolysis Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESS 100 Percent Survivors NNT = 17 90 Drotrecogin alfa (activated) (n=850) 80 Placebo (n=840) 6% Absolute mortality difference 70 P=.006 (stratified log-rank test) 0 0 7 14 21 Days from Start of Infusion to Death Bernard GR, et al. N Engl J Med 2001;344:699-709. 28 Patient selection is important • “High risk” of dying • “Low risk” of bleeding – APACHE II score >24 – serious bleeding: 2 to 5% – ICH: 0.2 to 0.5% – Bleeding associated with: • NNT = 8 – Multi-organ failure • NNT=14 – Respiratory failure • NNT=17 – Shock • NNT=15 – 40% probability of dying? • • • • • Instrumentation Trauma Thrombocytopenia (<30) Meningitis INR >3 Management of Acute Lung Injury and the Acute Respiratory Distress Syndrome…to be continued MAINTENANCE AND RECOVERY GOAL: Don’t kill him • Avoid nosocomial complications – Ventilator-induced lung injury – Get tubes and lines out of him – Clots and bleeding • Avoid new infection – Hand washing – Semi-recumbent position – Get tubes and lines out of him – Minimize transfusions Glucose SICU Managed by Endo fellow Conventional Treatment (180-200) Intensive Treatment (80-110) ICU Deaths 63/783 (8.0%) 35/765 (4.6%) 0.005 Hospital Deaths 85/783 (10.9%) 55/765 (7.2%) 0.01 Hypoglycemia (<40) 6/783 (0.8%) 39/765 (5.1%) MICU Managed by RN protocol Conventional Treatment (180-200) Intensive Treatment (80-110) <0.000 1 ICU Deaths 162/605 (26.8%) 144/595 (24.2%) 0.31 Hospital Deaths 242/605 (40.0%) 222/595 (37.3%) 0.33 19/605 (3.1%) 111/595 (18.7%) <0.000 1 Hypoglycemia Van den Berghe et al, NEJM 2001; 345:1359 and 2006;354:449. Glucose, Part Deux •Severe sepsis •80-100 v 180-200 •Stopped after 488 pts •Hypoglycemia •17.0% v 4.1% p=0.36 •Hypoglycemia was assoc with death HR 3.3 Brunkhorst et al., NEJM 2008; 358:125-39. Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297 Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297 Surviving Sepsis Campaign Level 1 Recs re Maintenance • • • • • • • • • • • • • • Target Hgb 7-9 Do not use epo to treat sepsis-assoc anemia Do not use antithrombin Use sedation protocol with goals Use intermittent bolus sedation or daily awakenings Avoid neuromuscular blockers Use IV insulin to control hyperglycemia Provide glucose and monitor every 1-2h if receiving IV insulin Interpret with caution POC glucose Do not use HCO3 to treat lactic acidosis with pH>7.15 Use UFH or LMWH prophylaxis Use mechanical device when heparin contraindicated Use H2blocker or PPI for stress ulcer prophylaxis Discuss goals of care and set realistic expectations What is it? • • • • SIRS + Infection = Sepsis Sepsis + Organ Failure = Severe Sepsis Sepsis + Shock = Septic Shock Mortality increases with more organ failure How common is it? • • • • Significant mortality – Top 10 cause of death Significant morbidity Significant cost Is getting more common What causes it? • • • • • • Inflammation Coagulopathy Blood flow Cell failure Organ failure Death • Host factors • Infection factors • Nosocomial complications – VAP/BSI – Ventilators How do you treat it? • Recognition • Resuscitation = ABCs + Atbx – Goal-directed therapy • Initial Management – Customize care – Drotrecogin alfa (activated) • Maintenance – Avoid complications • Transfusion • Sedation • Ventilation • For questions/comments, please feel free to contact me: [email protected] • 292-6933