Sepsis: still misunderstood after all these years...

1. Sepsis: still misunderstood after all these years... Naeem Ali, MD Assistant Professor Director, Medical Intensive Care Unit The Ohio State University Medical Center 2008

2. Ann Surg. 1886 April; 3(4): 321–333.

3. Objectives • To identify the severe sepsis syndrome • To prioritize treatments for patients with septic shock • To understand the current controversies and upcoming studies in severe sepsis

4. What is sepsis? • How common is sepsis? • What causes sepsis? • How do you treat sepsis?

5. 6 hours Recognition Resuscitation 24 hours Initial Management Hospitalization Maintenance Pre and post-discharge Recovery

6. 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

7. Karol Wojtyla (1920-2005) • 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

8. Sepsis:Defining a Disease Continuum SIRS = Systemic Inflammatory Response Syndrome Infection/Trauma Sepsis Severe Sepsis SIRS 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/mm3or 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

9. SIRS with a presumed or confirmed infectious process Sepsis:Defining a Disease Continuum SIRS = Systemic Inflammatory Response Syndrome Infection/Trauma Sepsis Severe Sepsis SIRS Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81

10. 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?

11. Sepsis:Defining a Disease Continuum Infection/Trauma Sepsis Severe Sepsis SIRS • 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

12. Neurologic Tachycardia Hypotension Altered CVP Altered PAOP Altered Consciousness Confusion Psychosis Cardiovascular Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2300 Oliguria Anuria  Creatinine Respiratory Renal Jaundice  Enzymes  Albumin PT  Platelets  PT/APTT  Protein C  D-dimer Hepatic Coagulation

13. Sepsis: Timing of Organ Failures Wheeler et al. NEJM 1999; 340: 207-14

14. Mortality increases with increasing organ failure Hebert et al.Chest 1993;104:230-5

15. Neurologic Tachycardia Hypotension Altered CVP Altered PAOP Altered Consciousness Confusion Psychosis Cardiovascular Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2300 Oliguria Anuria  Creatinine Respiratory Renal Jaundice  Enzymes  Albumin PT  Platelets  PT/APTT  Protein C  D-dimer Hepatic Coagulation Sepsis:Defining a Disease Continuum Infection/Trauma Sepsis Severe Sepsis SIRS • 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

16. Sepsis 400,000 7-17% Severe Sepsis 300,000 20-53% Septic Shock 53-63% Mortality Increases in Septic Shock Patients Incidence Mortality Balk, R.A. Crit Care Clin 2000;337:52

17. 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

18. This seems kind of bad.Glad it doesn’t happen much RECOGNITION

19. http://www.cnn.com/2004/SHOWBIZ/Movies/10/11/obit.reeve/index.html Accessed 8/23/05

20. 600 1,800 Severe Sepsis Cases Rate per 100,000 Population US Population 1,600 500 1,400 Sepsis Cases (x103) 1,200 Total US Population (million) 400 1,000 300 800 2001 2025 2050 Year Severe Sepsis is common and increasing in incidence Severe Sepsis Cases US Population Angus DC, et al. JAMA 2000;284:2762-70. Angus DC, et al. Crit Care Med 2001;29:1303-10. At LEAST the 10th Leading Cause of Death Severe Sepsis Stroke Breast CA Lung CA * 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)

21. MORTALITY Mortality rate is decreasing but more are dying overall • 1979 – 1984 – 27.8% • 43,579 • 21.9/100,000 population • 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.

22. 215,000 deaths a year in US ~590 Deaths Every day

23. 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

24. 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 OSUMC-Specific Data:January 1995 – August 26, 2006

25. This doesn’t sound that greatMaybe we should figure out what causes this Risk factors and Pathogenesis

26. 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

27. Organ Failure MOSF Death Infection Inflammation Cellular Failure A Theoretical Picture of Sepsis Infection factors Host factors Cytokines Dysregulated Coagulation Poor Perfusion Apoptosis Mitochondrial Dysfunction Metabolic Derangement

28. Microvascular Blood Flow Normal Septic shock De Backer et al, AJRCCM 2002; 166:98-104.

29. 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.

30. Sites of Infection in Severe Sepsis Angus et al, Crit Care Med 2001; 29: 1303-10

31. OR if >65 is 13! Extremes of age are associated with higher incidence Cases Incidence AGE Angus et al, Crit Care Med 2001; 29: 1303-10

32. Population-Adjusted Incidence of Sepsis, According to Sex, 1979-2000 38.8% severe sepsis MEN (OR 1.3) • 659,935 cases • 240.4 cases/100K WOMEN Annual Increase of 8.7% Martin, G. S. et al. N Engl J Med 2003;348:1546-1554

33. OR 1.9 Race is associated with Incidence of Sepsis Black Other White Highest incidence Youngest age at onset Highest mortality was among African-American men Martin et al N Engl J Med 2003;348:1546-1554

34. Important Patient-Related Factors • CO-MORBIDITIES • Immunosuppression • AIDS (OR 5.1) • Cancer • Any (OR 2.8) • Solid (OR 1.8) • Liquid (OR 15.7) • Cirrhosis (OR 2.6) • Alcohol dependence (OR 1.5) • Chronic catheters (OR 64) • TRANSFUSIONS (OR 6.0) • Diabetes • GENETIC PRE-DISPOSITION • Innate immune system • Cytokine genes • Other polymorphisms

35. All right, all right, I get it.But isn’t that guy dying on us?Shouldn’t we do something about that? TREATMENT

36. 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

37. 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

38. RESUSCITATION PHASEGOAL: Keep him alive for 24 hours • A – Airway • Intubation • B – Breathing • Mechanical ventilation • C – Circulation • IV access • Goal directed therapy • Steroids Treat the Infection

39. 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.

40. 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

41. 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

42. Early Goal-Directed Therapy Results 28-day Mortality 60 49.2% P = 0.01* 50 40 33.3% 30 20 10 0 Standard Therapy n=133 EGDT n=130 N Engl J Med 2001;345:1368-77.

43. Limitations Single center and a single group of investigators Is it generalizable? Is the whole protocol necessary? Blood? Inotropes? Continuous ScvO2 monitoring?

44. 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

45. 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

46. A Comparison of Albumin and Saline for FluidResuscitation 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

47. 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+

48. Original ArticleVasopressin 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

49. 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

50. Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion Russell JA et al. N Engl J Med 2008;358:877-887