Diagnosing & Managing Sepsis Syndrome:

1. Diagnosing & Managing Sepsis Syndrome: 

2. Statement of Need Sepsis kills more than 210,000 Americans each year and is becoming more common, especially in the hospital. Sepsis is a medical emergency that can be difficult to define, diagnose, and treat, but every minute counts in the effort to save lives.

3. Introduction to Sepsis Definition, Etiology, Morbidity and Mortality

4. Definition of Sepsis • Sepsis • Systemic response to infection • Manifested by two or more SIRS criteria as a result of proven or suspected infection • Temperature ≥ 38C or ≤ 36C • HR ≥ 90 beats/min • Respirations ≥ 20/min • WBC count ≥ 12,000/mm3 or ≤ 4,000/mm3 or > 10% bands • PaCO2 < 32 mmHg ACCP/SCCM Consensus Conference. Crit Care Med. 1992;20(6):864-74.

5. Case Study

6. Case Study: Mr. Z • He tells you “My tooth is killing me! You can pull it if you need to. I feel like it is going to explode.” • Mr. Z is a 47 year-old male who was admitted to the emergency department. He is complaining of a toothache that has been present for 7 days. • His tooth pain is severe and he cameto the emergency department since he could not see his dentist until themorning. He has drainage from tooth #20, for which a culture has been obtained and sent to the lab.

7. Case Study: Mr. Z • He is started on Cefoxitin (Mefoxin®) 2 g IV q6h. • Mr. Z is alert and oriented. • He has a history of hypertension and had a hemorrhagic stroke 10 years ago but has had no major health issues since this time. • His heart and lung sounds are normal and his skin is cool and moist. He has good capillary refill, abdomen soft and non-tender.

8. Case Study: Mr. Z SPO2: Pulse oximetry oxygen saturation; NIBP: Non-invasive blood pressure Questions • Does Mr. Z have signs of sepsis? • Yes • 2) What is a blood test that would be useful? • Lactate

9. Case Study: Mr. Z

10. Case Study: Mr. Z • A decrease in lactate shows improved perfusion. • If the lactate had remained elevated, more fluids could have been given. • The use of the lactate allowed the clinician to better evaluate the seriousness of the situation. • Often, vital signs are normal when lactates are elevated.

11. Sepsis is Serious. • Sepsis is a serious medical condition caused by an overwhelming immune response to infection. • Complex chain of events: • Inflammatory and anti-inflammatory processes • Humoral and cellular reactions • Circulatory abnormalities • Results in impaired blood flow, which damages organs by depriving them of nutrients and oxygen. http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

12. The Intracellular Immune Response to Infection Adapted from Holmes CL, Russell JA, Walley KR. Chest. 2003;124:1103-15.

13. Symptoms of Sepsis • Sepsis can begin in different parts of the body and can have many different symptoms. • Rapid breathing and a change in mental status, may be the first signs of sepsis. • Other symptoms include: • Fever • Chills/hypothermia • Decreased urination • Tachycardia • Nausea and vomiting

14. Clinical Manifestations of Shock  Platelets  PT/APTT  Protein C  D-dimer Delirium and Encephalopathy Hyperpyrexia or Hypothermia Adrenal Dysfunction Acute Lung Injury or ARDS Oliguria Anuria  Creatinine Metabolic acidosis Jaundice  Enzymes  Albumin  PT Gut Dysfunction Altered Glucose Metabolism ARDS: Acute respiratory distress syndrome; PT: Prothrombin time; APTT: Activated partial thromboplastin time

15. The Sepsis Continuum SIRS with a presumed or confirmed infection Local or systemic infection or traumatic injury • A clinical response arising from a nonspecific insult, including ≥ 2 of the following: • Temperature > 38ºC or < 36ºC • Heart rate > 90 beats/min • Respiratory rate > 20 breaths/min or PaCO2 < 32 Torr • WBC > 12,000 cells/mm3, < 4,000 cells/mm3, or > 10% immature • Sepsis with ≥ 1 sign of organ failure: • Cardiovascular (refractory hypotension) • Renal • Respiratory • Hepatic • Hematologic • CNS • Unexplained metabolic acidosis Adapted from Bone RC, Balk RA, Cerra FB et al. Chest. 1992;101:1644-55.

16. The Relationship Between SIRS, Sepsis, and Severe Sepsis Other Sepsis Severe Sepsis Pancreatitis Infection SIRS Trauma Burns Bone RC, Balk RA, Cerra FB et al. Chest. 1992;101:1644-55.

17. Locations for Common Infection Skin and soft tissue Lungs Vascular Catheters(endovascular) Abdomen Appendix http://www.nigms.nih.gov/Education/factsheet_sepsis.htm Urinary Tract

18. Microbes • Many different types of microbes can cause sepsis: • Bacteria (most common) • Fungi • Viruses • Severe cases often result from a localized infectionbut sepsis can also spread throughout the body. Staphylococcus sp. (Bacteria) Aspergillus sp. (Fungi) Influenza (Virus) CDC/ Matthew J. Arduino CDC/ Robert Simmons CDC/ Erskine. L. Palmer, PhD; M. L. Martin http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

19. Mortality Rates • Sepsis remains the leading cause of death in critically ill patients in the United States. • Each year 750,000 people will develop sepsis. AIDS Breast Cancer Severe Sepsis National Center for Health Statistics, 2001. American Cancer Society, 2001. Angus DC, Linde-Zwirble WT, Lidicker J et al. Crit Care Med. 2001;29(7):1303-10.

20. Sepsis Incidence in Men and Women 300 200 100 0 Men Women Population-Adjusted Incidence of Sepsis (No./100,000) 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 Martin GS et al. N Engl J Med. 2003;348:1546-54.

21. Sepsis Incidence by Race 500 400 300 200 100 0 Other Black White Population-Adjusted Incidence of Sepsis (No./100,000) 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 Martin GS, Mannino DM, Eaton S et al. N Engl J Med. 2003;348:1546-54.

22. Sepsis Incidence in the United States: 2000 250 200 150 Incidence per 100,000 100 50 0 Sepsis Breast Acute Multiple Lung Colon AIDS Cancer Myocardial Sclerosis Cancer Cancer Infarction Martin GS, Mannino DM, Eaton S et al. N Engl J Med. 2003;348:1546-54. SEER Cancer Statistics Review. National Cancer Institute. www.cancer.gov. 2007. HIV/AIDS Surveillance Report. Centers for Disease Control. 2001;11.Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. NHLBI, NIH. 2006.Turabelidze G. J Neurol Sci. 2008;269:158-62.

23. Sepsis Morbidity and Mortality • In severe cases, one or more organs fail. • Worst case scenario: • Blood pressure drops • Septic shock • Multiple organ system failure • Death • The number of sepsis cases per year has been on the rise: • Aging population, the increased longevity of people with chronic diseases, the spread of antibiotic-resistant organisms, an upsurge in invasive procedures and broader use of immunosuppressive and chemotherapeutic agents. http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

24. How Do I Decide Who is Really Sick With an Infection?

25. Sepsis Biomarkers Use in Diagnosis, Risk, and Response

26. Utility of Biomarkers • Diagnosis/differentiation Prognostication • Value of baseline • Value of change over time Following success/failure of therapy

27. Diagnosis of Sepsis • Bacteria in the blood or other body fluids • Source of the infection • A high or low white blood cell count • A low platelet count • Low blood pressure • Too much acid in the blood (acidosis) • Altered kidney or liver function  • Biomarkers

28. Sepsis Biomarkers: Screening • Diagnosis of sepsis and evaluation of its severity is complicated by the highly variable and non-specific nature of signs and symptoms. • Distinguishing patients with localized infections or SIRS from those with sepsis is challenging. • SIRS is not specific to sepsis and can result from other conditions such as acute pancreatitis and immunodeficiencies. • Biomarkers of sepsis may improve diagnosis and therapeutic decision making. Lever A, Mackenzie I. Br Med J. 2007;335:879–83.

29. Sepsis Biomarkers • More than 170 biomarkers have been assessed for sepsis prognosis and diagnosis • Some common biomarkers include: • White blood cell count • Interleukins and other cytokines • Procalcitonin (PCT) • C-reactive protein (CRP) • Lactate • Procoagulant factors Pierrakos C, Vincent JL. Crit Care. 2010,14:R15.

30. Anaerobic Glycolysis (Cytoplasm) (Mitochondria) O2 Glycogen Glucose Pyruvate Citric Acid Cycle CO2 H2O Lactate 1 Glu + 2 ADP + 2 Pi 2 Lactate + 2 ATP 1 Glu + 6 O2 + 38 ADP + 38 Pi 6 CO2 + 6 H20 + 38 ATP Lactic Acidosis Aerobic Glycolysis Mizock BA, Falk JL. Crit Care Med. 1992;20:80-95.

31. Diagnostic and Therapeutic Markers 80 60-80% Normal 60 50% Lactic Acidosis (≥ 4 mmol/L) 40 SvO2

32. Serum Lactate as a Predictor of Mortality 30 25 20 15 10 5 0 50 40 30 20 10.0 0.0 28% 38-40% % of Mortality Rate % of Mortality Rate 0-2.4 2.5-3.9 > 4.0 0-2.4 2.5-3.9 > 4.0 N = 827 N = 238 N = 112 Initial Lactate (mmol/L)2 Lactate1 Death within 3 days 28 day in-hospital mortality 1 Trzeciak S, Dellinger RP, Chansky ME et al. Intensive Care Med. 2007;33:970-7. 2 Shapiro NI, Howell MD, Talmor D et al. Ann Emerg Med. 2005; 45:524-8.

33. Serum Lactate as a Predictor of Mortality 7 6 5 4 3 2 1 0 Non-survival Survival p = 0.001 p < 0.001 Mean Lactate Level (mmol/L) Arrival Scene (T1) Emergency Department (T2) Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

34. Value of Blood Lactate Levels First Lactate Measurement N = 124 < 3.5 mmol/l ≥ 3.5 mmol/l 11 Missing (0 Died) 7 Missing (4 Died) 8/66 (12%) Mortality 24/58 (41%) Mortality p < 0.001 Second Lactate Measurement N = 55 N = 51 < 3.5 mmol/l ≥ 3.5 mmol/l < 3.5 mmol/l ≥ 3.5 mmol/l 8/54 (15%) Mortality 0/1(0%) Mortality 2/14 (14%) Mortality 18/37(49%) Mortality p = 1.00 p = 0.025 N = 106 Second Lactate Cumulative < 3.5 mmol/l ≥ 3.5 mmol/l 10/68 (15%) Mortality 18/38 (47%) Mortality p < 0.001 Adapted from Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

35. Lactate, SBP, and Mortality 60 50 40 30 20 10 0 Mortality (%) > 3.5 < 100 Lactate (mmol/l) > 100 < 3.5 SBP (mmHg) Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

36. Serum Lactate and Mortality in Severe Sepsis • Initial serum lactate evaluated in 839 adults admitted with severe sepsis. p = 0.001 50 45 40 35 30 25 20 15 10 5 0 p = 0.022 p < 0.001 28-Day Mortality (%) • High initial serum lactate associated with ↑ mortality regardless of presence of shock or MODS. p = 0.024 Low Int High Low Int High Non-Shock Shock Mikkelsen ME, Miltiades AN, Gaieski DF et al. Crit Care Med. 2009;37:1670-7.

37. Improving Lactate a Good Prognostic Sign 8 6 4 2 0 p < 0.05 Non-survivors Lactate (mmol/L) p < 0.05 p < 0.01 Survivors INITIAL +8h +16h +24h FINAL Time Bakker J, Gris P, Coffernils M et al. Am J Surg. 1996;171:221-6.

38. Hospital Origin and Mortality Origin Mortality ED 52.4% 27.6% ICU 12.8% 41.3% Wards 34.8% 46.8% You have to go to the disease instead of waiting for it to come to you! Surviving Sepsis Campaign. http://ssc.sscm.org.

39. Risk Stratification of Sepsis Hypotension, vasopressors 36.7% Lactate > 4 mmol/L only 30.0% SBP < 90 mmHg and lactate > 4 mmol/L 46.1% Surviving Sepsis Campaign. http://ssc.sscm.org.

40. Sepsis Testing and Results Guidelines, Algorithms, and Protocols

41. Factors to Consider When Evaluating Sepsis • Blood gases • Electrolytes • Glucose • Hematocrit • Lactate

42. Sepsis Resuscitation Bundle The Sepsis Resuscitation Bundle is published by the Surviving Sepsis Campaign and is used by multiple hospitals across the country. The goal is to perform all indicated tasks 100% of the time within the first 6 hours of identification of severe sepsis. Surviving Sepsis Campaign. http://ssc.sscm.org.

43. Sepsis Resuscitation Bundle • Measure serum lactate. • Obtain blood cultures prior to antibiotic administration. • Administer broad-spectrum antibiotic, within 3 hours of emergency department (ED) admission and within 1 hour of non-ED admission. • In the event of hypotension and/or a serum lactate > 4 mmol/L: • Deliver an initial minimum of 20 ml/kg of crystalloid or an equivalent. • Apply vasopressors for hypotension not responding to initial fluid resuscitationto maintain mean arterial pressure (MAP) > 65 mmHg. • In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L: • Achieve a central venous pressure (CVP) of > 8 mmHg. • Achieve a central venous oxygen saturation (ScvO2) > 70% or mixed venous oxygen saturation (SvO2) > 65%. Surviving Sepsis Campaign. http://ssc.sscm.org.

44. Sepsis Treatment Guidelines • Antibiotic therapy • Begin intravenous antibiotics as early as possible • Always within the first hour of recognizing severe sepsis (1D) and septic shock. (1B) • Broad-spectrum • One or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source. (1B) • Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, & minimize costs. (1C) • Consider combination therapy in Pseudomonas infections. (2D) Surviving Sepsis Campaign. http://ssc.sscm.org.

45. Sepsis Treatment Guidelines • Antibiotic therapy • Consider combination empiric therapy in neutropenic patients. (2D) • Combination therapy no more than 3-5 days and de-escalation following susceptibilities. (2D) • Duration of therapy typically limited to 7-10 days • Longer if response slow, undrainable foci of infection, or immunologic deficiencies. (1D) • Stop antimicrobial therapy if cause is found to be non-infectious. (1D) Surviving Sepsis Campaign. http://ssc.sscm.org.

46. Applications Identification, Treatment, and Outcomes

47. Identification of Sepsis If YES, patient has SIRS If YES, patient has Sepsis If YES, patient has Severe Sepsis Daniels R. J Antimicrob Chemother. 2011;66(Suppl 2):ii11–ii23.

48. Improve Patient Outcomes • Lactate clearance is associated with improved patient outcome. • Lactate measurement is associated with increased risk of death independent of other aspects of sepsis bundle guidelines. Nguyen HB, Rivers EP, Knoblich BP et al. Crit Care Med. 2004;32(8):1637-42. Afessa B, Keegan MT, Schramm GE et al. Crit Care Med. 2011;15(Suppl 1): P286. Boldt J, Kumle B, Suttner S et al. Acta Anaesthesiol Scand. 2001;45:194–9.