The document discusses systemic inflammatory response syndrome (SIRS) and sepsis. It defines SIRS as a systemic inflammatory response to various stresses and infections, with specific criteria for diagnosis. Sepsis is defined as SIRS caused by a confirmed or suspected infection. The document outlines the continuum of sepsis, from SIRS to septic shock, and risk factors. It discusses the pathogenesis of sepsis and treatments including antibiotics, fluid resuscitation, and activated protein C.

1. Systemic Inflammatory Response Syndrome (SIRS) PRANEE SITAPOSA, MD.

2. SEPSIS and It’s Disease spectrum Various stages of disease Bacteremia SIRS Sepsis syndrome Sepsis shock : early and refractory

3. Definition Infection Presence of microorganisms in a normally sterile site. Bacteremia Cultivatable bacteria in the blood stream. Sepsis The systemic response to infection. If associated with proven or clinically suspected infection, SIRS is called “sepsis”. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit Care Med. 1992;20:864-874.

4. SIRS (Systemic Inflammatory Response Syndrome) The systemic response to a wide range of stresses. Temperature >38 °C (100.4°) or <36°C (96.8°F). Heart rate >90 beats/min. Respiratory rate >20 breaths/min or PaCO 2 <32 mmHg. White blood cells > 12,000 cells/ml or < 4,000 cells/ml or >10% immature (band) forms. Note Two or more of the following must be present. These changes should be represent acute alterations from baseline in the absence of other known cause for the abnormalities. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit Care Med. 1992;20:864-874.

5. Severe Sepsis Sepsis with organ hypoperfusion one of the followings : SBP < 90 mmHg Acute mental status change PaO 2 < 60 mmHg on RA (PaO 2 /FiO2 < 250) Increased lactic acid/acidosis Oliguria DIC or Platelet < 80,000 /mm 3 Liver enzymes > 2 x normal American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit Care Med. 1992;20:864-874.

6. MODS (Multiple Organ Dysfunction Syndrome) Sepsis with multiorgan hypoperfusion Two or more of the followings: SBP < 90 mmHg Acute mental status change PaO 2 < 60 mmHg on RA (PaO 2 /FiO 2 < 250) Increased lactic acid/acidosis Oliguria DIC or Platelet < 80,000 /mm 3 Liver enzymes > 2 x normal American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit Care Med. 1992;20:864-874.

7. Relationship between SIRS and Sepsis Bone RC et al, Chest1992;101:164-55.

8. The Sepsis Continuum A clinical response arising from a nonspecific insult, with  2 of the following: T >38 o C or <36 o C HR >90 beats/min RR >20/min WBC >12,000/mm 3 or <4,000/mm 3 or >10% bands SIRS = systemic inflammatory response syndrome SIRS with a presumed or confirmed infectious process Chest 1992;101:1644. Sepsis with organ failure Refractory hypotension Sepsis SIRS Severe Sepsis Septic Shock

9. Mortality rate in SIRS Rangel - Frausto, et al. JAMA 273:117-123, 1995.

10. The Response to Pathogens “Cross-Talk” NEJM 2003;348:138-150.

11. Inflammatory Response to Sepsis NEJM 2006;355:1699-1713.

12. Procoagulant Response in Sepsis NEJM 2006;355:1699-1713.

13. Pathogenesis of sepsis and septic shock Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

14. Pathogenesis of Severe Sepsis Infection Microbial Products (exotoxin/endotoxin) Cellular Responses Oxidases Platelet Activation Kinins Complement Coagulopathy/DIC Vascular/Organ System Injury Multi-Organ Failure Death Endothelial damage Endothelial damage Coagulation Activation Cytokines TNF, IL-1, IL-6

15. Normal Systemic Response to Infection and Injury (1) Leukocytosis Mobilizes neutrophils into the circulation Tachycardia Increases cardiac output, blood flow to injuried tissue Fever Raises core temperature; peripheral vasoconstriction shunts blood flow to injuried tissue. Occurs much more often when infection is the trigger for systemic responses Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

16. Normal Systemic Response to Infection and Injury (2) Acute-Phase Responses Anti-infective Increases synthesis of complement factors, microbe pattern-recognition molecules(mannose-binding lectin, LBP, CRP, CD14, Others) Sequesters iron (lactoferrin) and zinc (metallothionein) Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

17. Normal Systemic Response to Infection and Injury (3) Anti-inflammatory Releases anti-inflammatory neuroendocrine hormones (cortisol, ACTH, epinephrine, α -MSH) Increases synthesis of proteins that help prevent inflammation within the systemic compartment Cytokine antagonists (IL-1Ra, sTNF-Rs) Anti-inflammatory mediators (e.g.,IL-4, IL-6, IL-6R, IL-10, IL-13, TGF- β ) Protease inhibitors (e.g., α 1-antiprotease) Antioxidants (haptoglobin) Reprograms circulating leukocytes (epinephrine, cortisol, PGE 2 , ?other) Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

18. Normal Systemic Response to Infection and Injury (4) Procoagulant Walls off infection, prevents systemic spread Increases synthesis or release of fibrinogen, PAI-1, C4b Decreases synthesis of protein C, anti-thrombin III Metabolic Preserves euglycemia, mobilizes fatty acids, amino acids Epinephrine, cortisol, glucagon, cytokines Thermoregulatory Inhibits microbial growth Fever Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

19. Risk factors of sepsis aggressive oncological chemotherapy and radiation therapy use of corticosteroid and immunosuppressive therapies for organ transplants and inflammatory diseases longer lives of patients predisposed to sepsis, the elderly, diabetics, cancer patients, patients with major organ failure, and with granulocyopenia. Neonates are more likely to develop sepsis ( ex . group B Streptococcal infections ). increased use of invasive devices such as surgical protheses, inhalation equipment, and intravenous and urinary catheters. indiscriminate use of antimicrobial drugs that create conditions of overgrowth, colonization, and subsequent infection by aggressive, antimicrobial - resistant organisms . Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

20. Patients at increased risks of developing sepsis Underlying diseases : neutropenia, solid tumors, leukemia, dysproteinemias, cirrhosis of the liver, diabetes, AIDS, serious chronic conditions. Surgery or instrumentation : catheters . Prior drug therapy : Immuno-suppressive drugs, especially with broad-spectrum antibiotics. Age : males, above 40 y; females, 20-45 y . Miscellaneous conditions : childbirth, septic abortion, trauma and widespread burns, intestinal ulceration. Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

21. Source ( usually an endogenous source of infection ) intestinal tract oropharynx instrumentation sites contaminated inhalation therapy equipment IV fluids. Most frequent sites of infection : Lungs, abdomen, and urinary tract. Other sources include the skin/soft tissue and the CNS. Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

22. Diagnosis History community or nosocomially acquired infection immunocompromised patient exposure to animals, travel, tick bites, occupational hazards, alcohol use, seizures, loss of consciousness, medications underlying diseases ; specific infectious agents Some clues to a septic event include Fever or unexplained signs with malignancy or instrumentation Hypotension Oliguria or anuria Tachypnea or hyperpnea Hypothermia without obvious cause Bleeding Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

23. Specific Infectious agents Splenectomy (traumatic or functional) S pneumoniae, H influenzae, N meningitidis Neutropenia (<500 neutrophil/ml) Gram-negative, including P aeruginosa , gram-positives, including S aureus Fungi, especially Candida species Hypogammaglobulinemia (e.g.,CLL) S pneumoniae, E coli Burns MRSA, P aeruginosa , resistant gram-negatives MacArthur RD, et al. Mosby, 2001:3-10. Wheeler AP, et al. NEJM 1999;340:207-214. Chaowagul W, et al. J Infect Dis 1989;159:890-899.

24. Specific Infectious agents Aids P aeuginosa (if neutropenic), S aureus , PCP pneumonia Intravascular devices S aureus , S epidermidis Nosocomial infections MRSA, Enterococcus species, resistant gram-negative, Candida species Septic patients in NE of Thailand Burkholderia pseudomallei MacArthur RD, et al. Mosby, 2001:3-10. Wheeler AP, et al. NEJM 1999;340:207-214. Chaowagul W, et al. J Infect Dis 1989;159:890-899.

25. Diagnosis Physical Examination essential In all neutropenic patients and in patients with as suspected pelvic infection the physical exam should include rectal, pelvic, and genital examinations perirectal, and/or perineal abscesses pelvic inflammatory disease and/or abscesses, or prostatitis Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

26. Signs and Symptoms Nonspecific symptoms of sepsis : not pathognomonic fever chills constitutional symptoms of fatigue, malaise anxiety or confusion absent symptoms in serious infections, especially in elderly individuals Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

27. Complications Adult respiratory distress syndrome ( ARDS ) Disseminated Intravascular Coagulation ( DIC ) Acute Renal failure ( ARF ) Intestinal bleeding Liver failure Central Nervous System dysfunction Heart failure Death Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

28. Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock Dellinger RP, et al. Crit Care Med 2004; 32:858-873.

29. Before the initiation of antimicrobial therapy, at least two blood cultures should be obtained At least one drawn percutaneously At least one drawn through each vascular access device if inserted longer than 48 hours Other cultures such as urine, cerebrospinal fluid, wounds, respiratory secretions or other body fluids should be obtained as the clinical situation dictates Other diagnostic studies such as imaging and sampling should be performed promptly to determine the source and causative organism of the infection may be limited by patient stability Weinstein MP. Rev Infect Dis 1983;5:35-53 Blot F. J Clin Microbiol 1999; 36: 105-109. Diagnosis Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

30. Sepsis resuscitation bundle Serum lactate measured Blood cultures obtained before antibiotics administered Improve time to broad-spectrum antibiotics In the event of hypotension or lactate > 4 mmol/L (36 mg/dL) a. Deliver an initial minimum of 20 mL/kg of crystaloid (or colloid equivalent) b. apply vasopressors for ongoing hypotension In the event of persistent hypotension despite fluid resuscitation or lactate > 4 mmol/L (36 mg/dL) a. achieve central venous pressure of > 8 mmHg b. achieve central venous oxygen saturation of > 70% Hurtado FJ. et al. Crit Care Clin;2006; 22:521-9.

31. Sepsis management bundle Fluid resuscitation Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Use of vasopressors/inotropes when fluid resuscitation optimized Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

32. Sepsis management bundle Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris) for severe sepsis Low tidal volume mechanical ventilation for ARDS Tight glucose control Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

33. Infection Control Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

34. Early Goal-Directed Therapy CVP : central venous pressure MAP : mean arterial pressure ScvO 2 : central venous oxygen saturation NEJM 2001;345:1368-77 .

35. Early Goal-Directed Therapy Results 49.2% 33.3% 0 10 20 30 40 50 60 Standard Therapy n=133 EGDT n=130 P = 0.01* *Key difference was in sudden CV collapse, not MODS 28-day Mortality NEJM 2001;345:1368-77.

36. Antibiotic use in Sepsis (1) The drugs used depends on the source of the sepsis Community acquired pneumonia third ( ceftriaxone ) or fourth ( cefepime ) generation cephalosporin is given with an aminoglycoside ( usually gentamicin ) Nosocomial pneumonia Cefipime or Imipenem-cilastatin and an aminoglycoside Abdominal infection Imipenem - cilastatin or Pipercillin - tazobactam and aminoglycoside Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

37. Antibiotic use in Sepsis (2) Nosocomial abdominal infection Imipenem-cilastatin and aminoglycoside or Pipercillin-tazobactam and Amphotericin B Skin / soft tissue Vancomycin and Imipenem - cilastatin or Piperacillin - tazobactam Nosocomial skin/soft tissue Vancomycin and Cefipime Urinary tract infection Ciprofloxacin and aminoglycoside Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

38. Antibiotic use in Sepsis (3) Nosocomial urinary tract infection: Vancomycin and Cefipime CNS infection : Vancomycin and third generation cephalosporin or Meropenem Nosocomial CNS infection: Meropenem and Vancomycin Drugs will change depending on the most likely cause of the patient's sepsis Single drug regimens are usually only indicated when the organism causing sepsis has been identified and antibiotic sensitivity testing Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

39. New Drug in Treating Severe Sepsis It is the first agent approved by the FDA effective in the treatment of severe sepsis proven to reduce mortality . Activated Protein C ( Xigris ) mediates many actions of body homeostasis . It is a potent agent for the : suppression of inflammation prevention of microvascular coagulation reversal of impaired fibrinolysis Angus DC, et al . Crit Care Med 2001, 29:1303-1310.

40. NEJM;355:1699-1723.

41. Sepsis Cascade

42. Activated Protein C ( Xigris ) NEJM;355:1640, October 19, 2006.

43. Thank you