Sepsis: stopping an insidious killer

1. Sepsis: stopping an insidious killer What you must know to understand, identify, and treat this lethal condition

2. Learning Objectives • Describe the physiologic response to sepsis. • Discuss the signs and symptoms of sepsis. • State strategies for managing sepsis.

3. A woman, age 65 • Admitted because of a hip infection after hip replacement surgery. The infection, caused by Staphylococcus aureus, has been difficult to treat, so she’s admitted for more aggressive antibiotic therapy. • On admission, a nurse records this information: • Heart rate: 113 beats/minute (tachycardia) • Respiratory rate: 28 breaths/minute (tachypnea) • Temperature: 100.9° F (38.3° C) (febrile) • White blood cell count (WBC): 21,200/μl(leukocytosis)

4. A woman, age 65 • Within 24 H of admission to a medical unit, her urine output falls. Believing she may be dehydrated, the physician orders 1,500 ml of normal saline solution. But she doesn’t respond well to the fluid administration. • The next day, her pulse oximeter reading falls from 96% to 88%. In response, she’s given nasal oxygen at 3 L/minute, which increases her oximeter reading to 92%. Then, < 36 hours after the start of oxygen therapy, her BP drops, and she is transferred to the intensive care unit (ICU).

5. A woman, age 65 • In the ICU, she’s intubated and given the only treatments available for sepsis: a) aggressive fluid replacement to return oxygen saturation to normal b) tight glycemic control to keep her blood glucose level below 150 mg/dl c) corticosteroid replacement d) activated protein C (Xigris). • Despite these efforts, she dies after 10 days in the ICU.

6. Infection or Sepsis ? • The confusion between infection and sepsis is responsible for delays in identifying sepsis. And delays in treating sepsis can result in tragic outcomes. • Sepsis is lethal, and its development is insidious. Be vigilant in recognizing the condition.

8. Epidemiology • Prior to 1987, gram-negative organisms were predominant. In the past 20 years, sepsis caused by gram-positive organisms has increased markedly, and now predominant. Additionally, over the same time period, the incidence of fungal sepsis has increased by over 200%. • Changes due to  numbers of IC patients & debilitated surgical patients, & increased use of indwelling catheters and devices. • The causative organisms implicated in sepsis have changed over time, and many cases have non-diagnostic or negative cultures. • The identified sites of primary infection are:lung(47%), unknown/other (28%), peritoneum (15%), and urinary tract (10%).

9. Severe Sepsis Among Adults in PGH ICUs 223/1207 (18.5%) with severe sepsis Mean duration of stay 14 days (S.D.12) ICU mortality rate 58.9% (95% CI 52%, 66%) Respiratory tract most common site Gram negative infections common: Pseudomonas aeruginosa, Klebsiella, Acinetobacter Most frequent organ dysfunction: resp., CVS, neuro Source: Taguiang-Abu C. and Alejandria M., Phil. J. Internal Medicine 2008

10. Risk Factors: Immunosuppresion OR 2.45 (C.I. 1.11, 5.42) Cardiovascular dysfunction OR 3.57 (C.I. 1.56, 8.16) Hematologic dysfunction OR 3.45 (C.I 1.43, 8.29) Inappropriate antibiotic OR 9.20 ( C.I. 4.27, 19.82) Severe Sepsis Among Adults in PGH ICUs Source: Taguiang-Abu C. and Alejandria M., Phil. J. Internal Medicine 2008

11. Special Concerns – Sepsis in the Elderly • Increased in the elderly; WHY? • Decrease in cell-mediated & humoral immune function • Cytokine & chemokine signaling networks are altered • Induction of proinflammatory cytokines after septic stimuli not adequately controlled by anti-inflammatory mechanism • Pronounced procoagulant state

12. Definitions of Sepsis (ACCP/SCCM Consensus Conference) • Bacteremia– presence of viable bacteria in the blood. Similarly, the presence of other pathogens in blood would be described appropriately as viremia, fungemia, or parasitemia • Infection– microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of otherwise sterile host tissues by those organisms

13. SEPSIS • Systemic inflammatory response to an infection • Infection = presence of microorganisms (bacteria, fungi, viral, parasitic) in a normally sterile site • If associated with proven or clinically suspected infection SIRS = SEPSIS

14. Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis Altered Consciousness Confusion Psychosis Tachycardia Hypotension  CVP  PAOP Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2300 Oliguria Anuria  Creatinine Jaundice  Enzymes  Albumin  PT  Platelets  PT/APTT  Protein C  D-dimer

15. Organ Dysfunction Associated with Severe Sepsis and Septic Shock • Skin: Skin lesions in sepsis can arise by at least 5 mechanisms: • Disseminated intravascular coagulation and coagulopathy - for example, in sepsis due to gram-negative and gram-positive bacteria. • Invasion of blood vessel walls - for example, in ecthymagangrenosum, Rocky Mountain spotted fever, meningococcemia, disseminated candidiasis, Aspergillus infection, and mucormycosis.

16. Ecthymagangrenosum • The initial skin lesions of ecthymagangrenosum are erythematous to purpuricmacules, hemorrhagic vesicles, bullae, or nodules. They rapidly progress to a painless, indurated ulcer with a central necrotic black eschar and surrounding erythema. • The most common sites of distribution are the axillae and anogenital regions. • Early clue to severe infection caused by Pseudomonas aeruginosaand, less commonly, to other bacteria and fungi.

17. Organ Dysfunction Associated with Severe Sepsis and Septic Shock • Immune complex formation with vasculitis―for example, endocarditis, disseminated gonococcal disease, typhoid fever, and meningococcemia (later phases). • Embolism―for example, endocarditis and, rarely, mycotic aneurysm. • Toxin formation―for example, toxic shock syndrome, scarlet fever

18. Organ Dysfunction Associated with Severe Sepsis and Septic Shock • Endocrine- Relative adrenal insufficiency Hypo/hyperglycemia Persistent hypotension

19. SEPTIC SHOCK • Sepsis with hypotension that requires pressor therapy despite adequate fluid resuscitation (or normotensive on vasopressors) accompanied by perfusion abnormalities described for Severe Sepsis • If no response in >1hr: Refractory Septic Shock MODS Dysfunction of > 1 organ requiring intervention to maintain homeostasis

20. Differential Diagnosis

21. Pathogenesis • Determinants of the Sepsis Syndrome: • Virulence of the organism. b)Inoculum of the organism. Greater# of invaders  greater inflammatory response c) Site of Infection- what organisms invade what areas d) Host Response– the balance between inflammatory & anti-inflammatory response e)Genetic Factors– susceptibility and regulation

22. Pathogenesis • Organisms: cause sepsis syndrome either by Direct Invasion or Intoxication. A.Sources of Direct Invasion: • Gram (-)’s: some of the enterics, pseudomonas • Gram (+)’s have become the leading cause of Septic Shock • TB (less common) • Virus (becoming more common) eg. SARS • Fungal (alarming growth in infection rate over last decade in the US)

23. Pathogenesis B.Intoxication: elaboration of proteins by a number of bacteria S. aureus can secrete toxic shock syndrome toxin-1 (TSST-1) S. pyogenes secretes streptococcal pyrogenicexotoxin A (SPEA)

24. Sepsis & Inflammation • Microorganisms have unique cell-wall molecules called pathogen-associated molecular patterns that bind to pattern-recognition receptors (toll-like receptors [TLRs]) on the surface of immune cells. • The LPS of GNB binds to LPS-binding protein, CD14 complex. The peptidoglycan of GPB and the LPS of GNB bind to TLR-2 and TLR-4, respectively.

25. Sepsis & Inflammation • Interaction of a PAMP with a Tlr results in a cellular cascade which leads to activation of innate immune mechanisms 􀂄Message sent to nucleus resulting in transcription of repressed genes 􀂄 Antimicrobial peptide synthesis and release 􀂄 Beginning of a specific adaptive antibody response 􀂄Release of Mediators of inflammation 􀂄 Normally protective but some type of dysregulation leads to signs of SEPSIS

29. Cytokines & other inflammatory mediator cascades • Infection stimulates neutrophils & monocytesto produce reactive oxygen intermediates. • Interleukin-10 is an antiinflammatory cytokine that inactivates macrophages and has other antiinflammatoryeffects. • Stimulated monocytes-macrophages produce proinflammatorycytokines  TNF- IL-1, IL-6, IL-8  interferon- • Infection activates the complement & coagulation pathways.

31. Sepsis and Inflammation • Animal models using large endotoxin or bacterial load lead to a cytokine storm and death • Failure of trial agents that block the inflammatory cascade to reduce mortality in humans leads to question of whether death in sepsis is due to uncontrolled inflammation

32. Sepsis & Immunosuppression • Septic patients have features of immunosuppression • Sepsis may initially have increased inflammatory mediators and later an anti-inflammatory state

35. Clinically, this procoagulant state of sepsis is manifested by decreased platelets, protein C deficiency, and positive D-dimers.

36. aProtein C modulates both the inflammatory and the coagulation cascades – Endothelial dysfunction caused by proinflammatory cytokines decreases thrombomodulin, a protein that binds with thrombin. The complex formed is required to convert protein C to aProtein C, an important anti-inflammatory, antithrombotic, and profibrinolytic molecule. Patients with sepsis are deficient in protein C and at increased risk for thrombosis and continued inflammation.

37. Activated Protein C - Proposed Mechanisms • Anti-inflammatory effects - Inhibits cytokine production & release - Inhibits neutrophil activation & endothelial damage • Anticoagulant effects - Endogenous APC levels are depleted in sepsis - APC cleaves and inactivate factors Va & Vllla - Ultimately limits generation of thrombin • Fibrinolysis effects - Inactivates PAI-1 to promote homeostatic thrombolysisby tPA - Inhibits TAFI activation to maintain fibrinolysis Crit Care Mod 2001 ;29(Supp/):S69-S74 RSS 2001

38. How infection leads to septic shock ? • Release of the inflammatory mediators described above leads to: Endothelial damage resulting in fluid leakage  Loss of vascular resistance  Reduced cardiac inotropy  Extensive coagulation & DIC B. End result is end-organ damage that eventually will lead to organ failure & death.

39. Coagulation  Inflammation Homeostasis Is Lost In Sepsis • Proinflammatory mediators • Endothelial injury • Tissue factor expression • Thrombin production Fibrinolysis • Increased PAl-1 • Increased TAFIa • Reduced Protein C (Activated Protein C inhibits PAI-1) Homeostasis PAI-1= plasminogen activator inhibitor-1;TAFIa= thrombin activatablefibrinolysis inhibitor. Carvalho and Freeman. J Crit Illness. 1994;9:51; Kidokoro et al. Shock. 1996;5:223; Vervloet et al. SeminThrombHemost. 1998;24:33.

40. What Determines Clinical Outcome of Sepsis? • Balance between proinflammatory & counter-regulatory anti-inflammatory events in response to infection determines clinical outcome. • Excessive proinflammatoryresponse causes systemic toxicity clinically manifested by as sepsis. • Excessive anti-inflammatory response causes immunoparalysis associated with increased propensity for overwhelming infection & late mortality.

41. Bacterial, fungal, viral infection Endotoxin, Cell walls Superantigens (Exotoxins) Macrophages, monocytes T Cells Cytokine release – TNF-a, IL-1, IL-6, IL-8, IL-10 Platelet and coagulation activation Complement activation Endothelial injury, coagulation, DIC, shock, end organ damage Irrerverisble shock – Multiorgan failure - Death

42. Clinical Manifestations • Fever  First & most common manifestation The greater the height of temperature, the more likely is bacteremia. Hypothermia & normal body temperature can be seen in patients who are bacteremic.  Hypothermia is a poor prognostic indicator in bacteremic patients.

43. Clinical Manifestations • Hemodynamic Changes  Tachycardia in association with fever is to be expected. Bradycardia is unusual, being found in typhoid fever & brucellosis. Hypotension is the most important determinant of outcome.

44. Clinical Manifestations Preshock the stage at which hypotension is reversible.  Characterized by warm skin, diminished mentation(often worse in the elderly), & oliguria.  Failure to reverse hypotension in its early stages results in serious end organ damage.

45. Clinical Manifestations Persistent hypotensionoften not reversed by antibiotics & other measures.  Characterized by cool skin, ARF, &, later, hepatic injury.

46. Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.

47. Physiologic Characteristics of the Various Forms of Shock Note:CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure.

48. Mechanisms of Vasodilatory or Distributive shock

49. Clinical Manifestations C.Acid-Base Disturbances  Reduced tissue perfusion results in shift from aerobic to anaerobic metabolism causing lactic acid accumulation. Respiratory alkalosis usually seen first as a consequence of tachypnea. The first pronounced change, signaling impending shock.  Seen at the time when hemodynamic changes are reversible with fluid resuscitation.

50. Clinical Manifestations Critical to recognize this early reversible stage of septic shock. Metabolic acidosisdevelops just prior to or accompanies hypotension.  Signals the beginning of a fatal downward spiral.  Reflects severe organ hypoperfusion& failure.