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  • Sepsis

    1. 1. Sherry L Knowles Compliments of StudyPro                                                                                                                                   
    2. 2. Sepsis Syndrome <ul><li>Sepsis encompasses a spectrum of clinical conditions caused by the immune response to infection and is characterized by systemic inflammation and coagulation. </li></ul><ul><li>Sepsis includes the full range of responses from systemic inflammatory response (SIRS) to organ dysfunction to multiple organ failure and ultimately death. </li></ul>
    3. 3. Sepsis Morbidity & Mortality <ul><li>Leading cause of death in noncoronary ICU patients </li></ul><ul><li>13th leading cause of death in U.S. </li></ul><ul><li>Over 500,000 episodes each year </li></ul><ul><li>35-70% mortality </li></ul><ul><li>20-50% positive blood cultures </li></ul><ul><li>40% hospital deaths after injury due to MODS </li></ul>
    4. 4. Sepsis On The Rise <ul><li>Incidences projected to rise to 1.0 million cases annually in the US within the next decade due to: </li></ul><ul><li>Aging population </li></ul><ul><li>Increased awareness and diagnosis </li></ul><ul><li>Immunocompromised patients </li></ul><ul><li>Invasive procedures </li></ul><ul><li>Resistant pathogens </li></ul>
    5. 5. <ul><li> SIRS Sepsis Severe Septic MODS Death </li></ul><ul><li>Infection Sepsis Shock </li></ul>Sepsis Syndrome
    6. 6. Infection Response <ul><ul><li>Dual Response </li></ul></ul><ul><ul><li>Innate immunity </li></ul></ul><ul><ul><li>Acquired immunity </li></ul></ul><ul><ul><li>Multiple Causes </li></ul></ul><ul><ul><li>Trauma </li></ul></ul><ul><ul><li>Bacterial </li></ul></ul><ul><ul><li>Viral </li></ul></ul><ul><ul><li>Parasitic </li></ul></ul><ul><ul><li>Fungal </li></ul></ul><ul><ul><li>Prions </li></ul></ul><ul><ul><li>Unknown </li></ul></ul>
    7. 7. Systemic Inflammatory Response Syndrome (SIRS) Systemic inflammatory response to a non-specific insult that includes ≥ 2 of the following symptoms: – Temperature > 38 C or < 36 C – Heart rate > 90 beats/min – Respiratory rate > 20/min, or paO2 < 32 mmHg – WBC > 12,000/mm3 or < 4,000/mm3, or > 10% bands
    8. 8. Sepsis Syndrome Sepsis – ‘ SIRS’ response with presumed/confirmed infection Severe Sepsis – Sepsis associated with organ dysfunction, hypoperfusion (lactic acidosis, oliguria, altered mental status etc.), or hypotension (SBP < 90 mmHg or ↓ SBP > 40 mmHg) Septic Shock – Sepsis with perfusion abnormalities and hypotension despite adequate fluid resuscitation
    9. 9. Multiple Organ Dysfunction Syndrome (MODS) Multiple Organ Failure – Presence of severe dysfunction of at least two organ system lasting for more than 24 hours. – Four or more systems - mortality near to 100 percent
    10. 11. Stages of Sepsis <ul><li>Systemic Inflammatory Response Syndrome (SIRS) Two or more of the following: </li></ul><ul><ul><ul><ul><li>Temperature of >38 o C or <36 0 C </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Heart rate of >90 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Respiratory rate of >20 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WBC count >12 x 10 9 /L or <4 x 10 9 /L or 10% bands </li></ul></ul></ul></ul><ul><li>Sepsis SIRS plus a culture-documented infection </li></ul><ul><li>Severe Sepsis Sepsis plus organ dysfunction, hypotension, or hypoperfusion (including but not limited to lactic acidosis, oliguria, or acute mental status changes) </li></ul><ul><li>Septic Shock Hypotension (despite fluid resuscitation) plus hypoperfusion </li></ul>
    11. 12. Compensatory anti-inflammatory response syndrome (CARS) Overcompensating Anti-inflammatory Response A syndrome in which anti-inflammatory mediator release overcompensates for the systemic inflammatory response leading to a state of immune suppression, increased susceptibility to infection, and impaired recovery.
    12. 13. Complications <ul><li>Adult respiratory distress syndrome (ARDS) </li></ul><ul><li>Disseminated Intravascular Coagulation (DIC) </li></ul><ul><li>Acute Renal failure (ARF) </li></ul><ul><li>Intestinal bleeding </li></ul><ul><li>Liver failure </li></ul><ul><li>Central Nervous system dysfunction </li></ul><ul><li>Heart failure </li></ul><ul><li>Death </li></ul>
    13. 14. Capillary Damage Capillary Damage during Systemic Inflammatory Response Syndrome (SIRS)                                                                                                      
    14. 15. Risk Factors <ul><li>Extreme Age (under 1 and > 65 years) </li></ul><ul><li>Surgical/Invasive Procedures </li></ul><ul><li>Malnutrition </li></ul><ul><li>Alcoholism </li></ul><ul><li>Broad-spectrum antibiotics </li></ul><ul><li>Chronic illness </li></ul><ul><li>Immune deficiency disorders </li></ul><ul><li>Antibiotic resistance </li></ul>
    15. 16. Growing Risk Factors <ul><li>Aging population </li></ul><ul><li>Increased awareness and diagnosis </li></ul><ul><li>Increasing immunocompromised patients </li></ul><ul><li>Invasive procedures </li></ul><ul><li>Increasing life-sustaining technology </li></ul><ul><li>Resistant pathogens </li></ul>
    16. 17. Systemic Response <ul><li>Initial systemic response </li></ul><ul><ul><li>Release of cytokines from the inflammatory system </li></ul></ul><ul><ul><ul><ul><li>Inflammation </li></ul></ul></ul></ul><ul><ul><li>Initiation of coagulation abnormalities </li></ul></ul><ul><ul><ul><ul><li>Activation of coagulation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibition of fibrinolysis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Platelet activation </li></ul></ul></ul></ul><ul><li>Activation of secondary systems </li></ul><ul><ul><li>Complement system, contact system, multiple cytokines and chemical mediators, free oxygen radicals, and nitric oxide. </li></ul></ul>
    17. 18. Inflammatory Cascade <ul><li>Pro-inflammatory cytokines promote endothelial cell adhesion, induce the release of free radicals and activate the coagulation cascade </li></ul><ul><li>Anti-inflammatory mediators provide a negative feedback mechanism for inflammatory and coagulation reactions. </li></ul><ul><ul><ul><li>If an imbalance develops between SIRS and CARS, homeostasis is violated: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>If SIRS predominates the result may be sepsis/ severe sepsis/ septic shock. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>If CARS predominates, the immune system may be suppressed, leaving the patient susceptible to life-threatening infections. </li></ul></ul></ul></ul></ul>
    18. 20. Coagulation Cascade <ul><li>Coagulation cascade </li></ul><ul><ul><ul><li>Activation of coagulation </li></ul></ul></ul><ul><ul><ul><li>Inhibition of fibrinolysis </li></ul></ul></ul><ul><ul><ul><li>Potentates the inflammation cascade </li></ul></ul></ul>
    19. 21. Impaired Fibrinolysis <ul><li>Impaired Fibrinolysis </li></ul><ul><ul><ul><li>Fibrinolysis is the breakdown of clots </li></ul></ul></ul><ul><ul><ul><li>Normally activated with coagulation </li></ul></ul></ul><ul><ul><ul><li>Fibrinolysis suppressed in sepsis </li></ul></ul></ul>
    20. 23. Sepsis Mediators <ul><ul><li>Myocardial depressant factor(s) </li></ul></ul><ul><ul><li>Enkephalins </li></ul></ul><ul><ul><li>Adrenocorticoid hormone </li></ul></ul><ul><ul><li>Prekallikrein </li></ul></ul><ul><ul><li>Interleukin-1 </li></ul></ul><ul><ul><li>Cytokinines (acid metabolites) (eg, </li></ul></ul><ul><ul><li>leukotrienes, prostaglandins, </li></ul></ul><ul><ul><li>thromboxanes) </li></ul></ul><ul><ul><li>The coagulation cascade </li></ul></ul><ul><ul><li>The complement system </li></ul></ul><ul><ul><li>The fibrinolytic system </li></ul></ul><ul><ul><li>Histamines </li></ul></ul><ul><ul><li>Bradykinins </li></ul></ul><ul><ul><li>Catecholamines </li></ul></ul><ul><ul><li>Glucocorticoids </li></ul></ul><ul><ul><li>Tumor necrosis factor </li></ul></ul><ul><ul><li>Beta-endorphins </li></ul></ul>The following systems and mediators are stimulated in sepsis:
    21. 24. Multiple Cascades
    22. 25. Homeostasis Gets Lost
    23. 26. Sepsis 101
    24. 27. Signs & Symptoms <ul><li>Fever, chills, hypotension </li></ul><ul><li>Hyper/Hypothermia </li></ul><ul><li>Hyperventilation </li></ul><ul><li>Tachycardia </li></ul><ul><li>Diaphoresis </li></ul><ul><li>Apprehension, irritability </li></ul><ul><li>Change in mental status </li></ul>
    25. 28. Cardiovascular Signs <ul><li>“ Warm shock” -  CO,  SVR </li></ul><ul><li>“ Cold shock” -  CO,  SVR </li></ul><ul><li>Anaerobic metabolism - lactic acidosis </li></ul><ul><li>Myocardial depressant factor </li></ul>
    26. 29. Pulmonary Signs <ul><li>Tachypnea </li></ul><ul><li>Hyperventilation, respiratory alkalosis </li></ul><ul><li>ARDS, respiratory failure </li></ul><ul><li>Ventilation-perfusion mismatch </li></ul><ul><li>Widened alveolar-arterial oxygen gradient </li></ul><ul><li>Reduced lung compliance </li></ul>
    27. 30. Hematologic Findings <ul><li>Neutrophilic leukocytosis </li></ul><ul><li>Leukemoid reaction </li></ul><ul><li>Neutropenia </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Toxic granulations </li></ul><ul><li>DIC </li></ul>
    28. 31. Renal and Gastrointestinal Signs <ul><li>Acute tubular necrosis, oliguria, anuria </li></ul><ul><li>Upper GI bleeding </li></ul><ul><li>Cholestatic jaundice </li></ul><ul><li>Increased transaminase levels </li></ul><ul><li>Hypoglycemia </li></ul>
    29. 32. Skin <ul><li>Furuncles, cellulitis, bullous lesions </li></ul><ul><li>Intravenous sites, phlebitis </li></ul><ul><li>Erythema multiforme </li></ul><ul><li>Ecchymotic or purpuric lesions </li></ul><ul><li>DIC, petechiae </li></ul><ul><li>Ecthyma gangrenosum </li></ul><ul><li>Purpura fulminans </li></ul>
    30. 33. Many Organs Affected <ul><li>Lungs </li></ul><ul><li>Kidneys </li></ul><ul><li>Liver </li></ul><ul><li>GI tract </li></ul><ul><li>Skin </li></ul><ul><li>Heart </li></ul><ul><li>Brain </li></ul>
    31. 34. Signs <ul><li>Fever </li></ul><ul><li> WBC </li></ul><ul><li>Hypothermia without obvious cause </li></ul><ul><li>Increased respiratory rate </li></ul><ul><li>Tachypnea or hyperpnea </li></ul><ul><li>Oliguria </li></ul><ul><li>Warm, pink skin </li></ul>
    32. 35. Later Signs <ul><li>Fever </li></ul><ul><li>Hypotension </li></ul><ul><li>Tachypnea or hyperpnea </li></ul><ul><li>Hypothermia without obvious cause </li></ul><ul><li>Anuria </li></ul><ul><li>Bleeding </li></ul><ul><li>Cool, pale skin </li></ul>
    33. 36. Endotoxins <ul><li>Endotoxin Effects </li></ul><ul><ul><ul><li>Increases cardiac output </li></ul></ul></ul><ul><ul><ul><li>Increases vascular permeability </li></ul></ul></ul><ul><ul><ul><li> respiratory rate (stimulates the medulla) </li></ul></ul></ul><ul><ul><ul><li>Part of febrile response </li></ul></ul></ul><ul><ul><ul><li>Bacterium most accessible on fever spike </li></ul></ul></ul>
    34. 37. Warm Phase – Cold Phase <ul><li>Warm (Hyper-dynamic) Phase </li></ul><ul><ul><ul><li>Increased cardiac output </li></ul></ul></ul><ul><ul><ul><li>Increased perfusion to organs </li></ul></ul></ul><ul><ul><ul><li>Increased respiratory rate </li></ul></ul></ul><ul><li>Cold (Hypo-dynamic) Phase </li></ul><ul><ul><ul><li>Hypovolemic shock </li></ul></ul></ul><ul><ul><ul><li>Fluid volume in tissues </li></ul></ul></ul><ul><ul><ul><li>Cool and pale </li></ul></ul></ul>
    35. 38. Hemodynamic Changes <ul><li>Warm (Hyper-dynamic) Phase </li></ul><ul><ul><ul><li>Increased cardiac output </li></ul></ul></ul><ul><ul><ul><li> systemic vascular resistance </li></ul></ul></ul><ul><ul><ul><li>Increased Respiratory rate </li></ul></ul></ul><ul><li>Cold (Hypo-dynamic) Phase </li></ul><ul><ul><ul><li>Severe distributive shock </li></ul></ul></ul><ul><ul><ul><li> systemic vascular resistance </li></ul></ul></ul><ul><ul><ul><li>High mortality if not treated in early phase </li></ul></ul></ul>
    36. 40. Complications <ul><li>Adult respiratory distress syndrome (ARDS) </li></ul><ul><li>Disseminated Intravascular Coagulation (DIC) </li></ul><ul><li>Acute Renal failure (ARF) </li></ul><ul><li>Intestinal bleeding </li></ul><ul><li>Liver failure </li></ul><ul><li>Central Nervous system dysfunction </li></ul><ul><li>Heart failure </li></ul><ul><li>Death </li></ul>
    37. 41. Treatment for Sepsis <ul><li>Improve Perfusion </li></ul><ul><ul><ul><li>Prevent organ dysfunction </li></ul></ul></ul><ul><li>Treat The Cause </li></ul><ul><ul><ul><li>Seek primary site of infection </li></ul></ul></ul><ul><ul><ul><li>Direct therapy to primary cause </li></ul></ul></ul><ul><li>Stabilize The Patient </li></ul><ul><ul><ul><li>Fluids (lots of fluids) </li></ul></ul></ul><ul><ul><ul><li>Vasoconstrictors </li></ul></ul></ul>
    38. 42. Treatment for Warm Phase – Cold Phase <ul><li>Warm (Hyper-dynamic) Phase </li></ul><ul><ul><ul><li>Fluids (lots of fluids) </li></ul></ul></ul><ul><ul><ul><li>Find & Treat cause </li></ul></ul></ul><ul><ul><ul><li>Vasoconstrictors </li></ul></ul></ul><ul><li>Cold (Hypo-dynamic) Phase </li></ul><ul><ul><ul><li>Fluids (treat hypovolemic shock) </li></ul></ul></ul><ul><ul><ul><li>Continue treating cause </li></ul></ul></ul><ul><li>Treat Early </li></ul><ul><ul><ul><li>Mortality increases sharply the later the treatment </li></ul></ul></ul>
    39. 43. Treatment Summary <ul><li>Antibiotics (early administration) </li></ul><ul><li>Hemodynamic support </li></ul><ul><ul><ul><li>– Fluid Resuscitation </li></ul></ul></ul><ul><li>Restore tissue perfusion </li></ul><ul><li>Normalize cellular metabolism </li></ul><ul><li>– Vasopressor agents </li></ul><ul><li>Dopamine, Norepinephrine, Dobutamine </li></ul><ul><li>Xigris (Activated Protein C) </li></ul>
    40. 44. Treatment Summary cont. <ul><li>Source control </li></ul><ul><li>– Surgical debridement of infected, devitalized tissue </li></ul><ul><li>– Catheter replacement </li></ul><ul><li>Supplemental oxygen (treatment ARDS) </li></ul><ul><li>Nutritional support </li></ul>
    41. 45. Activated Protein C (Xigris) <ul><li>Mediates many actions of body homeostasis: </li></ul><ul><ul><ul><li>suppression of inflammation </li></ul></ul></ul><ul><ul><ul><li>prevention of microvascular coagulation </li></ul></ul></ul><ul><ul><ul><li>reversal of impaired fibrinolysis </li></ul></ul></ul>
    42. 46. Xigris Facts <ul><li>Xigris has a short half-life </li></ul><ul><li>Xigris should be discontinued 2 hours prior to performing an invasive surgical procedure </li></ul><ul><li>Immediately stop the administration of Xigris if clinically important bleeding occurs. </li></ul>
    43. 47. Xigris Contraindications <ul><li>Xigris is contraindicated in patients with the following clinical situations: </li></ul><ul><ul><li>Active internal bleeding </li></ul></ul><ul><ul><ul><li>Recent—within 3 months—hemorrhagic stroke </li></ul></ul></ul><ul><ul><ul><li>Recent—within 2 months—intracranial or intraspinal surgery, or severe head trauma </li></ul></ul></ul><ul><ul><li>Trauma with increased risk of life-threatening bleeding </li></ul></ul><ul><ul><li>Presence of an epidural catheter </li></ul></ul><ul><ul><li>Intracranial neoplasm or mass lesion or evidence of cerebral herniation </li></ul></ul><ul><ul><li>Known hypersensitivity to drotrecogin alfa (activated) or any component of this product </li></ul></ul>
    44. 48. Xigris (Activated Protein C)
    45. 49. Immunotherapies for Septic Shock <ul><li>Corticosteroids </li></ul><ul><li>Antiendotoxin monoclonal antibodies E-5, HA-1A </li></ul><ul><li>Anti-TNF antibodies </li></ul><ul><li>IL-1 receptor antagonists </li></ul>
    46. 50. Steroids & Septic Shock
    47. 51. Vasopressin & Septic Shock <ul><li>Proposed Mechanisms </li></ul><ul><li>Vasopressin levels in septic shock may be inappropriately low and contribute to hypotension </li></ul><ul><li>Vasopressin blunts the vasodilatory response from NO by reducing synthesis of iNO synthase, and blocks KATP channels in smooth muscle </li></ul><ul><li>Vasopressor action of vasopressin is increased in autonomic failure (eg. septic shock) </li></ul><ul><li>Vasopressin potentiates vasoconstrictor effects of norepinephrine </li></ul>
    48. 52. Other Treatment Modalities <ul><li>Granulocyte transfusions </li></ul><ul><li>Recombinant colony-stimulating factors </li></ul><ul><li>Diuretics </li></ul><ul><li>Pentoxifylline, ibuprofen, naloxone </li></ul><ul><li>Oral non-absorbable anti-microbial agents </li></ul>
    49. 53. The End ?
    50. 54. References <ul><li>American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. </li></ul><ul><li>Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10. </li></ul><ul><li>Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235-43. </li></ul><ul><li>Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA 1995;272:117-23. </li></ul><ul><li>Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998;24:33-44. </li></ul><ul><li>Kuhl DA. Current strategies for managing the patient with sepsis. Am J Health-Syst Pharm 2002;59(suppl 1):S9-13. </li></ul><ul><li>Bernard GR, Vincent J, Laterre P, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. </li></ul><ul><li>Drotrecogin alfa (activated) (Xigris), Eli Lilly and Company, 2004 (prescribing information). </li></ul><ul><li>Centers for Disease Control. Increase in national hospital discharge survey rates for septicemia—United States, 1979-1987. JAMA 1990; 263: 937-8. </li></ul><ul><li>Balk RA. Severe sepsis and septic shock. Critical Care Clinics.2000; 2: 179-92. </li></ul><ul><li>American College of Chest Physicians/Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864-74. </li></ul><ul><li>Bernard et al. A recent definition of severe sepsis. N. Engl. J Med 2001; 344: 699-709. </li></ul><ul><li>Matuschak GM. Multiple systems organ failure: clinical expression, pathogenesis, and therapy, in Hall JB, Schmidt GA, Wood LDH: Principles of Critical Care, McGraw-Hill, New York, 1992. </li></ul><ul><li>Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340: 207-13. </li></ul>