Sepsis is a systemic inflammatory response to infection that can lead to organ dysfunction and death. It is a major cause of death in intensive care units. The incidence of sepsis is rising due to an aging population and increased use of invasive medical procedures and devices. Sepsis progresses through a spectrum from systemic inflammatory response syndrome to severe sepsis with organ dysfunction to septic shock with hypotension and perfusion abnormalities if not treated promptly.

1. Sherry L Knowles Compliments of StudyPro

2. Sepsis Syndrome Sepsis encompasses a spectrum of clinical conditions caused by the immune response to infection and is characterized by systemic inflammation and coagulation. Sepsis includes the full range of responses from systemic inflammatory response (SIRS) to organ dysfunction to multiple organ failure and ultimately death.

3. Sepsis Morbidity & Mortality Leading cause of death in noncoronary ICU patients 13th leading cause of death in U.S. Over 500,000 episodes each year 35-70% mortality 20-50% positive blood cultures 40% hospital deaths after injury due to MODS

4. Sepsis On The Rise Incidences projected to rise to 1.0 million cases annually in the US within the next decade due to: Aging population Increased awareness and diagnosis Immunocompromised patients Invasive procedures Resistant pathogens

5. SIRS Sepsis Severe Septic MODS Death Infection Sepsis Shock Sepsis Syndrome

6. Infection Response Dual Response Innate immunity Acquired immunity Multiple Causes Trauma Bacterial Viral Parasitic Fungal Prions Unknown

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. 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. 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

11. Stages of Sepsis Systemic Inflammatory Response Syndrome (SIRS) Two or more of the following: Temperature of >38 o C or <36 0 C Heart rate of >90 Respiratory rate of >20 WBC count >12 x 10 9 /L or <4 x 10 9 /L or 10% bands Sepsis SIRS plus a culture-documented infection Severe Sepsis Sepsis plus organ dysfunction, hypotension, or hypoperfusion (including but not limited to lactic acidosis, oliguria, or acute mental status changes) Septic Shock Hypotension (despite fluid resuscitation) plus hypoperfusion

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.

13. 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

14. Capillary Damage Capillary Damage during Systemic Inflammatory Response Syndrome (SIRS)

15. Risk Factors Extreme Age (under 1 and > 65 years) Surgical/Invasive Procedures Malnutrition Alcoholism Broad-spectrum antibiotics Chronic illness Immune deficiency disorders Antibiotic resistance

16. Growing Risk Factors Aging population Increased awareness and diagnosis Increasing immunocompromised patients Invasive procedures Increasing life-sustaining technology Resistant pathogens

17. Systemic Response Initial systemic response Release of cytokines from the inflammatory system Inflammation Initiation of coagulation abnormalities Activation of coagulation Inhibition of fibrinolysis Platelet activation Activation of secondary systems Complement system, contact system, multiple cytokines and chemical mediators, free oxygen radicals, and nitric oxide.

18. Inflammatory Cascade Pro-inflammatory cytokines promote endothelial cell adhesion, induce the release of free radicals and activate the coagulation cascade Anti-inflammatory mediators provide a negative feedback mechanism for inflammatory and coagulation reactions. If an imbalance develops between SIRS and CARS, homeostasis is violated: If SIRS predominates the result may be sepsis/ severe sepsis/ septic shock. If CARS predominates, the immune system may be suppressed, leaving the patient susceptible to life-threatening infections.

20. Coagulation Cascade Coagulation cascade Activation of coagulation Inhibition of fibrinolysis Potentates the inflammation cascade

21. Impaired Fibrinolysis Impaired Fibrinolysis Fibrinolysis is the breakdown of clots Normally activated with coagulation Fibrinolysis suppressed in sepsis

23. Sepsis Mediators Myocardial depressant factor(s) Enkephalins Adrenocorticoid hormone Prekallikrein Interleukin-1 Cytokinines (acid metabolites) (eg, leukotrienes, prostaglandins, thromboxanes) The coagulation cascade The complement system The fibrinolytic system Histamines Bradykinins Catecholamines Glucocorticoids Tumor necrosis factor Beta-endorphins The following systems and mediators are stimulated in sepsis:

24. Multiple Cascades

25. Homeostasis Gets Lost

26. Sepsis 101

27. Signs & Symptoms Fever, chills, hypotension Hyper/Hypothermia Hyperventilation Tachycardia Diaphoresis Apprehension, irritability Change in mental status

28. Cardiovascular Signs “ Warm shock” -  CO,  SVR “ Cold shock” -  CO,  SVR Anaerobic metabolism - lactic acidosis Myocardial depressant factor

29. Pulmonary Signs Tachypnea Hyperventilation, respiratory alkalosis ARDS, respiratory failure Ventilation-perfusion mismatch Widened alveolar-arterial oxygen gradient Reduced lung compliance

30. Hematologic Findings Neutrophilic leukocytosis Leukemoid reaction Neutropenia Thrombocytopenia Toxic granulations DIC

31. Renal and Gastrointestinal Signs Acute tubular necrosis, oliguria, anuria Upper GI bleeding Cholestatic jaundice Increased transaminase levels Hypoglycemia

32. Skin Furuncles, cellulitis, bullous lesions Intravenous sites, phlebitis Erythema multiforme Ecchymotic or purpuric lesions DIC, petechiae Ecthyma gangrenosum Purpura fulminans

33. Many Organs Affected Lungs Kidneys Liver GI tract Skin Heart Brain

34. Signs Fever  WBC Hypothermia without obvious cause Increased respiratory rate Tachypnea or hyperpnea Oliguria Warm, pink skin

35. Later Signs Fever Hypotension Tachypnea or hyperpnea Hypothermia without obvious cause Anuria Bleeding Cool, pale skin

36. Endotoxins Endotoxin Effects Increases cardiac output Increases vascular permeability  respiratory rate (stimulates the medulla) Part of febrile response Bacterium most accessible on fever spike

37. Warm Phase – Cold Phase Warm (Hyper-dynamic) Phase Increased cardiac output Increased perfusion to organs Increased respiratory rate Cold (Hypo-dynamic) Phase Hypovolemic shock Fluid volume in tissues Cool and pale

38. Hemodynamic Changes Warm (Hyper-dynamic) Phase Increased cardiac output  systemic vascular resistance Increased Respiratory rate Cold (Hypo-dynamic) Phase Severe distributive shock  systemic vascular resistance High mortality if not treated in early phase

40. 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

41. Treatment for Sepsis Improve Perfusion Prevent organ dysfunction Treat The Cause Seek primary site of infection Direct therapy to primary cause Stabilize The Patient Fluids (lots of fluids) Vasoconstrictors

42. Treatment for Warm Phase – Cold Phase Warm (Hyper-dynamic) Phase Fluids (lots of fluids) Find & Treat cause Vasoconstrictors Cold (Hypo-dynamic) Phase Fluids (treat hypovolemic shock) Continue treating cause Treat Early Mortality increases sharply the later the treatment

43. Treatment Summary Antibiotics (early administration) Hemodynamic support – Fluid Resuscitation Restore tissue perfusion Normalize cellular metabolism – Vasopressor agents Dopamine, Norepinephrine, Dobutamine Xigris (Activated Protein C)

44. Treatment Summary cont. Source control – Surgical debridement of infected, devitalized tissue – Catheter replacement Supplemental oxygen (treatment ARDS) Nutritional support

45. Activated Protein C (Xigris) Mediates many actions of body homeostasis: suppression of inflammation prevention of microvascular coagulation reversal of impaired fibrinolysis

46. Xigris Facts Xigris has a short half-life Xigris should be discontinued 2 hours prior to performing an invasive surgical procedure Immediately stop the administration of Xigris if clinically important bleeding occurs.

47. Xigris Contraindications Xigris is contraindicated in patients with the following clinical situations: Active internal bleeding Recent—within 3 months—hemorrhagic stroke Recent—within 2 months—intracranial or intraspinal surgery, or severe head trauma Trauma with increased risk of life-threatening bleeding Presence of an epidural catheter Intracranial neoplasm or mass lesion or evidence of cerebral herniation Known hypersensitivity to drotrecogin alfa (activated) or any component of this product

48. Xigris (Activated Protein C)

49. Immunotherapies for Septic Shock Corticosteroids Antiendotoxin monoclonal antibodies E-5, HA-1A Anti-TNF antibodies IL-1 receptor antagonists

50. Steroids & Septic Shock

51. Vasopressin & Septic Shock Proposed Mechanisms Vasopressin levels in septic shock may be inappropriately low and contribute to hypotension Vasopressin blunts the vasodilatory response from NO by reducing synthesis of iNO synthase, and blocks KATP channels in smooth muscle Vasopressor action of vasopressin is increased in autonomic failure (eg. septic shock) Vasopressin potentiates vasoconstrictor effects of norepinephrine

52. Other Treatment Modalities Granulocyte transfusions Recombinant colony-stimulating factors Diuretics Pentoxifylline, ibuprofen, naloxone Oral non-absorbable anti-microbial agents

53. The End ?

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