Sepsis And Septic Shock

SUBJECT: Medicine II TOPIC: Sepsis and Septic Shock LECTURER: Dr. Gabriel TRANSGROUP: shar, maqui, viki

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EPIDEMIOLOGY

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500,000 – 750,000 cases annually in the United States and rising Most common cause of death in non-coronary ICU and two-thirds of cases occur in hospitalized patients Increasing incidence of severe sepsis is attributable to the aging population with chronic diseases Widespread use of antimicrobial agents, indwelling catheters, mechanical devices and ventilators increase incidence 30% mortality when shock is present Severe sepsis $22K/pt, $16 billion/year

DEFINITIONS

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Systemic Inflammatory Response (SIRS) o Widespread inflammatory response o Two or more of the following

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System

Hemodynamic changes Microvascular abnormalities Intracellular defects

C. Toxins • Gram (+) organisms (Staph and Strep) liberate exotoxin • Gram (-) organisms produce endotoxin • Pseudomonas produces both endotoxin and exotoxin • Endotoxin is a heat stable polysaccharide derived from the cell wall of a gram (-) bacteria • Endotoxin – lipid moiety – lipid A = active part • Core oligosaccharide and polysaccharide are probably inert

Temp > 38°C or ˂ 36°C Heart Rate > 90 bpm Tachypnea (RR > 20) or hyperventilation (PaCoz ˂ 32 mmHg) WBC > 12,000 cells/mm3, < 4000 cells/mm3 or presence of >10% immature neutrophils

TIME-COURSE OF INFLAMMATORY RESPONSE DURING SEPSIS

Sepsis o SIRS + definitive source of infection Severe Sepsis o Sepsis + organ dysfunction, hypoperfusion, or hypotension o Hypoperfusion and perfusion abnormalities may include but not limited to lactic acidosis, oliguria or an acute mental state. Septic Shock o Sepsis + hypotension despite fluids o Perfusion abnormalities  Lactic acidosis  Oliguria  Acute AMS Multiple Organ System Failure o Abnormal function of two or more organs such that homeostasis cannot be achieved without intervention

PATHOPHYSIOLOGY Systemic Inflammatory response System (SIRS) • Severe infection – bacteremia/endotoxemia • Large areas of devitalized tissue – surgery/trauma

THE CASCADE OF EVENTS IN SIRS Lipopolysaccharide + lipopolysaccharide binding protein bind to macrophages then inflammatory cascade stimulated by TNF. 1.

A. Systemic activation of leukocytes leads to the release of a variety of mediators • TNF – α, IL-1, IL-6

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Complement system (C5 alpha) • Bacterial factors B. Dissemination of this response

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Activation of the complement cascade leads to activation of leukocytes, release of inflammatory mediators such as proteases and oxygen free radicals. This leads to localized tissue damage and increased capillary permeability. Tumor necrosis factor (TNF) plays a pivotal role via the cyclooxygenase pathway.

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DATE: July 2, 2008

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to produce IL-2 which stimulates cytotoxic T cells. IL-1 and TNF act synergistically a. Induction of cyclooxygenase b. Platelet activation factor (PAF) c. Nitric oxide synthase IL-6 and IL-8 are involved in the reparative process they cause and down regulation of TNF and IL-1 production.

Arachidonic Acid Metabolites • Prostacyclin (PGI2) – vasodilator, inhibits platelet activity • Thromboxane A2 – vasoconstrictor and platelet aggregator Platelet Activation Factor • Hypotension • Increased vascular permeability • Platelet aggregation Cell Necrosis/Hypoxia/Ischemia/Sepsis/Acidosis Lead to release of lysosomal enzymes • Directly cytotoxic • Myocardial depression • Coronary vasoconstriction • Activation of kininogens and kinis • Vasodilation • Increased capillary refill • Activation of clotting systems Endothelium The vascular endothelium is an organ which regulates: • Blood vessel tone • Vascular permeability • Coagulation • Angiogenesis • WBC and platelet activity • Phagocytosis of bacteria The endothelium produces a number of vasoactive substances • Nitric oxide (EDRF) • Prostacyclin • Endothelin – 1 Nitric Oxide (NO) • Produced from L-arginine synthetase (NOS) • Activity is via cGMP

by

nitric

oxide

Effect • Vasodilation • Inhibition of platelet aggregation

THE CASCADE OF EVENTS IN SEPTIC SHOCK The dominant hemodynamic feature in septic shock is peripheral vascular failure. • Leading to persistent hypotension resistant to vasoconstrictors

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Usually high output due to low SVR/increased HR Nevertheless, there usually is a myocardial depressant factor present: o Decreased SV decreased left ventricular stroke work: Tx = volume loading Ventricular dilatation occurs due to decreased compliance

Cardiac dysfunction may also be affected by: • Acidosis • Hypoxemia • Myocardial edema Microcirculatory Changes = Capillary Leak Syndrome • Vasodilatation • Maldistribution of flow • A-V shunting • Increased capillary permeability + interstitial edema • Decreased oxygen extraction • Primary defect of oxygen utilization at cellular level Capillary endothelial injury follows: • DIC • Microemboli • Release of vasoactive components • Complement activation • Extravascular migration of leukocytes N.B. capillary permeability is increased so that fluid is lost into the interstitial space leading to hypovolemia/interstitial edema/organ dysfunction. Reperfusion of the microcirculation leads to the generation of large quantities of oxygen free radicals leading to tissue damage, particularly to the gut mucosa. Organ Dysfunction: The brain and kidneys are normally protected from swings in blood pressure by autoregulation: 1. In early sepsis – autoregulation curve shifts rightwards (due to and increase in sympathetic tone) 2. In late sepsis – vasoparesis occurs - Autoregulation fails “steal phenomena” may occur (areas of ischemia may have their blood stolen by areas with good perfusion) A. Heart - Myocardial O2 supply is dependent diastolic BP Circulating myocardial depressant factor

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B. Lungs Ventilation/perfusion mismatches Initially due to increased dead space Subsequently due to shunt - Acidosis – tachypnea, decreased PaCO2 Nosocomial pneumonia approximately 70%

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3. Interleukin 1 (IL-1) – stimulates T helper cells

C. Kidneys Oliguria o Pre-renal (by a long way most common) o Renal o Post renal Pre-renal failure due to intravascular dehydration, circulating nephrotoxins, drugs

G. Metabolic - Hyperglycemia due to sepsis and catecholamines (both cause insulin resistance) Lactic acidosis Muscular breakdown Generalized catabolic state

D. Liver ICU jaundice Uncontrolled production of inflammatory cytokines by the Kuppfer cells, primed by ischemia and stimulated by endotoxin (derived from the gut), leads to cholestasis and hyperbilirubinemia

SIGNS AND SYMPTOMS OF SEPSIS • • • • • • • • • • • • • • • •

E. Splanchnic Circulation GUT mucosa is usually protected from injury by autoregulation Hypotension and hypovolemia leads to superficial mucosal injury which leads to atrophy and translocation of bacteria into the portal circulation and stimulate liver macrophages causing cytokine release and amplification of SIRS CNS Confusion/stupor/coma secondary to: o Hypoperfusion injury o Septic encephalopathy o Metabolic encephalopathy o drugs Microbial Agents

Endotoxin (LPS)

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Adaptive Immunity Innate Immune Response Mechanism

Release of Mediators

Sepsis Man

DIC DEATH SSXs: Fever Myalgia Tachycardia Tachypnea Leukocytosis Somnolence

WORK-UP FOR SEPTIC SHOCK Laboratory Studies CBC with differentials Hemoglobin, hematocrit, platelet Comprehensive Chemistry Panel Sodium and chloride level Bicarbonate BUN and creatinine Glucose Liver function test

TNF Cytokines Complement C5a Coagulation Factors Activation of Vascular Endothelium Phospholipid –

Resuscitation: ABC Restore tissue perfusion Appropriate antibiotics Tissue oxygenation Steroids Nutrition

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Serum lactate levels

Coagulation Studies Prothrombin time Partial thromboplastin time Fibrinogen level Blood Cultures Urinalysis/Urine Culture Gram’s Stain or Culture for sputum, abscesses, CSF

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Temperature increased or decreased WBC count increased or decreased Rigors Sweating Nausea and vomiting Tachycardia Hypotension Tachypnea (acute lung injury) Warm pink peripheries Confusion Oliguria Increased glucose Increased lactate Increasingly negative base excess Decreased albumin Increased INR. Increased aPTT, decreased platelets, DIC Jaundice

Imaging Studies Chest X-ray X-ray of the abdomen Abdominal ultrasonography Abdominal CT scan Plain radiograph of the extremities

MANAGEMENT OF SEPSIS Resuscitate: ABCs Restore tissue perfusion Identify and eradicate source of infection Assure adequate tissue oxygenation Activated protein C Steroids Glucose control Nutrition

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Procedures Orotracheal intubation Mechanical ventilation Urinary foley catheter Cutaneous or soft tissue drainage Lumbar puncture Intravenous access for CVP

SEPTIC SHOCK ALGORITHM EXAMPLE

Consider introducing activated protein C for 96h if no risk of bleeding and no clinical improvement

Referral to ICU

Beyond ICU Rehabilitation program

Checking availability of antibiotics and if possible narrowing spectrum Surgical relook if needed

Shock onset Respirator y support Oh

24-48 h

6h

Day

Antibiotics Broad spectrum Surgical cure if needed

Fluid challenges Vasopressors if patient remains hypotensive

Refractory septic shock

Fluid challeng es

Adrenocorticotrophi c hormone test Start low-dose steroids

Consider weaning from vasopressors and other life

Stop steroids Normal adrenal function

Stop steroids

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Hemodynami c resuscitation

Non-refractory septic shock