SUBJECT: Medicine II TOPIC: Sepsis and Septic Shock LECTURER: Dr.

Gabriel TRANSGROUP: shar, maqui, viki EPIDEMIOLOGY

DATE: July 2, 2008

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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

Hemodynamic changes Microvascular abnormalities Intracellular defects


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


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

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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


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

Lipopolysaccharide + lipopolysaccharide binding protein bind to macrophages then inflammatory cascade stimulated by TNF. 1. 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.

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

A. Systemic activation of leukocytes leads to
the release of a variety of mediators • TNF – α, IL-1, IL-6 Complement system (C5 alpha) • Bacterial factors B. Dissemination of this response



3. Interleukin 1 (IL-1) – stimulates T helper cells 4.
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.

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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

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

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

Effect • Vasodilation • Inhibition of platelet aggregation


The dominant hemodynamic feature in septic shock is peripheral vascular failure. • Leading to persistent hypotension resistant to vasoconstrictors

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


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 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 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 F. CNS Confusion/stupor/coma secondary to: o Hypoperfusion injury o Septic encephalopathy o Metabolic encephalopathy o drugs Microbial Agents

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

• • • • • • • • • • • • • • • • • 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

Endotoxin (LPS)

Adaptive Immunity Innate Immune Response Mechanism Man

Release of Mediators

SSXs: Fever Myalgia Tachycardia Tachypnea Leukocytosis Somnolence

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

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

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


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

Imaging Studies Chest X-ray X-ray of the abdomen Abdominal ultrasonography Abdominal CT scan Plain radiograph of the extremities Procedures Orotracheal intubation Mechanical ventilation Urinary foley catheter Cutaneous or soft tissue drainage Lumbar puncture Intravenous access for CVP

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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


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

Beyond ICU Rehabilitation program

Referral to ICU Shock onset Respirator y support Oh Antibiotics Broad spectrum Surgical cure if needed 6h

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

24-48 h


Hemodynami c resuscitation

Non-refractory septic shock Fluid challeng es
Consider weaning from vasopressors and other life

Refractory septic shock

Fluid challenges Vasopressors if patient remains hypotensive

Stop steroids Normal adrenal function

Adrenocorticotrophi c hormone test Start low-dose steroids

Stop steroids