Sepsis

Sherry L KnowlesCompliments of StudyPro 

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.

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

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

SIRS Sepsis Severe Septic MODS DeathInfection Sepsis Shock

Sepsis Syndrome

Infection Response

Dual Response

• Innate immunity

• Acquired immunity

Multiple Causes

• Trauma• Bacterial• Viral• Parasitic • Fungal• Prions• Unknown

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

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

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

Stages of Sepsis• Systemic Inflammatory Response Syndrome (SIRS)

Two or more of the following:

– Temperature of >38oC or <360C

– Heart rate of >90

– Respiratory rate of >20

– WBC count >12 x 109/L or <4 x 109/L or 10% bands

• SepsisSIRS plus a culture-documented infection

• Severe SepsisSepsis plus organ dysfunction, hypotension, or

hypoperfusion(including but not limited to lactic acidosis, oliguria, or acute mental

status changes)

• Septic ShockHypotension (despite fluid resuscitation) plus hypoperfusion

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.

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

Capillary DamageCapillary Damage during Systemic Inflammatory

Response Syndrome (SIRS)              

Risk Factors

• Extreme Age (under 1 and > 65 years)

• Surgical/Invasive Procedures

• Malnutrition

• Alcoholism

• Broad-spectrum antibiotics

• Chronic illness

• Immune deficiency disorders

• Antibiotic resistance

Growing Risk Factors

• Aging population

• Increased awareness and diagnosis

• Increasing immunocompromised patients

• Invasive procedures

• Increasing life-sustaining technology

• Resistant pathogens

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.

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.

Coagulation Cascade

• Coagulation cascade

• Activation of coagulation

• Inhibition of fibrinolysis

• Potentates the inflammation cascade

Impaired Fibrinolysis

• Impaired Fibrinolysis

• Fibrinolysis is the breakdown of clots

• Normally activated with coagulation

• Fibrinolysis suppressed in sepsis

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:

Multiple Cascades

Homeostasis Gets Lost

Sepsis 101

Signs & Symptoms

• Fever, chills, hypotension

• Hyper/Hypothermia

• Hyperventilation

• Tachycardia

• Diaphoresis

• Apprehension, irritability

• Change in mental status

Cardiovascular Signs

• “Warm shock” - CO, SVR

• “Cold shock” - CO, SVR

• Anaerobic metabolism - lactic acidosis

• Myocardial depressant factor

Pulmonary Signs

• Tachypnea

• Hyperventilation, respiratory alkalosis

• ARDS, respiratory failure

• Ventilation-perfusion mismatch

• Widened alveolar-arterial oxygen gradient

• Reduced lung compliance

Hematologic Findings

• Neutrophilic leukocytosis

• Leukemoid reaction

• Neutropenia

• Thrombocytopenia

• Toxic granulations

• DIC

Renal and Gastrointestinal Signs

• Acute tubular necrosis, oliguria, anuria

• Upper GI bleeding

• Cholestatic jaundice

• Increased transaminase levels

• Hypoglycemia

Skin

• Furuncles, cellulitis, bullous lesions

• Intravenous sites, phlebitis

• Erythema multiforme

• Ecchymotic or purpuric lesions

• DIC, petechiae

• Ecthyma gangrenosum

• Purpura fulminans

Many Organs Affected

• Lungs

• Kidneys

• Liver

• GI tract

• Skin

• Heart

• Brain

Signs

• Fever

WBC

• Hypothermia without obvious cause

• Increased respiratory rate

• Tachypnea or hyperpnea

• Oliguria

• Warm, pink skin

Later Signs

• Fever

• Hypotension

• Tachypnea or hyperpnea

• Hypothermia without obvious cause

• Anuria

• Bleeding

• Cool, pale skin

Endotoxins

• Endotoxin Effects

– Increases cardiac output

– Increases vascular permeability

respiratory rate (stimulates the medulla)

– Part of febrile response

– Bacterium most accessible on fever spike

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

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

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

Treatment for Sepsis

3. Improve Perfusion– Prevent organ dysfunction

2. Treat The Cause – Seek primary site of infection

– Direct therapy to primary cause

1. Stabilize The Patient– Fluids (lots of fluids)

– Vasoconstrictors

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

Treatment Summary

1. Antibiotics (early administration)

2. Hemodynamic support– Fluid Resuscitation

Restore tissue perfusion

Normalize cellular metabolism

– Vasopressor agents

Dopamine, Norepinephrine, Dobutamine

3. Xigris (Activated Protein C)

Treatment Summarycont.

3. Source control– Surgical debridement of infected, devitalized

tissue

– Catheter replacement

4. Supplemental oxygen (treatment ARDS)

5. Nutritional support

Activated Protein C (Xigris)

Mediates many actions of body homeostasis:

• suppression of inflammation

• prevention of microvascular coagulation

• reversal of impaired fibrinolysis

Xigris Facts

1. Xigris has a short half-life

2. Xigris should be discontinued 2 hours prior to performing an invasive surgical procedure

3. Immediately stop the administration of Xigris if clinically important bleeding occurs.

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

Xigris (Activated Protein C)

Immunotherapies for Septic Shock

• Corticosteroids

• Antiendotoxin monoclonal antibodies E-5, HA-1A

• Anti-TNF antibodies

• IL-1 receptor antagonists

Steroids & Septic Shock

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

Other Treatment Modalities

• Granulocyte transfusions

• Recombinant colony-stimulating factors

• Diuretics

• Pentoxifylline, ibuprofen, naloxone

• Oral non-absorbable anti-microbial agents

The End ?

1. 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.

2. 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.

3. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235-43.

4. 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.

5. 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.

6. Kuhl DA. Current strategies for managing the patient with sepsis. Am J Health-Syst Pharm 2002;59(suppl 1):S9-13.

7. 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.

8. Drotrecogin alfa (activated) (Xigris), Eli Lilly and Company, 2004 (prescribing information).

9. Centers for Disease Control. Increase in national hospital discharge survey rates for septicemia—United States, 1979-1987. JAMA 1990; 263: 937-8.

10. Balk RA. Severe sepsis and septic shock. Critical Care Clinics.2000; 2: 179-92.

11. 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.

12. Bernard et al. A recent definition of severe sepsis. N. Engl. J Med 2001; 344: 699-709.

13. 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.

14. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340: 207-13.

References