Septicemia and Systemic Septicemia and Systemic Inflammatory Response Inflammatory Response

Syndrome (SIRS)Syndrome (SIRS)

EpidemiologyEpidemiology The most common cause of mortality in the The most common cause of mortality in the

intensive care unit is septic shock . Even with the intensive care unit is septic shock . Even with the best treatment mortality ranges from 15% in best treatment mortality ranges from 15% in patients with sepsis to 40-60% in patients with patients with sepsis to 40-60% in patients with septic shock. septic shock.

Septic shock develops in about 40% of sepsis Septic shock develops in about 40% of sepsis patients. patients.

Around 750,000 cases of sepsis are diagnosed Around 750,000 cases of sepsis are diagnosed per year and around 31% of those diagnosed die. per year and around 31% of those diagnosed die. The annual health care cost from caring for The annual health care cost from caring for patients with sepsis is $5-10 billion.patients with sepsis is $5-10 billion.

Factors contribute to the Factors contribute to the increasing incidence of sepsisincreasing incidence of sepsis: :

Widespread us of corticosteroid and immunosuppressive therapies for Widespread us of corticosteroid and immunosuppressive therapies for organ transplants and inflammatory diseases.organ transplants and inflammatory diseases.

Aggressive cancer chemotherapy and radiation therapy.Aggressive cancer chemotherapy and radiation therapy. Longer lives of patients predisposed to sepsis, the elderly, diabetics, Longer lives of patients predisposed to sepsis, the elderly, diabetics,

cancer patients, patients with major organ failure, and with cancer patients, patients with major organ failure, and with granulocytopenia.granulocytopenia.

Increased use of invasive devices such as surgical protheses, inhalation Increased use of invasive devices such as surgical protheses, inhalation

equipment, and intravenous catheters and urinary catheters.equipment, and intravenous catheters and urinary catheters. Neonates are more likely to develop sepsis. Neonates are more likely to develop sepsis.

Indiscriminate use of antimicrobial drugs that create conditions of Indiscriminate use of antimicrobial drugs that create conditions of overgrowth, colonization, and subsequent infection by aggressive, overgrowth, colonization, and subsequent infection by aggressive, antimicrobial-resistant organisms.antimicrobial-resistant organisms.

Microorganisms 1Microorganisms 1 Although septic shock can be caused by viruses and fungi, Although septic shock can be caused by viruses and fungi,

most is due to bacterial infections. most is due to bacterial infections.

Common Common gram-negativegram-negative bacteriabacteria causing septic shock causing septic shock include opportunistic normal flora of the intestines such as include opportunistic normal flora of the intestines such as EscherichiaEscherichia colicoli, Klebsiella , Klebsiella speciesspecies, Enterobacter , Enterobacter speciesspecies, , and and Proteus Proteus species. species.

Another opportunistic gram-negative causing septic shock Another opportunistic gram-negative causing septic shock is is Pseudomonas aeruginosaPseudomonas aeruginosa. .

The most common obligate anaerobe to cause sepsis is The most common obligate anaerobe to cause sepsis is Bacteroides fragilisBacteroides fragilis. Approximately. Approximately 45% of the cases of 45% of the cases of septicemia are due to gram-negative bacteria.septicemia are due to gram-negative bacteria.

Microorganisms 2Microorganisms 2 Common gram-positive bacteria causing septic Common gram-positive bacteria causing septic

shock include shock include Staphylococcus aureus, Staphylococcus aureus, Streptococcus pneumoniae, EnterococcusStreptococcus pneumoniae, Enterococcus species species that are normal flora of the intestines, and that are normal flora of the intestines, and Streptococcus pyogenesStreptococcus pyogenes. .

The most common cause of neonatal sepsis is The most common cause of neonatal sepsis is Group B Group B StreptococcusStreptococcus (GBS). Approximately (GBS). Approximately 45% 45% of the cases of septicemia are due to gram-of the cases of septicemia are due to gram-positive bacteria.positive bacteria.

Approximately 10% of the cases of septicemia are Approximately 10% of the cases of septicemia are due to fungi, mainly the yeast due to fungi, mainly the yeast CandidaCandida. .

The sources for sepsis are The sources for sepsis are infections elsewhere in the body. infections elsewhere in the body.

lung infections: lung infections: Streptococcus pneumoniae, Haemophilus Streptococcus pneumoniae, Haemophilus influenzae, Legionellainfluenzae, Legionella species, species, Chlamydia pneumoniaeChlamydia pneumoniae. .

wound, soft tissue infections: wound, soft tissue infections: Streptococcus pyogenesStreptococcus pyogenes, , Staphylococcus aureusStaphylococcus aureus, , ClostridiumClostridium species, species, Pseudomonas Pseudomonas aeruginosaaeruginosa, anaerobes, coagulase-negative , anaerobes, coagulase-negative StaphylococcusStaphylococcus species. species.

urinary tract infections: urinary tract infections: Escherichia coli, Klebsiella Escherichia coli, Klebsiella speciesspecies, , Enterobacter Enterobacter speciesspecies, Proteus , Proteus species, species, EnterococcusEnterococcus species. species.

central nervous system: central nervous system: Streptococcus pneumoniaeStreptococcus pneumoniae, , Neisseria meningitidis, Listeria monocytogenes, Neisseria meningitidis, Listeria monocytogenes, Escherichia coli, Haemophilus influenzaeEscherichia coli, Haemophilus influenzae, , Pseudomonas Pseudomonas aeruginosaaeruginosa, , Klebsiella Klebsiella species, species, StaphylococcusStaphylococcus species. species.

Pathogenesis Pathogenesis In order to protect against infection, one of the things the body In order to protect against infection, one of the things the body

must initially do is detect the presence of microorganisms. The must initially do is detect the presence of microorganisms. The body does this by recognizing molecules unique to body does this by recognizing molecules unique to microorganisms that are not associated with human cells. These microorganisms that are not associated with human cells. These unique molecules are called unique molecules are called pathogen-associated molecular pathogen-associated molecular patternspatterns..

Molecules unique to bacterial cell walls, such as peptidoglycan Molecules unique to bacterial cell walls, such as peptidoglycan monomers, teichoic acids, LPS, mycolic acid, formyl peptides, and monomers, teichoic acids, LPS, mycolic acid, formyl peptides, and mannose, bind to mannose, bind to pattern-recognition receptorspattern-recognition receptors on a variety of on a variety of defense cells of the body causing them to synthesize and secrete defense cells of the body causing them to synthesize and secrete a variety of proteins called cytokines. a variety of proteins called cytokines.

These cytokines can, in turn promote innate immune defenses These cytokines can, in turn promote innate immune defenses such as such as inflammation, phagocytosis, activation of the complement inflammation, phagocytosis, activation of the complement pathways, and activation of the coagulation pathway.pathways, and activation of the coagulation pathway.

Pathogenesis Pathogenesis CytokinesCytokines are intercellular regulatory proteins produced by one cell that are intercellular regulatory proteins produced by one cell that

subsequently bind to other cells in the area and influence their activity in subsequently bind to other cells in the area and influence their activity in some manner.some manner.

Cytokines such as Cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8)(IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8) are known as are known as proinflammatory cytokinesproinflammatory cytokines because they because they promote inflammationpromote inflammation. .

Some cytokines, such as IL-8, are also known as chemokines. They Some cytokines, such as IL-8, are also known as chemokines. They promote an inflammatory response by enabling white blood cells to leave promote an inflammatory response by enabling white blood cells to leave the blood vessels and enter the surrounding tissue, by chemotactically the blood vessels and enter the surrounding tissue, by chemotactically attracting these white blood cells to the infection site, and by triggering attracting these white blood cells to the infection site, and by triggering neutrophils to release killing agents for extracellular killing. neutrophils to release killing agents for extracellular killing.

In addition to promoting an inflammatory response, these same cytokines In addition to promoting an inflammatory response, these same cytokines activate the complement pathways as well as the coagulation pathway. activate the complement pathways as well as the coagulation pathway.

PathogenesisPathogenesis InflammationInflammation is the first response to infection and injury and is critical to is the first response to infection and injury and is critical to

body defense. Basically, the inflammatory response is an attempt by the body defense. Basically, the inflammatory response is an attempt by the body to restore and maintain homeostasis after injury. Most of the body body to restore and maintain homeostasis after injury. Most of the body defense elements are located in the blood, and inflammation is the means defense elements are located in the blood, and inflammation is the means by which body defense cells and defense chemicals leave the blood and by which body defense cells and defense chemicals leave the blood and enter the tissue around an injured or infected site. enter the tissue around an injured or infected site.

The release of proinflammatory cytokines eventually leads to vasodilation The release of proinflammatory cytokines eventually leads to vasodilation of blood vessels. of blood vessels.

VasodilationVasodilation is a reversible opening of the junctional zones between is a reversible opening of the junctional zones between endothelial cells of the blood vessels and results in increased blood vessel endothelial cells of the blood vessels and results in increased blood vessel permeability. This enables plasma, the liquid portion of the blood, to enter permeability. This enables plasma, the liquid portion of the blood, to enter the surrounding tissue. The plasma contains defense chemicals such as the surrounding tissue. The plasma contains defense chemicals such as antibody molecules, complement proteins, lysozyme, and defensins. antibody molecules, complement proteins, lysozyme, and defensins. Increased capillary permeability also enables white blood cells to squeeze Increased capillary permeability also enables white blood cells to squeeze out of the blood vessels and enter the tissue. As can be seen, inflammation out of the blood vessels and enter the tissue. As can be seen, inflammation is necessary part of body defense.is necessary part of body defense.

Excessive or prolonged inflammation can, however, cause harm. Excessive or prolonged inflammation can, however, cause harm.

PathogenesisPathogenesis

At moderate levels, inflammation, At moderate levels, inflammation, products of the complement pathways, products of the complement pathways, and products of the coagulation pathway and products of the coagulation pathway are essential to body defense.are essential to body defense.

However, these same processes and However, these same processes and products when excessive, can cause products when excessive, can cause considerble harm to the body.considerble harm to the body.

Systemic Inflammatory Response Systemic Inflammatory Response Syndrome (SIRS):Syndrome (SIRS):

The Shock CascadeThe Shock Cascade

Systemic Inflammatory Systemic Inflammatory Response Syndrome (SIRS):Response Syndrome (SIRS):

During a severe systemic infection, an During a severe systemic infection, an excessive inflammatory response excessive inflammatory response triggered by overproduction of triggered by overproduction of cytokines such as TNF-alpha, IL-1, IL-cytokines such as TNF-alpha, IL-1, IL-6, IL-8, and PAF6, IL-8, and PAF often occurs. often occurs.

This leads to the following sequence of This leads to the following sequence of cytokine-induced events:cytokine-induced events:

Blood vessels dilateBlood vessels dilate During a severe systemic infection, an During a severe systemic infection, an excessive excessive

inflammatory response triggered by overproduction inflammatory response triggered by overproduction of cytokines such as TNF-alpha, IL-1, IL-6, IL-8, and of cytokines such as TNF-alpha, IL-1, IL-6, IL-8, and PAFPAF often occurs. This leads to the following sequence of often occurs. This leads to the following sequence of cytokine-induced events: cytokine-induced events:

Blood vessels dilateBlood vessels dilate and phagocytic WBCs called and phagocytic WBCs called neutrophils adhere to capillary walls in massive neutrophils adhere to capillary walls in massive amountsamounts. .

Chemokines such as IL-8 activate neutrophils causing them Chemokines such as IL-8 activate neutrophils causing them to to release proteases release proteases and toxic oxygen radicalsand toxic oxygen radicals while while still in the blood vessels. These are the same toxic still in the blood vessels. These are the same toxic chemicals neutrophils use to kill microbes, but now they are chemicals neutrophils use to kill microbes, but now they are dumped onto the vascular endothelial cells to which the dumped onto the vascular endothelial cells to which the neutrophils have adhered. This results in neutrophils have adhered. This results in damage to the damage to the capillary walls and leakage of bloodcapillary walls and leakage of blood. .

Prolonged vasodilationProlonged vasodilation Prolonged vasodilationProlonged vasodilation and increased capillary permeability and increased capillary permeability causes plasma to causes plasma to

leave the bloodstreamleave the bloodstream and enter the tissue. and enter the tissue. Prolonged vasodilationProlonged vasodilation also leads also leads to to decreased vascular resistancedecreased vascular resistance that, in turn, results in a that, in turn, results in a drop in blood drop in blood pressure (hypotension) and reduced perfusion of blood through tissues and pressure (hypotension) and reduced perfusion of blood through tissues and organsorgans. .

Damage to the capillaries and prolonged vasodilationDamage to the capillaries and prolonged vasodilation result in result in blood and blood and plasma leaving the bloodstreamplasma leaving the bloodstream and entering the tissue. This can lead to a and entering the tissue. This can lead to a decreased volume of circulating blood (hypovolemia)decreased volume of circulating blood (hypovolemia)

Activation of the blood coagulation pathway and concurrent down-Activation of the blood coagulation pathway and concurrent down-regulation of anticoagulation mechanismsregulation of anticoagulation mechanisms cause cause clots to form within the clots to form within the blood vessels throughout the body. blood vessels throughout the body. This is calledThis is called disseminated intravascular disseminated intravascular coagulation (DIC)coagulation (DIC). This further limits the perfusion of blood and oxygen through . This further limits the perfusion of blood and oxygen through tissues and organs. tissues and organs.

Damage to the capillaries and prolonged vasodilationDamage to the capillaries and prolonged vasodilation result in result in blood and blood and plasma leaving the bloodstreamplasma leaving the bloodstream and entering the tissue. This can lead to a and entering the tissue. This can lead to a decreased volume of circulating blood (hypovolemia)decreased volume of circulating blood (hypovolemia)

Disseminated intravascular Disseminated intravascular coagulationcoagulation

Activation of the blood coagulation Activation of the blood coagulation pathway and concurrent down-pathway and concurrent down-regulation of anticoagulation regulation of anticoagulation mechanismsmechanisms cause cause clots to form within clots to form within the blood vessels throughout the the blood vessels throughout the body. body. This is calledThis is called disseminated disseminated intravascular coagulation (DIC)intravascular coagulation (DIC). This . This further limits the perfusion of blood and further limits the perfusion of blood and oxygen through tissues and organs. oxygen through tissues and organs.

Acute respiratory distress Acute respiratory distress syndrome (ARDS)syndrome (ARDS)

The The increased capillary increased capillary permeabilitypermeability and and injury to injury to capillaries in the alveoli of the capillaries in the alveoli of the lungslungs results in results in acute acute inflammation, pulmonary edema, inflammation, pulmonary edema, and loss of gas exchange. and loss of gas exchange. This is This is called called acute respiratory distress acute respiratory distress syndrome (ARDS)syndrome (ARDS). .

Liver, kidney, bowelLiver, kidney, bowel Reduced perfusion and capillary Reduced perfusion and capillary

damage in the liver damage in the liver results inresults in impaired liver function and a impaired liver function and a failure to maintain normal blood failure to maintain normal blood glucose levels. Reducedglucose levels. Reduced perfusion also leads to kidney perfusion also leads to kidney and bowel injury.and bowel injury.

Heart failureHeart failure The combination of hypotension, The combination of hypotension,

hypovolemia, DIC, loss of perfusion, hypovolemia, DIC, loss of perfusion, and ARDS, leads to and ARDS, leads to acidosisacidosis and and decreased cardiac output. Cytokine-decreased cardiac output. Cytokine-induced overproduction of nitric induced overproduction of nitric oxide (NO) by cardiac muscle cells oxide (NO) by cardiac muscle cells leads to leads to heart failureheart failure. .

MSOF and DeathMSOF and Death

Collectively, this cascade of events Collectively, this cascade of events results in results in irreversible septic irreversible septic shockshock, , multiple system organ multiple system organ failure (MSOF)failure (MSOF), and , and deathdeath

SymptomsSymptoms Symptoms of sepsis are usually Symptoms of sepsis are usually

nonspecific and include fever, chills, nonspecific and include fever, chills, and constitutional symptoms of and constitutional symptoms of fatigue, malaise, anxiety, or fatigue, malaise, anxiety, or confusion. These symptoms are not confusion. These symptoms are not limited to infection and may be seen limited to infection and may be seen in a variety of noninfectious in a variety of noninfectious inflammatory conditions. inflammatory conditions.

SymptomsSymptoms

1. temperature > 38°C or < 36°C1. temperature > 38°C or < 36°C

2. heart rate > 90 beats/minute2. heart rate > 90 beats/minute

3. respiration > 20/min or PaCO2 < 32mm Hg3. respiration > 20/min or PaCO2 < 32mm Hg

4. leukocyte count > 12,000/mm3, < 4,000/mm3 4. leukocyte count > 12,000/mm3, < 4,000/mm3 or > 10% immature (band) cells.or > 10% immature (band) cells.

DefinitionsDefinitions Sepsis was defined as the systemic host response to Sepsis was defined as the systemic host response to

infection with SIRS plus a documented infection. infection with SIRS plus a documented infection.

Severe sepsis was defined as sepsis plus end-organ Severe sepsis was defined as sepsis plus end-organ dysfunction or hypoperfusion.dysfunction or hypoperfusion.

Septic shock was defined as sepsis with hypotension, Septic shock was defined as sepsis with hypotension, despite fluid resuscitation, and evidence of inadequate despite fluid resuscitation, and evidence of inadequate tissue perfusion. tissue perfusion.

While SIRS, sepsis, and septic shock commonly are While SIRS, sepsis, and septic shock commonly are associated with bacterial infection, bacteremia may not be associated with bacterial infection, bacteremia may not be present. present.

MORTALITYMORTALITY

The mortality rate in SIRS has been The mortality rate in SIRS has been reported to be about 7%, that in reported to be about 7%, that in sepsis is about 16-20%, and that in sepsis is about 16-20%, and that in septic shock is about 45% septic shock is about 45%

TREATMENTTREATMENT The drugs used depends on the source of the sepsis The drugs used depends on the source of the sepsis

1. Community acquired pneumonia1. Community acquired pneumonia a 2 drug regimen is usually utilized. Usually a third (ceftriaxone) a 2 drug regimen is usually utilized. Usually a third (ceftriaxone) or fourth (cefepime) generation cephalosporin is given with an aminoglycoside (usually gentamicin).or fourth (cefepime) generation cephalosporin is given with an aminoglycoside (usually gentamicin).

2. Nosocomial pneumonia:2. Nosocomial pneumonia: Cefipime or Imipenem-cilastatin and an aminoglycoside. Cefipime or Imipenem-cilastatin and an aminoglycoside. 3. Abdominal infection3. Abdominal infection: Imipenem-cilastatin or Pipercillin-tazobactam and aminoglycoside.: Imipenem-cilastatin or Pipercillin-tazobactam and aminoglycoside. 4. Nosocomial abdominal infection:4. Nosocomial abdominal infection: Imipenem-cilastatin and aminoglycoside or Pipercillin- Imipenem-cilastatin and aminoglycoside or Pipercillin-

tazobactam and Amphotericin B.tazobactam and Amphotericin B.

5. Skin/soft tissue:5. Skin/soft tissue: Vancomycin and Imipenem-cilastatin or Piperacillin-tazobactam Vancomycin and Imipenem-cilastatin or Piperacillin-tazobactam

6. Nosocomial skin/soft tissue:6. Nosocomial skin/soft tissue: Vancomycin and Cefipime Vancomycin and Cefipime 7. Urinary tract infection:7. Urinary tract infection: Ciprofloxacin and aminoglycoside Ciprofloxacin and aminoglycoside

8. Nosocomial urinary tract infection8. Nosocomial urinary tract infection: Vancomycin and Cefipime: Vancomycin and Cefipime 9. CNS infection:9. CNS infection: Vancomycin and third generation cephalosporin or Meropenem Vancomycin and third generation cephalosporin or Meropenem

10. Nosocomial CNS infection:10. Nosocomial CNS infection: Meropenem and Vancomycin Meropenem and Vancomycin