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From Sepsis to Septic Shock

Neal R. Chamberlain, Ph.D., Associate Professor

Department of Microbiology/Immunology

Specific Educational Objectives: The student should be able to:

1. Recite the most likely causes of sepsis based on the knowledge of the initial site of infection and where these organisms usually come from (sources of infection).

2. Recite the most common causes of anaerobic sepsis and pediatric sepsis.

3. Recite the factors that increase the risk of a patient getting sepsis and the patient types most like to get sepsis.

4. Recite the major sites of infection that can lead to sepsis.

5. Describe the sequence of events that lead to septic shock (know the microbial triggers and the host mediators that led to septic shock). A basic understanding of what types of shock is caused by sepsis.

6. Describe the differences between the following: sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS).

OVERVIEW

Sepsis is a systemic response that is caused by the presence of pathogenic microorganisms or their toxins, or both, in the bloodstream. During sepsis, the body mounts an immune response to the infection or the microbial toxins, or both. In the early stages of sepsis, the immune response can be characterized as a systemic inflammatory response syndrome (SIRS). In the later stages of sepsis, the immune system can mount a response that results in an unbalanced state, with inflammation overwhelming the factors that control the inflammatory response. This unbalanced inflammatory state causes leakage of blood from the vascular space into the interstitial spaces in the tissues, resulting in hypotension and hypoperfusion of the organs (severe sepsis or septic shock) (Table SS-1). Hypoperfusion of the organs can result in organ failure (MODS; Table SS-1).


Table SS-1. Clinical Definitions of the Progression from Sepsis to MODS

Disease Stage

Clinical Definition

Signs and Symptoms

Comments

Sepsis

The presence of a documented or suspected infection and some of the signs of a systemic inflammatory response (signs and symptoms are listed in the columns to the right).

Infection is defined as a pathologic process caused by:

1. the invasion of a normally sterile tissue, fluid or body cavity by a pathogenic or potentially pathogenic microorganism 2. the release of a microbial toxin in the bloodstream.

General variables

Alteration in mental status, Alteration in body temperature (> 38.3°C or < 36°C), Tachycardia    (> 90 beats/minute or greater than 2 SD above normal value for age), Tachypnea (> 20 respirations per min or PaCO2 < 32 mm Hg), Hyperglycemia (plasma glucose >120 mg/ml or 7.7 mmol/L in the absence of diabetes), significant edema

Inflammatory variables

Altered WBC count (leukocyte count > 12,000/mm3; leukocytosis, < 4,000/mm3; leukopenia), Normal white blood cell count with an increased number of immature neutrophils cells (> 10% immature [band] cells), Plasma C-reactive protein (>2 SD above the normal value) and Plasma procalcitonin (>2 SD above the normal value)

Hemodynamic variables

Arterial hypotension (Systolic blood pressure (SBP) <90 mm Hg, Mean arterial blood pressure <70, or an SBP decrease of >40 mm Hg in adults or <2 SD below normal for age), Mixed venous oxygen saturation (Svo2) >70% (should not be used in children and newborns as a sign of sepsis since their Svo2 is normally lower [75-80%]), Cardiac index >3.5 L . min-1.M-23

Tissue Perfusion variables

Hyperlactatemia (> 1 mmol/L), Decreased capillary refill or mottling.

Organ Dysfunction variables

Arterial hypoxemia, Acute oliguria, Creatinine increase, coagulation abnormalities (INR >1.5 or aPTT >60 sec), Ileus (absent bowel sounds), Thrombocytopenia (platelets <100,000/microliter), Hyperbilirubinemia

Severe sepsis

Sepsis complicated by organ dysfunction

Hypotension and hypoperfusion abnormalities

Examples of hypoperfusion abnormalities include lactic acidosis [> 4 mmol/L (36 mg/dl) lactate], oliguria, and acute alteration in mental status.

A hypotensive patient has a mean arterial pressure < 70 mm Hg. Resuscitation with IV fluids raises the blood pressure to normal levels.

Septic shock

Sepsis-induced hypotension, despite adequate fluid resuscitation, plus hypoperfusion abnormalities

Hypotension and hypoperfusion abnormalities.

In contrast to severe sepsis, a patient with septic shock remains hypotensive despite fluid resuscitation.

Hypoperfusion abnormalities are as mentioned in severe sepsis.

MODS

Presence of altered organ functions that cannot be normalized without intervention

WBC, white blood cell; MODS, multiple organ dysfunction syndrome.

The timing of clinical intervention is essential to the survival of septic patients. Early identification of sepsis with appropriate treatment significantly increases the chance that the patient will survive. However, even with appropriate and aggressive treatment, 50–60% of patients with septic shock will die if the process is identified too late.

Etiology

Most cases of sepsis occur as the result of an infection of the urinary tract, lungs, or the peritoneum. Other sources of sepsis include skin, soft tissue, and central nervous system (CNS) infections. Approximately 50% of these infections are due to gram-negative bacteria, and slightly less than 50% are caused by gram-positive bacteria. Less common causes of sepsis include fungi, viruses such as the human immunodeficiency virus (HIV), and protozoa.

Sepsis in the Neonate

Sepsis in the neonate (< 1 month old) is usually caused by Streptococcus agalactiae (group B Streptococcus) and less commonly by Escherichia coli. Approximately 2 of 1000 live-born infants are infected by S agalactiae (group B streptococcal sepsis), with a case fatality of 5–10%. During labor or delivery, the neonate can become infected with E coli or S agalactiae. Infection with these organisms may initially manifest as pneumonia or meningitis. Other causes of neonatal sepsis include Klebsiella and Enterobacter.

Pediatric Sepsis

The most common causes of sepsis in the pediatric age group include Streptococcus pneumoniae, Neisseria meningitidis, and Staphylococcus aureus. Antecedent infections that may cause sepsis in this group of patients include meningitis, skin infections, bacterial rhinosinusitis, and otitis media. Common causes of meningitis include S pneumoniae and N meningitidis. S aureus is a common cause of skin infections, and S pneumonia is frequently the cause of bacterial rhinosinusitis and otitis media. Other causes of sepsis in the pediatric population include E coli, S agalactiae (Group B Streptococcus), Klebsiella, and Enterobacter.

Sepsis in Adults

An antecedent infection usually serves as the source of sepsis in adults. The most common sites of infection in adults are the urinary tract, the respiratory tract, and the abdomen. Urinary tract infections are common in sexually active women and can ascend from the bladder to the kidneys and into the bloodstream. Males with benign prostatic hyperplasia are more likely to be diagnosed with urinary tract infections that can also ascend to the kidneys and then into the bloodstream.

Many adults are diagnosed with pneumonia each year. Bacteria are the most common cause of pneumonia in adults, and frequently bacteria leave the lungs and enter the bloodstream.

Many older adults have diverticulosis. The diverticula can occasionally release bacteria into the peritoneum, causing peritonitis or intra-abdominal abscesses. The rich vascular supply of the peritoneum allows bacteria to enter the bloodstream. More details on the causes of sepsis in adults are listed in Table SS-2.

Table SS-2. Bacterial Causes of Adult Sepsis and the Common Sites of Infection

Bacterial Agents

Gram-negative bacteria

Common Site(s) of Infection

Comments

Escherichia coli

UTIs and prostatitis

Most common cause of UTIs and prostatitis in adults.

Klebsiella pneumoniae

UTIs and pneumonia

Common cause of pneumonia in alcoholics.

Enterobacter

UTIs

Pseudomonas aeruginosa

Infected burn wounds and pneumonia in cystic fibrosis patients.

Sepsis due to this bacterium has the highest mortality rate.

Proteus

UTIs

UTIs due to these organisms have an elevated urine pH.

Bacteroides fragilis

Peritoneal infections

Most common cause of anaerobic sepsis.

Bacterial Agents

Gram-positive bacteria

Common Site of Infection

Comments

Streptococcus pneumoniae

Pneumonia and meningitis

Most common cause of pneumonia and meningitis in adults.

Streptococcus pyogenes

Skin and soft tissue infections.

Produces superantigens (pyrogenic exotoxins) that cause streptococcal toxic shock syndrome. Bacteria are usually present in the bloodstream.

Staphylococcus aureus

Skin and soft tissue infections.

Produces a superantigen toxin called toxic shock syndrome toxin that causes toxic shock syndrome in menstruating women or in patients with an infected wound.

Enterococcus

UTIs

UTI, urinary tract infection.

Special Concerns

Elderly patients are more susceptible to sepsis, have less physiologic reserve to tolerate the insult from infection, and are more likely to have underlying diseases, all of which adversely impact survival. Elderly patients also are more likely to have atypical presentations, such as hypothermia rather than a fever, or nonspecific presentations when septic. The common causes of sepsis in the elderly are the same as those seen in younger adults (see Table SS-2).

Epidemiology

Bacteria are the most common cause of sepsis. Gram-negative bacteria cause 50% of the cases of septic shock, resulting in 115,000 deaths per year. Gram-negative bacteria cause more deaths due to sepsis than do gram-positive bacteria. Septic shock caused by gram-positive bacteria (< 50% of cases) is now more common because of the increased incidence in cases of pneumonia and the use of intravascular devices.

Sources of Infection (Table SS-3; see next page)

The most frequent infectious sources of septic shock include pneumonia, peritonitis, and urinary tract infections. Other sources of infection include skin and soft tissues, intestinal tract, central nervous system (CNS), oropharynx, instrumentation sites, contaminated inhalation therapy equipment, and intravenous fluids. The source of the infection is an important determinant of clinical outcome. Certain cases of sepsis are more likely to develop into severe sepsis. For instance, severe sepsis is most likely to occur in patients with nosocomial pneumonia. Severe sepsis is more likely to occur in patients with intra-abdominal infection and polymicrobial bacteremia or postoperative wound infections and bacteremia. However, patients with bacteremia associated with intravascular catheters or indwelling urinary catheters have a lower risk of developing severe sepsis.


Table SS-3. Suspected Sources of Sepsis

Source

Pneumonia

Peritonitis

Skin and Soft Tissue Infections

Urinary Tract Infections

Bacterial Meningitis

Major community- acquired pathogens

Streptococcus pneumoniae
Haemophilus influenzae

Legionella sp.
Chlamydia pneumoniae

Escherichia coli
Bacteroides fragilis

Streptococcus pyogenes
Staphylococcus aureus
Clostridium
sp.

Polymicrobial infections
Aerobic gram- negative bacilli
Pseudomonas aeruginosa
Anaerobes
Staphylococcus sp.

Escherichia coli
Klebsiella sp.
Enterobacter sp.
Proteus sp.

Streptococcus pneumoniae
Neisseria meningitidis
Listeria monocytogenes
Escherichia coli
Haemophilus influenzae

Major nosocomial pathogens

Aerobic gram- negative bacilli

Aerobic gram- negative bacilli
Anaerobes
Candida sp.

Staphylococcus aureus
Aerobic gram- negative bacilli

Aerobic gram negative bacilli
Enterococcus sp.

Pseudomonas aeruginosa
Escherichia coli
Klebsiella
sp.
Staphylococcus sp.

Patients at increased risk of developing sepsis

Manifestations

Symptoms of sepsis are usually nonspecific and include fever, chills, and constitutional symptoms of fatigue, malaise, anxiety, or confusion. Symptoms may be absent in serious infections, especially in elderly patients. There is a continuum of clinical manifestations that usually begin with sepsis and can end with MODS. See Table SS-1 on the next page for details concerning the signs and symptoms associated with sepsis. Remember, patients treated early in this disease continuum have fewer complications and have a much better chance of survival.

Table SS-1. Clinical Definitions of the Progression from Sepsis to MODS

Disease Stage

Clinical Definition

Signs and Symptoms

Comments

Sepsis

The presence of a documented or suspected infection and some of the signs of a systemic inflammatory response (signs and symptoms are listed in the columns to the right).

Infection is defined as a pathologic process caused by:

1. the invasion of a normally sterile tissue, fluid or body cavity by a pathogenic or potentially pathogenic microorganism 2. the release of a microbial toxin in the bloodstream.

General variables

Alteration in mental status, Alteration in body temperature (> 38.3°C or < 36°C), Tachycardia    (> 90 beats/minute or greater than 2 SD above normal value for age), Tachypnea (> 20 respirations per min or PaCO2 < 32 mm Hg), Hyperglycemia (plasma glucose >120 mg/ml or 7.7 mmol/L in the absence of diabetes), significant edema

Inflammatory variables

Altered WBC count (leukocyte count > 12,000/mm3; leukocytosis, < 4,000/mm3; leukopenia), Normal white blood cell count with an increased number of immature neutrophils cells (> 10% immature [band] cells), Plasma C-reactive protein (>2 SD above the normal value) and Plasma procalcitonin (>2 SD above the normal value)

Hemodynamic variables

Arterial hypotension (Systolic blood pressure (SBP) <90 mm Hg, Mean arterial blood pressure <70, or an SBP decrease of >40 mm Hg in adults or <2 SD below normal for age), Mixed venous oxygen saturation (Svo2) >70% (should not be used in children and newborns as a sign of sepsis since their Svo2 is normally lower [75-80%]), Cardiac index >3.5 L . min-1.M-23

Tissue Perfusion variables

Hyperlactatemia (> 1 mmol/L), Decreased capillary refill or mottling.

Organ Dysfunction variables

Arterial hypoxemia, Acute oliguria, Creatinine increase, coagulation abnormalities (INR >1.5 or aPTT >60 sec), Ileus (absent bowel sounds), Thrombocytopenia (platelets <100,000/microliter), Hyperbilirubinemia

Severe sepsis

Sepsis complicated by organ dysfunction

Hypotension and hypoperfusion abnormalities

Examples of hypoperfusion abnormalities include lactic acidosis [> 4 mmol/L (36 mg/dl) lactate], oliguria, and acute alteration in mental status.

A hypotensive patient has a mean arterial pressure < 70 mm Hg. Resuscitation with IV fluids raises the blood pressure to normal levels.

Septic shock

Sepsis-induced hypotension, despite adequate fluid resuscitation, plus hypoperfusion abnormalities

Hypotension and hypoperfusion abnormalities.

In contrast to severe sepsis, a patient with septic shock remains hypotensive despite fluid resuscitation.

Hypoperfusion abnormalities are as mentioned in severe sepsis.

MODS

Presence of altered organ functions that cannot be normalized without intervention

WBC, white blood cell; MODS, multiple organ dysfunction syndrome.

Organ Dysfunction Associated with Severe Sepsis and Septic Shock

Perfusion of the organs is reduced in patients with severe sepsis to septic shock. Some of the organ dysfunctions that results from this reduced perfusion are listed below. Severe sepsis and septic shock can simultaneously affect several organs, resulting in a mixture of signs and symptoms.

Lung: Decrease in arterial PO2; acute respiratory distress syndrome (ARDS) due to leakage of the contents of the capillaries into alveoli; tachypnea.

• Kidney (acute renal failure [ARF]) and proteinuria.

• Liver: Elevated levels of serum bilirubin and alkaline phosphatase; cholestatic jaundice.

• Gastrointestinal tract: Nausea, vomiting, diarrhea, and ileus.

• Heart: Cardiac output is initially normal or elevated. Later on, impaired cardiac contractility can occur.

• Brain: Confusion.

• Skin: Some organisms are more likely to cause changes in the skin. Some organisms produce toxins that can cause dilatation of the blood vessels in the skin resulting in a rash or erythroderma. Some organisms will cause damage to the endothelial cells, which line the blood vessels and cause leakage of the blood from the vascular space into the skin, resulting in petechiae or purpuras. Other organisms enter the skin from the blood stream and cause erythema and necrosis (ecthyma gangrenosum).  

  1. Petechiae or purpura: Usually due to infections with Neisseria meningitidis or Rickettsia rickettsii
  2. Generalized erythroderma: Toxic shock syndrome (TSS) presents with a sunburn-like rash, which then causes skin peeling. It is due to either S aureus or Streptococcus pyogenes
  3. Ecthyma gangrenosum: The most common cause of this skin damage is due to Pseudomonas aeruginosa infections
  4. Complications associated with septic shock:  The reported incidence of the complications in sepsis is most frequently CNS dysfunction followed by liver failure, ARF, disseminated intravascular coagulation (DIC), and then by ARDS. Patients with septic shock are most likely to develop ARF, followed by DIC, and then by ARDS. Complications include:

Pathogenesis

The systemic response to sepsis is a complex sequence of events that can be defined as a spectrum of clinical conditions caused by the immune response of a patient to an infection that is characterized by systemic inflammation, hypotension, and hypoperfusion of the patient’s organs.

Immunologic Response to Sepsis

Following a microbial infection or a microbial intoxication, the immune response triggers a complex series of events that cause an overwhelming inflammatory response. Dilation of the peripheral vasculature occurs, and it becomes “leaky,” resulting in peripheral pooling of the blood, hypotension, and hypoperfusion of organs.

1.  Various microbial triggers cause the white blood cells to produce large amounts of proinflammatory cytokines.

2.  With either type of microbial trigger, the immune response begins with an overwhelming inflammatory response due to increased production of proinflammatory cytokines, which include tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-12, interferon gamma (IFN-λ), and IL-6.

3.  Proinflammatory cytokines can act directly or indirectly through secondary mediators to affect organ function. The secondary mediators include nitric oxide, thromboxanes, leukotrienes, platelet-activating factor, prostaglandins, and complement.

4. The primary and secondary mediators cause the activation of the complement cascade and the coagulation cascade and production of prostaglandins and leukotrienes.

Diagnosis

The diagnosis of sepsis requires a high index of suspicion, a thorough history and physical examination, appropriate laboratory studies, and a close follow-up of the patient’s hemodynamic status.

History

A thorough history helps to determine if the infection causing the sepsis was community acquired or nosocomially acquired and if the patient is immunocompromised. Important details include exposure to animals, travel, tick bites, occupational hazards, alcohol use, seizures and loss of consciousness, medications, and underlying diseases that may predispose the patient to specific infectious agents. Some clues to a septic event include fever, hypotension, oliguria (diminished excretion of urine), or anuria (no urine excreted); tachypnea and hypothermia without obvious cause; and bleeding.

Physical Examination

In all neutropenic patients and in patients with a suspected pelvic infection, the physical examination should include rectal, pelvic, and genital examinations. Such examinations may reveal rectal, perirectal, or perineal abscesses, pelvic inflammatory disease or abscesses, or prostatitis.

Laboratory Studies

A large number of laboratory tests are usually ordered for patients suspected of having sepsis (Table SS-4). Cultures of suspected sites of infection are important so that the causative organism(s) can be identified and antibiotic sensitivities can be determined to guide appropriate antimicrobial therapy. Laboratory tests can be useful to alert the physician of the potential for the increasing severity of the patient’s condition. Some of these tests can be helpful in indicating whether sepsis is due to processes other than microbial infection.

Table SS-4 Laboratory Studies Useful in Assessing a Septic Patient

Laboratory Test

Comments

Blood chemistry, blood lactic acid level

 and electrolytes

Respiratory alkalosis signals impending shock that is reversible with fluid resuscitation

Metabolic acidosis can develop just prior to hypotension or can occur at the same time

Hyperbilirubinemia, and proteinuria are often present

Hyperventilation commonly induces respiratory alkalosis

Cultures of blood, sputum, urine, CSF, and other obviously infected sites should be performed.

At least two sets of blood cultures should be obtained over a 24-hour period. During intermittent fever spikes, the bacteremia is most prominent 0.5 hours before the spike, and blood taken at this time is more likely to contain detectable bacteria

CBC with differential

In early stages of the disease process, leukocytosis with left shift and thrombocytopenia are frequently observed, Leukopenia may occur in certain patients (elderly). Neutrophils may contain toxic granulations, Döhle bodies, or cytoplasmic vacuoles. Later in the disease process, thrombocytopenia worsens

Procalcitonin (PCT)

A good nonspecific marker for differentiating systemic bacterial inflammatory responses from nonbacterial systemic inflammatory responses.

C-reactive protein

A nonspecific marker for inflammation.

BUN and creatinine 

Later in the disease process azotemia is more prominent.

Coagulation profile

Later on in the disease process there is a prolongation of PT and PTT times, decreased fibrinogen, and the presence of D-dimers and fibrin split products, suggesting DIC.

Blood glucose

Diabetics can develop hyperglycemia.

Liver function tests

Serum bilirubin and alkaline phosphatase levels can become elevated and cholestatic jaundice may develop later in the disease process as liver function is affected.

Arterial blood gas

ARDS can result in lower oxygen levels in the bloodstream.

Imaging studies

Chest radiograph to look for antecedent pneumonia

CT of abdomen may reveal presence of abdominal abscesses if the source of the infection is still unknown

MRI may reveal hard to find sites of infection in the head or abdomen

CSF, cerebrospinal fluid; CBC, complete blood cell count; BUN, blood urea nitrogen; DIC, disseminated intravascular coagulation; ARDS, adult respiratory distress syndrome.

Therapy and prevention

Treatment of the Septic Patient

Early diagnosis and intervention are highly effective in stopping the sequence of events leading to septic shock. There are three priorities when treating the septic patient.

1.  Immediate stabilization of the patient. The immediate concern when treating patients with severe sepsis is reversal of life-threatening abnormalities (ABCs: airway, breathing, circulation). Patients with severe sepsis should be admitted to an intensive care unit, and their vital signs (blood pressure, heart rate, respiratory rate, and temperature) should be monitored.

2. The blood must be rapidly cleared of microorganisms. Prompt and early institution of empiric treatment with antimicrobials is essential and decreases the development of shock and lowers the mortality rate. The drugs used depend on the source of the infection (Table SS-5).

Table SS-5 Antimicrobial Agents Used to Treat Septic Patients

Clinical Situation

Antimicrobial Agent(s)

Community-acquired pneumonia

A third- (ceftriaxone) or fourth- (cefepime) generation cephalosporin is given with an aminoglycoside (gentamicin)

Nosocomial pneumonia

Cefepime or imipenem-cilastatin and an aminoglycoside

Abdominal infection

Imipenem-cilastatin or piperacillin-tazobactam and aminoglycoside

Nosocomial abdominal infection

Imipenem-cilastatin and aminoglycoside or piperacillin-tazobactam and amphotericin B

Skin and soft tissue infection

Vancomycin and imipenem-cilastatin or piperacillin-tazobactam

Nosocomial skin and soft tissue infections

Vancomycin and cefepime

Urinary tract infection

Ciprofloxacin and aminoglycoside

Nosocomial urinary tract infection

Vancomycin and cefepime

CNS* infection

Vancomycin and third generation cephalosporin or meropenem

Nosocomial CNS* infection

Meropenem and vancomycin

*CNS, central nervous system.

3. The original focus of infection must be treated.

Prevention of Sepsis

Revised 12/2/09

©2009 Neal R. Chamberlain, Ph.D., All rights reserved.

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