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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).

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.

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

• Mortality increases as the number of symptoms of sepsis increases and as the severity of the disease process increases. Early and appropriate intervention can significantly increase the chance that a septic patient will survive.
• Sepsis is the seventh leading cause of death in children aged 1–4 years, and is the ninth leading cause of death in children aged 5–14 years.
• Sepsis is the cause of 1.4% of all deaths that occur annually in the U.S (34,234 deaths in 2006). There are about 400,000 cases of sepsis diagnosed per year, and approximately 50% of these patients progress to septic shock.
• Septic shock is the most common cause of mortality in the intensive care unit. In 2006, it was the tenth leading cause of death in the U.S. About 50–60% of patients with septic shock die each year.

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.

Patients at increased risk of developing sepsis

•  Patients with underlying diseases, including neutropenia, solid tumors, leukemia, dysproteinemias, cirrhosis of the liver, diabetes mellitus, acquired immune deficiency syndrome (AIDS), and other serious chronic conditions.
• Antecedent surgery or instrumentation, including catheters and prosthetic devices.
• Prior drug therapy: Immunosuppressive drugs, especially broad-spectrum antibiotics.
• Patients of certain ages: Men older than 50 years, women aged 20–45 years, and neonates.
• Men older than 50 years are more likely to develop benign prostatic hyperplasia, which causes them to be more susceptible to development of cystitis and pyelonephritis. These infections can lead to sepsis, with the most common cause being E coli.
• Sexually active women between 20 and 45 years of age are much more likely to acquire urinary tract infections, which can lead to sepsis. The most common cause is E coli.
• During labor and delivery, neonates can be infected with E coli and S agalactiae, resulting in neonatal sepsis
• Other conditions associated with an increased risk for developing sepsis are childbirth, septic abortion, trauma, widespread burns (Pseudomonas aeruginosa and Staphylococcus aureus), and intestinal ulceration (Bacteroides and gram-negative rods).

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.

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:
   • ARDS
   • DIC
   • ARF
   • Intestinal bleeding
   • Liver failure
   • CNS dysfunction
   • Heart failure

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.

• Gram-negative bacteria produce endotoxin, which is also known as lipopolysaccharide (LPS). LPS is the most common gram-negative bacterial trigger of cytokine release. This microbial trigger binds to cell receptors on the host’s macrophages and activates regulatory proteins such as nuclear factor kappa B (NFκB). LPS activates the regulatory proteins by interacting with several receptors. The CD receptors pool the LPS–LPS-binding protein complex on the surface of the cell, and the Toll-like receptors (TLR) translate the signal into the cells.
• The most common gram-positive bacterial triggers include superantigens such as TSS toxin (TSST) and staphylococcal enterotoxin produced by S aureus and streptococcal pyrogenic exotoxin A (SpeA) produced by Streptococcus pyogenes. Instead of binding in the groove of the major histocompatibility complex (MHC), superantigens bind on the outer surface of the antigen-presenting cells’ MHC class II molecule as well as on the outer surface of certain T-cell receptors present on T cells. Superantigen binding causes T-cell activation and massive proinflammatory cytokine production and release, which can cause fever, endothelial cell damage, dilation of the peripheral vasculature, peripheral pooling of blood in the interstitial space, organ hypoperfusion, organ dysfunction, shock, and death. Unlike most antigens that activate only a few T cells (1 in 10,000 T cells) to cause an immune response, superantigens activate many T cells (1 in 5 T cells), causing a much more vigorous and sometimes life-threatening immune response.

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.

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).

*CNS, central nervous system.

3. The original focus of infection must be treated.

• Remove foreign bodies.
• Drain purulent exudate.
• Remove infected organs; debride or amputate gangrenous tissues.

Prevention of Sepsis

• Avoid trauma to mucosal surfaces that are normally colonized by gram-negative bacteria.
• Use trimethoprim-sulfamethoxazole prophylactically in children with leukemia.
• Use topical silver nitrate, silver sulfadiazine, or sulfamylon prophylactically in burn patients.

• Sterilization of the bowel aerobic flora with polymyxin or gentamicin with vancomycin and nystatin is effective in reducing gram-negative sepsis in neutropenic patients.
• Indwelling catheters should be properly cared for and frequently examined for the possibility of infection.
• Immunize patients to prevent S pneumoniae pneumonia and N meningitidis meningitis.
• Detection and treatment of pregnant patients with vaginal colonization by S agalactiae reduces neonatal morbidity and mortality rates from group B streptococcal sepsis. Obtain vaginal and perianal swab samples from the pregnant patient who is 35 to 37 weeks’ gestation, and obtain cultures of these samples to determine if the patient is colonized with S agalactiae. Pregnant patients who are colonized with S agalactiae should be treated with intrapartum penicillin to reduce the chances of neonatal sepsis.

Revised 12/2/09

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

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