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Sepsis and Septic Shock

Neal R. Chamberlain, Ph.D., 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.

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

5. Know the microbial triggers and the host mediators that led to sepsis and septic shock.

6. Describe the differences between the following: sepsis and septic shock.

OVERVIEW

Sepsis is a systemic response that is caused by the presence of pathogenic microorganisms and/or their toxins (superantigens) in the bloodstream. During sepsis, the body mounts a dysregulated immune response to the infection and/or a super-antigen.

Definitions

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection and/or superantigen.

Septic shock is a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

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, 20-30% of patients with septic shock will die if intervention is 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-1.

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-1).

Epidemiology

• Mortality increases as the number of symptoms of sepsis increases and as the severity of the disease increases. Early and appropriate intervention can significantly increase the chance that a septic patient will survive.
• There are over 750,000 cases of severe sepsis diagnosed per year, and approximately 50% of these patients progress to septic shock.
• However, with advances in training, better surveillance and monitoring, and prompt initiation of therapy to treat the underlying infection and support failing organs, mortality is now from 20 to 30%.
• Pneumonia is the most common cause of sepsis, accounting for about half of all cases, followed by intraabdominal and urinary tract infections.
• Blood cultures in patients with sepsis are positive in only one third of cases, and in up to a third of cases, cultures from all sites are negative.
• Staphylococcus aureus and Streptococcus pneumoniae are the most common gram-positive isolates, whereas Escherichia coli, Klebsiella sp., and Pseudomonas aeruginosa predominate among gram-negative isolates.

Bacteria are the most common cause of sepsis. There is some debate concerning which group of organisms is currently the most common cause of sepsis. Gram positive bacteria were shown to be the most frequent cause of sepsis in the US in a 2003 study (see epidemiology section).  However, a study in 2009 (see epidemiology section) demonstrated that gram-negative bacterial infections were more common than gram-positive bacterial infections as a cause of sepsis (gram-negative- 62%; gram-positive- 47%; fungi-19%)

Septic shock caused by gram-positive bacteria was not as common as it is currently. It is now more common because of the increases in cases of pneumonia and the use of intravascular devices. Sepsis due to nosocomial pathogens has a higher rate of mortality that sepsis due to community-acquired pathogens. When bacteremia develops into septic shock there are no differences in outcomes based on the gram stain of the pathogen in the blood.

Sources of Infection (Table SS-2)

The most frequent infectious sources of septic shock include pneumonia, intra-abdominal, 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.

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 (BPH), 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. Remember, patients treated early in this disease have fewer complications and have a much better chance of survival.

Organ Dysfunction that may be associated with septic shock

Perfusion of the organs is reduced in patients with septic shock. Some of the organ dysfunctions that results from this reduced perfusion are listed below. 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
   

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 are due to dysregulation of the immune response of a patient to an infection. This dysregulated immune response can be 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. Dilatation 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.
• Gram-positive bacterial triggers include lipoteichoic acid, peptidoglycan, hemolysins (cytolysins) and superantigens. The superantigens include 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, dilatation 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 TNF-alpha and IL-1. TNF-alpha and IL-1 and/or the microbial triggers cause the cleavage of nuclear factor-kappa B (NF-kB) inhibitor. NF-kB can initiate mRNA to induce the production of other proinflammatory cytokines (IL-6, IL-12 and IFN-gamma).

3. IL-6 stimulates the release of acute-phase reactants (C-reactive protein and procalcitonin).

4. 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.

5. The primary and secondary mediators cause activation of the complement cascade.

IL-1 and TNF-alpha directly affect endothelial cells leading to expression of tissue factor. Tissue factor initiates the production of thrombin and promotes coagulation. IL-1 and TNF-alpha impair fibrinolysis through production of plasminogen activator inhibitor-1. Microvascular thrombi can result causing organ dysfunction

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-3). 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.

Clinical Diagnosis

Must suspect or have documented an infection.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and/or superantigen.

In the intensive care unit (ICU): organ dysfunction due to infection can be represented by an increase in the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score of 2 points or more (in hospital mortality of >10%).

The following are used to get a SOFA score; PaO2/FiO2, platelet count, bilirubin levels, mean arterial pressure, Glasgow coma score, creatinine levels, and urine output.

In the emergency department, outpatient, or general hospital ward settings, adults with suspected infection are more likely to have poor outcomes typical of sepsis if they have at LEAST TWO of the following (also called the quick SOFA or qSOFA);

1. Respiratory rate of 22/min or greater
2. Altered mentation
3. Systolic blood pressure of 100 mm Hg or less

Septic shock is a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone (40% or greater mortality).

Clinically identified by a vasopressor requirement to maintain a mean arterial pressure (MAP) of 65 mm Hg or greater AND serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia.

Example SOFA scoring sheet;

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.

Reference

Singer M, et.al., 2016. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8):801-810. Doi:10.1001/jama.201.0287

Revised 3/11/16

©2016 Neal R. Chamberlain, Ph.D., All rights reserved.

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