Sepsis

Published May 29, 2002

Department of
Infectious Diseases

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This chapter was adapted from an article that originally appeared in the January 2002 edition of The Cleveland Clinic Journal of Medicine.

National Guidelines

The term systemic inflammatory response syndrome (SIRS) was coined in 1992 by a panel comprised of American College of Chest Physicians and Society of Critical Care Medicine members. They convened to develop consensus definitions of critical illness for the purposes of clinical trial design.

SIRS describes the host response to critical illness of either infectious or noninfectious etiology, such as burns, trauma, and pancreatitis. More specifically

Sepsis is SIRS due to a presumed or known site of infection.
Severe sepsis is sepsis with an acute associated organ failure.
Septic shock, a subset of severe sepsis, is defined as a persistently low mean arterial blood pressure despite adequate fluid resuscitation.
Refractory septic shock is a persistently low mean arterial blood pressure despite vasopressor therapy and adequate fluid resuscitation.¹

SIRS can be readily diagnosed at the bedside by the presence of at least two of the following four signs: body temperature alterations (hyperthermia or hypothermia), tachycardia, tachypnea, and changes in white blood cell count (leukocytosis or leukopenia).

PREVALENCE AND INCIDENCE

Sepsis is the leading cause of death in noncoronary intensive care units (ICUs) and the 13th leading cause of death in the United States overall.² The best data we have on the incidence of severe sepsis is from a study performed in the United States by Angus and colleagues.³ This study determined that an estimated 751,000 cases of severe sepsis occur annually in the United States. More than 55% of these patients have underlying comorbidity, and more than one half of the cases occur in those aged 65 years and older. When patients with human immunodeficiency virus are excluded, the incidence of sepsis in men and women is similar.

The incidence of sepsis is expected to rise during the next decade owing to the aging population, a growing immunosuppressed population, the increased use of invasive catheters and prosthetic materials, and the growing problem of antimicrobial resistance. In the year 2010, it is estimated that there will be 934,000 new sepsis cases in the United States and in 2020, 1,100,000.³

PATHOPHYSIOLOGY

The Inflammatory Cascade
Severe sepsis can occur as a result of infection at any body site, including the lung, abdomen, skin or soft tissue, or urinary tract and as a result of a primary blood stream infection, such as meningococcemia. Bacteria are the pathogens most commonly associated with the development of sepsis, although fungi, viruses, and parasites do cause sepsis. The pathophysiology of sepsis is initiated by the outer membrane components of both gram-negative organisms (lipopolysaccharide [LPS], lipid A, endotoxin) and gram-positive organisms (lipoteichoic acid, peptidoglycan). These outer membrane components are able to bind to the CD14 receptor on the surface of monocytes (Figure 1). By virtue of the recently described toll-like receptors, a signal is then transmitted to the cell, leading to the eventual production of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-I).^4,5 These cytokines have a direct toxic effect on tissues; they also activate phospholipase A2. These and other effects lead to increased concentrations of platelet-activating factor, promotion of nitric oxide synthase activity, promotion of tissue infiltration by neutrophils, and promotion of neutrophil activity.^6,7

Link Between Inflammation and Coagulation
Interleukin-1 and TNF-alpha also have direct effects on the endothelial surface. As a result of these inflammatory cytokines, tissue factor, the first step in the extrinsic pathway of coagulation, is expressed on the surfaces of the endothelium and of monocytes. Tissue factor leads to the production of thrombin, which is a proinflammatory substance itself. Thrombin results in fibrin clots in the microvasculature, a sequela most easily recognized in meningococcal septic shock with purpura fulminans. Fibrinolysis is also impaired during the septic process. IL-1 and TNF-alpha lead to the production of plasminogen activator inhibitor-1, a potent inhibitor of fibrinolysis.⁸

Proinflammatory cytokines also disrupt the body's naturally occurring modulators of coagulation and inflammation, activated protein C (APC) and antithrombin. Protein C circulates as an inactive zymogen, but in the presence of thrombin and the endothelial surface-bound protein thrombomodulin, is converted to the enzyme-activated protein C. Recent studies have shown that proinflammatory cytokines can shear thrombomodulin from the endothelial surface as well as lead to downregulation of this molecule and, thus, prevent the activation of protein C.⁹ APC with its cofactor protein S turn off thrombin production by cleaving factor Va and VIIIa.¹⁰ APC also restores fibrinolytic potential by inhibiting plasminogen activator inhibitor-1.¹¹ In vitro studies reveal that APC has direct anti-inflammatory properties, including inhibiting the production of proinflammatory cytokines by LPS-stimulated monocytes, inhibiting leukocyte adhesion and rolling, and inhibiting neutrophil accumulation.^12-14

Antithrombin is the second naturally occurring endothelial regulator affected during sepsis. Antithrombin inhibits thrombin production at multiple steps in the coagulation cascade as well as by directly binding and inhibiting thrombin.¹⁵ Antithrombin, when bound to endothelial cell surface glycosaminoglycans (GAGs), leads to the production of the anti-inflammatory molecule prostacyclin (PGI₂).¹⁶ Evidence exists that neutrophil elastase cleaves GAGs off the surface of the endothelial lining, thus limiting the anti-inflammatory properties of antithrombin.¹⁷

Severe Sepsis: The Final Common Pathway
As a result of the viscious cycle of inflammation and coagulation, cardiovascular insufficiency and multiple organ failure occur and often lead to death. Cardiovascular insufficiency can occur at the level of the myocardium as a result of the myocardial-depressant effects of TNF or at the level of the vessel, due to vasodilation and capillary leak.¹⁸

SIGNS AND SYMPTOMS

Clinical signs that may lead the physician to consider sepsis in the differential diagnosis include fever or hypothermia, unexplained tachycardia, unexplained tachypnea, signs of peripheral vasodilation, unexplained shock, and unexplained mental status changes. Laboratory or invasive hemodynamic measurements that suggest sepsis include increased cardiac output with a low systemic vascular resistance, increased oxygen consumption, leukocytosis or leukopenia, unexplained lactic acidosis, unexplained impairment in renal or liver function, a prolonged prothrombin time, thrombocytopenia, unexplained hypophosphatemia, and an increased C-reactive protein.

Conditions other than sepsis can produce a systemic inflammatory response and organ dysfunction. Noninfectious illnesses that should be considered in the differential diagnosis include tissue injury due to trauma, hematoma, venous thrombosis, myocardial or pulmonary infarcts, transplant rejection, pancreatitis, hyperthyroidism, addisonian crisis, drug or blood product reaction, malignancies, and central nervous system hemorrhages.¹⁹

DIAGNOSIS

The diagnosis of severe sepsis requires the presence of a presumed or known site of infection, evidence of a systemic inflammatory response, and an acute sepsis-associated organ dysfunction. Below is a description of the specific diagnostic criteria used in past clinical trials to define patients with severe sepsis.

1) A presumed or known site of infection is indicated by one of the following:

Purulent sputum or respiratory sample, or a chest radiograph with new infiltrates not explained by a noninfectious process
Spillage of bowel contents noted during an operation
Radiographic or physical examination evidence of an infected collection
White blood cells in a normally sterile body fluid
Positive blood culture
Evidence of infected mechanical hardware by physical or radiographic examination

2) Evidence of a systemic inflammatory response is indicated by at least two of the following:

Fever or hypothermia—Core body temperature of greater than or equal to 38ºC or less than or equal to 36ºC
Tachypnea—greater than or equal to 20 breaths per minute or need for mechanical ventilation for an acute process
Tachycardia—heart rate greater than or equal to 90 beats per minute, unless the patient has a preexisting tachycardia
White blood cell count—greater than or equal to 12,000 cells/mm³ or less than or equal to 4,000 cells/mm³, or greater than 10% bands on differential

3) A sepsis-induced organ failure is indicated by one of the following criteria:

Cardiovascular dysfunction—mean arterial pressure less than or equal to 60 mm Hg, the need for vasopressors to maintain this blood pressure in the face of adequate intravascular volume (central venous pressure greater than 8 or pulmonary artery occlusion pressure greater than 12), or after an adequate fluid challenge has been given
Respiratory organ failure—an arterial oxygen pressure/fraction of inspired oxygen ratio less than 250 in the absence of pneumonia or less than 200 in the presence of pneumonia
Renal dysfunction—urine output less than 0.5 mL/kg/hr for 1 hour in the face of adequate intravascular volume or after an adequate fluid challenge
Hematologic dysfunction—thrombocytopenia with 80,000 platelets/mm³, a 50% drop in the previous 3 days, or a prothrombin-INR greater than 1.2 that cannot be explained by liver disease or concomitant warfarin usage
Unexplained metabolic acidosis—a pH less than 7.30 and a plasma lactate greater than 1.5 times the upper limit of normal for the laboratory

MANAGEMENT

The International Sepsis Forum, a group of experts in the field of critical care and infectious diseases, has developed guidelines on the management of severe sepsis and septic shock.²⁰ Below is an evidenced-based summary of the treatment recommendations for the management of severe sepsis, with updates based on recent literature.

Management of the infection responsible for severe sepsis should focus on two critical issues: the use of appropriate antimicrobial therapy and adequate source control of infection.

Appropriate Antimicrobial Therapy
When the clinician is faced with a patient with severe sepsis, the site of infection and the causative organism or organisms often are not known. Empiric antibiotics must be given in these cases. Appropriate empiric antimicrobial therapy must be guided by the knowledge of the most common site of infection and the most common infecting organisms. A recent clinical trial of patients with severe sepsis revealed that the lung is the most common site of infection followed by the abdomen. In terms of pathogen type, gram-positive organisms and gram-negative organisms cause sepsis with equal frequency; fungal organisms account for fewer cases. The most common gram-positive organisms are Staphylococcus aureus and Streptococcus pneumoniae, and the most common gram-negative organisms are Escherichia coli, Klebsiella species, Pseudomonas species, and Enterobacter species.²¹

The following guidelines should be considered in providing appropriate empiric antimicrobial therapy to patients with severe sepsis:

Community-acquired pneumonia
Patients should receive a macrolide agent and a third-generation cephalosporin, or a respiratory quinolone alone.²²
Nosocomial pneumonia
If P aeruginosa is suspected, patients should receive a beta-lactam agent active against nosocomial pathogens with an aminoglycoside. The use of a carbapenem or quinolone should be considered when an extended-spectrum beta-lactamase-producing Enterobacter or Klebsiella is suspected based on knowledge of the ICU microbiology, in patients with a prolonged or multiple hospital stay, or in patients who had received multiple antibiotics in the past. Vancomycin can be added if a high rate of methicillin-resistant S aureus (MRSA) infection occurs in one's institution.
Intra-abdominal sepsis
Antibiotics should be given that treat enteric gram-negative rods and anaerobes.
Intravascular catheter infections or
prosthetic device infections
Empiric coverage for gram-negative and gram-positive organisms should be given while awaiting microbiology data. Vancomycin should be given for MRSA if the incidence is high at the institution.

Empiric antifungal therapy should be given in patients at high risk for fungemia. High-risk patients include those who have had prior colonization with Candida at two or more sites, those being treated with more than two different antibiotics, those who have taken antibiotics for more than 14 days, those who have had prior placement of a Hickman catheter, and those who have undergone prior hemodialysis.²³

Source Control of Infection
Adequate source control of infection is as important as appropriate antimicrobial therapy in the treatment of a patient with severe sepsis. Source control of infection includes removal of infected foreign bodies, such as urinary catheters, intravascular catheters, peritoneal dialysis cannulas, prosthetic joints, vascular grafts, and mechanical valves. Incision and drainage of cutaneous abscesses as well as either open or percutaneous drainage of intra-abdominal abscesses also fall under the principle of adequate source control of infection. Furthermore, one specific clinical scenario requires specific mention. For patients with necrotizing fasciitis, mortality and extent of tissue loss are directly related to the rapidity of surgical intervention.²⁴

Hemodynamic Support
The first principle of hemodynamic support in the patient with septic shock is to provide adequate fluid resuscitation. Fluid resuscitation will produce tissue perfusion as indicated by these clinical endpoints: physical examination, urine output, central venous pressure, or pulmonary artery wedge pressure. The use of packed red blood cells as fluid resuscitation to achieve a hemoglobin of 10.0 mg/dL has not been shown to be more beneficial than transfusing patients to a hemoglobin level of 7.0 mg/dL.²⁵ With respect to vasopressor therapy, norepinephrine was shown in a randomized study to be superior to dopamine in volume-resuscitated hyperdynamic sepsis syndrome.²⁶ The use of epinephrine should be avoided in the setting of sepsis because this agent has harmful effects on gastric blood flow and lactate levels.²⁷ In addition, the use of renal-dose dopamine to treat or prevent acute renal failure is not justified.²⁸ When cardiac output is low in a patient with septic shock, dobutamine remains the inotropic agent of choice.

Therapy for patients with refractory septic shock requires particular attention. As many as 76% of septic shock patients unresponsive to fluid resuscitation and vasopressor therapy are adrenally hyporesponsive as defined by a less than 9 mg/dL rise in the cortisol level from baseline following an adrenocorticotropic hormone (ACTH) stimulation test. Administration of 50 mg intravenous hydrocortisone every 6 hours with 50 µg oral fludrocortisone every day for 7 days improved survival when compared with placebo in patients with refractory septic shock and adrenal hyporesponsiveness.²⁹ Therefore, administration of an ACTH stimulation testing followed by treatment with the above regimen in patients with refractory septic shock and adrenal hyporesponsiveness is recommended.

Ventilator Management for Acute Respiratory Distress
Thanks to the efforts of organized networks of acute respiratory distress syndrome (ARDS) investigators in the United States and elsewhere, much has been learned about the appropriate ventilator management of patients with ARDS due to sepsis. A recent randomized clinical trial demonstrated lower mortality and an increase in the number of days off the ventilator when a lower (6 mL/kg) tidal volume strategy was used compared with a standard (12 mL/kg) tidal volume strategy.³⁰ A recent trial of nitric oxide indicated that this agent is capable of transient improvements in oxygenation without an improvement in mortality or in the number of ventilator days.³¹ Similar findings were observed with prone-position ventilation.³² However, neither nitric oxide use nor prone-position ventilation can be recommended routinely for all patients with sepsis and ARDS based on randomized studies. Small studies in the late fibroproliferative phase of ARDS suggest that the use of corticosteroids may be beneficial.³³ An adequately powered study to address this issue is ongoing.

Adjuvant Therapies
Over the past 20 years, nearly 20,000 patients have been enrolled in clinical trials evaluating adjuvant therapies for the treatment of severe sepsis. The agents tested, primarily anti-inflammatory molecules, were capable of only modest absolute reductions (3% to 4%) in 28-day all-cause mortality compared with standard treatment. Recombinant human activated protein C ([rhAPC] drotrecogin alfa, activated; Xigris) recently became the first drug approved by the FDA for the treatment of severe sepsis. RhAPC is a molecule that targets the cascade of inflammation and coagulopathy characteristic of sepsis through its antithrombotic, profibrinolytic, and anti-inflammatory properties. The PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) trial was a worldwide phase III trial of RhAPC in the treatment of severe sepsis.²¹ RhAPC produced a 6% absolute reduction and 19.4% relative-risk reduction in 28-day all-cause mortality compared with placebo (p = 0.005). Most of the benefit observed with rhAPC in this trial occurred in patients at higher risk for death as indicated by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores greater than 25, presence of septic shock at baseline, and presence of two or more sepsis-induced organ failures at entry into the study. Although effective, rhAPC was associated with a nearly statistically significant greater number of serious bleeding events when compared with placebo. The benefit-risk ratio of this molecule can be maximized if it is used in patients with severe sepsis at high risk for death and avoided in patients thought to be at high risk for bleeding in the setting of a full-strength anticoagulant (Table 1).

Additional Treatment Components
Three additional components in the care of severe sepsis patients include ensuring adequate nutrition, providing deep venous thrombosis prophylaxis, and providing gastric ulcer prophylaxis. Adequate nutrition is best accomplished enterically to avoid catheter-related bloodstream infections, to maintain gut mucosa integrity, and to prevent the theoretical possibility of translocation of bacteria across the intestinal wall. Enteral feedings containing arginine and omega-3 fatty acids have been shown to decrease the number of ICU and ventilator days as well as the number of infectious complications, but have not yet shown a mortality advantage over standard tube feedings.³⁴ Deep venous thrombosis prevention can be accomplished with the use of subcutaneous heparin or continuous use of pneumatic compression stockings. Gastric ulcer prophylaxis may be accomplished with sucralafate, an H2 receptor antagonist, or a proton pump inhibitor.

OUTCOMES

In the previously mentioned study by Angus and colleagues,³ the overall hospital mortality rate for patients with severe sepsis was 28.6%. This figure would account for 215,000 deaths in the United States annually. Mortality in children is approximately 10%; this figure rises to more than 38.4% in those aged 85 years and older. The mortality rate for men is only slightly higher than the rate for women (29.3% versus 27.9%).

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REFERENCES

Disclaimer

Published May 29, 2002

Steven P.
LaRosa, MD

Department of
Infectious Diseases

Print Chapter

Definition

Prevalence
and Incidence

Pathophysiology

Signs and
Symptoms

Diagnosis

Management

Outcomes

References

National Guidelines

International Sepsis Forum

Published May 29, 2002

Department of Infectious Diseases

National Guidelines

Department of
Infectious Diseases