Key Clinical Questions
What is the definition of systemic inflammatory response syndrome (SIRS) and how do you differentiate SIRS from sepsis, severe sepsis, and septic shock?
Which patients presenting with sepsis need admission to the intensive care unit (ICU)?
Which septic patients need invasive monitoring (arterial catheter, central venous catheter)?
What interventions in the treatment of sepsis improve mortality?
Which septic patients deserve empiric steroids as part of the therapeutic regimen?
Introduction
Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury. The incidence and number of sepsis-related deaths has increased from 1979 to 2000, and sepsis remains the tenth most common cause of death in the United States. Despite the rising number of cases, earlier identification of sepsis and improved intensive medical care has been shown to reduce the overall mortality rate to approximately 17.9%. Severity is correlated with mortality; up to 40% of patients with severe sepsis and 60% of patients with septic shock die due to sepsis-related complications (Table 138-1).
Syndrome | Definition | Approximate Mortality |
---|---|---|
Systemic inflammatory response syndrome (SIRS) | At least two of the following four clinical features:
| 10% |
Sepsis | SIRS criteria plus a culture-proven infection or presumed presence of an infection | 20% |
Severe sepsis | Sepsis plus presence of one or more organ dysfunctions including:
| 20%–40% |
Septic shock | Sepsis and refractory hypotension with mean systemic blood pressure lower than 65 mm Hg unresponsive to crystalloid fluid challenge of 20–40 cc/kg | 40%–60% |
Successful shock resuscitation may be associated with considerable morbidity and mortality. Multiple organ dysfunction syndrome (MODS) refers to severe acquired dysfunction of at least two organ systems lasting at least 24 to 48 hours in the setting of sepsis, trauma, burns, or severe inflammatory conditions so that homeostasis cannot be maintained without intervention. Mortality is directly correlated with the number of dysfunctional organs and the duration of dysfunction (Table 138-2). An uncontrolled hyperinflammatory response is believed to be the cause of multiple organ dysfunction.
The American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) defined in 2001 at the International Sepsis Definitions Conference the following terms to describe the spectrum of systemic inflammation and sepsis. Systemic inflammatory response syndrome (SIRS) is defined as a clinical syndrome that results from activation of the immune system whether due to infection, trauma, burns, or a noninfectious inflammatory process. It includes at least two of the following: (1) temperature > 38 degrees Celsius or < 36 degrees Celsius; (2) heart rate > 90 beats/minute; (3) respiratory rate > 20 breaths/minute or paCO2 < 32 mm Hg; a (4) white blood cell count > 12,000 cells/mm3, or < 4000 cells/mm3, or > 10% immature (band) forms.
Sepsis is defined as a clinical syndrome that results from activation of the immune system with a documented infection. The definition of sepsis includes the above SIRS criteria plus a culture-proven infection or presumed presence of an infection. The severity of sepsis is graded according to the associated organ dysfunction and hemodynamic compromise. Severe sepsis is defined as the presence of sepsis and one or more organ dysfunctions. Organ dysfunction can be defined as acute lung injury including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, thrombocytopenia, altered mental status, mottled skin, capillary refill greater than three seconds, renal dysfunction, hepatic dysfunction, cardiac dysfunction based on echocardiography or measurement of cardiac index, or lactic acidosis indicating hypoperfusion. Septic shock is defined as the presence of sepsis and refractory hypotension with mean systemic blood pressure lower than 65 mm Hg unresponsive to crystalloid fluid challenge of 20 to 40 cc/kg leading to acute circulatory collapse.
Pathophysiology
Sepsis is as an uncontrolled inflammatory response to an infection in which a dysregulated host immune response leads to multiorgan involvement not limited to the source infected organ. Microbial antigens such as lipopolysaccharides (LPS) from Gram-negative bacteria bind to Toll-like receptors on inflammatory cells, thereby causing a complex immune reaction involving T-cells, macrophages, neutrophile, endothelial cells, and dendritic cells. Cytokines (such as IL-1, IL-6, IL-8), growth factors (such as TNFa), high-mobility group box-1 (HMGB-1), arachidonic acid metabolites, and nitric oxide and host genetics likely determine the nature of the response. The complement cascade, coagulation cascades, platelets, and leukocytes interact at the vascular endothelium level resulting in microvascular injury, thrombosis, and loss of endothelial integrity, which altogether results in tissue ischemia. This diffuse endothelial disruption is responsible for the various organ dysfunctions and global tissue hypoxia that accompany severe sepsis and septic shock. Global tissue hypoxia can occur from multiple mechanisms including decreased preload, vasoregulatory dysfunction, myocardial depression, and impaired tissue extraction due to microcirculatory dysfunction or mitochondrial dysfunction (cytopathic hypoxia). Some noninfectious processes (eg, pancreatitis) can also lead to a dysregulated host immune response and multiorgan dysfunction, and these conditions are categorized using the term SIRS. These patients appear septic without a clear infectious source.
Differential Diagnosis
The differential diagnosis for sepsis is broad, including conditions that present with high-output states and those with low-output shock. While many patients present with common conditions that meet SIRS criteria—nonmassive pulmonary embolus, alcohol withdrawal, even COPD exacerbations—other conditions can mimic sepsis with high cardiac output state and wide pulse pressure without shock including thyrotoxicosis, aortic regurgitation, arteriosclerosis, and cirrhosis. While all patients with sepsis do not present in shock, the differential diagnosis for shock should always be considered. In addition to septic shock, conditions that belong to the category of vasodilatory, or high cardiac output, shock include anaphylaxis, adrenal insufficiency, and neurogenic shock.
The other causes of shock should always remain in the differential for patients with sepsis as the presentation may combine two or more processes or may simply mimic two processes. For example, a patient with underlying poor cardiac function who becomes septic may not be able to generate the high cardiac outputs expected in sepsis and may not have the typical findings on physical examination of a septic patient. Moreover, the phenomenon of sepsis-induced myocardial dysfunction occurs when patients have normal cardiac function prior to their infection and the sepsis induces a global cardiac dysfunction, seen on echocardiography as global hypokinesis, which may impair the expected high cardiac output usually associated with a vasodilated circulation. The other causes of shock all fall into a category of low-output states, including cardiogenic shock, hypovolemic shock, and obstructive shock (Table 138-3).
Vasodilatory shock | Sepsis |
Anaphylaxis | |
Adrenal insufficiency | |
Neurogenic | |
Low-output shock states | Cardiogenic (eg, massive myocardial infarction, myocarditis, valvular disease) |
Hypovolemic (eg, hemorrhagic, gastrointestinal losses, burns, pancreatitis) | |
Obstructive (eg, massive PE, tension pneumothorax, auto-PEEP, tamponade, abdominal compartment syndrome) |
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A high index of suspicion for the clinical sepsis syndrome facilitates early identification of the inciting stimulus, and intervention may limit the ongoing immune response. Septic patients present with signs and symptoms ranging from fever and chills to delirium to shock. Presentation often varies according to infection source, patient age, underlying comorbidities (including immune system function and cardiac status), and timing of presentation relative to onset of sepsis. Early manifestations of sepsis—tachycardia, oliguria, and hyperglycemia—may be subtle and easily overlooked in the hospitalized patient. Signs of established sepsis include altered mental status, metabolic acidosis and respiratory alkalosis, hypotension with decreased systemic vascular resistance (SVR) and elevated cardiac output, and coagulopathy. Late manifestations include acute lung injury (ALI), ARDS, acute renal failure, hepatic dysfunction, and refractory shock. Sepsis can occur related to a systemic inflammatory response to any infectious source, but less than 50% of septic patients will have positive blood cultures. Therefore, aggressive clinical evaluation should occur inquiring about symptoms including fever, rigors, mental status changes, cough, shortness of breath, vomiting, diarrhea, dysuria, hematuria, and many other symptoms that might suggest the source of infection. Patients may also present with obvious or subtle physical examination findings. In an analogous manner to the thorough history, a complete physical examination can assess for potential infection sources from any organ system. Sometimes inconspicuous and missed infection sources may include the skin and soft tissue, central nervous system, gastrointestinal tract, and indwelling devices.
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In addition to stabilizing the patient, it is critical to identify the cause of the ongoing immunologic response. Obtaining cultures for blood, urine, and other fluids early, prior to administration of antibiotics, helps preserve the integrity of results and should be an extremely high priority, but not at the expense of administering antibiotics expediently. Identification of the underlying source remains paramount, and lack of source identification and control may render choice of antibiotics meaningless. The most common sites of infection in sepsis are the urinary and respiratory tracts, but any organ system may be involved. Urinary sources include cystitis, pyelonephritis, and perinephric abscess. Patients with kidney stones may develop Gram-negative septicemia. Sinusitis, mastoiditis, pneumonia, lung abscess, and empyema may be associated with sepsis. Gastrointestinal sources of sepsis may include esophageal rupture or perforation following a procedure or after vomiting, cholangitis, cholecystitis, intestinal infarction or perforation, acute pancreatitis, Clostridium dificile colitis, diverticulitis, and intraabdominal abscess. Postoperative mediastinitis and acute bacterial endocarditis may lead to sepsis. It is also critical not to consider skin and soft tissue sources of sepsis because of the possibility of an infected decubitus ulcer, postoperative wound, soft tissue abscess, or necrotizing fasciitis. Vascular causes include catheter infections (central and peripheral lines, arterial catheters, dialysis catheters, ventriculoperitoneal shunts) and septic thrombophlebitis. Infected articular prosthetic devices have also been associated with sepsis. Meningitis and intracranial abscess, sometimes associated with neurosurgery, are also considerations.
Relevant diagnostic studies based on symptoms, signs, and clinical suspicion in patients may include chest or abdominal radiography and culture of blood, urine, sputum, or other relevant body fluids that may be infected—cerebrospinal fluid (CSF) analysis, paracentesis in patients with ascites, or thoracentesis in patients with pleural effusion. Bacteremia is found in only approximately 50% of cases of severe sepsis and septic shock, while 20% to 30% of patients will have no microbial cause identified from any source. When relatively basic diagnostic evaluations—including plain films, blood cultures, and fluid cultures—do not yield a likely infectious culprit, advanced imaging including chest and abdominal computed tomography can assess for pulmonary infiltrates, intraabdominal abscesses, and obstructing renal stones. Biliary pathology may be better imaged with ultrasound, magnetic resonance imaging (MRI), or endoscopic retrograde pancreatography (ERCP) if necessary. Echocardiography to assess for endocarditis may be necessary based on physical examination findings, blood culture results, and the clinical picture.
Triage and Hospital Admission
All patients with a presentation of severe sepsis or septic shock should be admitted to or transferred to a monitored setting that is capable of continuous vital sign monitoring with the ability to measure central venous pressure (CVP) and central venous oxygen saturations (ScvO2). Those patients with SIRS and sepsis should be monitored closely if not placed in an intensive care unit setting so that they can be treated promptly if they start to show signs of deterioration. Vital signs should be monitored frequently and a low threshold to utilize other monitoring (telemetry and continuous pulse oximetry) should be considered. Patient response to initial resuscitation in the emergency department or on a medical floor should guide the clinician with respect to intensive care unit (ICU) admission with the capability of intraarterial blood pressure measurement and the delivery of vasoactive medications. Intermediate care units (sometimes called step-down units or transitional care units) vary from facility to facility in their capabilities for invasive monitoring and use of vasoactive agents. The protocols and policies at individual institutions will help determine placement of these patients, based on monitoring requirements. Due to the emphasis placed on early aggressive resuscitation, early antibiotics, and early source identification and control, septic patients require careful evaluation to determine admission location, and patients with marginally stable clinical parameters should be admitted to an ICU setting to expeditiously meet early care goals to improve outcomes.
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Management
Management of severe sepsis and septic shock requires a structured approach that assures proper diagnostic evaluation and implementation of evidence-based interventions in an expedient manner to improve outcomes (Figure 138-1). This approach requires (1) empiric antibiotic coverage of an infectious source while cultures are pending, (2) optimal fluid resuscitation, (3) pressor and/or inotrope therapy for selected patients, and (4) consideration of additional therapies such as drainage of abscesses, removal of lines, moderate (but not intensive) control of hyperglycemia, and (5) consideration of steroids in selected patient subsets when indicated.