(see also Shock and Fluid Resuscitation.)
Sepsis, severe sepsis, and septic shock are inflammatory states resulting from a systemic response to bacterial infection. In severe sepsis and septic shock, there is critical reduction in tissue perfusion; acute failure of multiple organs, including the lungs, kidneys, and liver, can occur. Common causes in immunocompetent patients include many different species of gram-positive and gram-negative bacteria. Immunocompromised patients may have uncommon bacterial or fungal species as a cause. Signs include fever, hypotension, oliguria, and confusion. Diagnosis is primarily clinical combined with culture results showing infection; early recognition and treatment is critical. Treatment is aggressive fluid resuscitation, antibiotics, surgical excision of infected or necrotic tissue and drainage of pus, and supportive care.
Sepsis represents a spectrum of disease ranging from systemic inflammatory response syndrome (SIRS) to septic shock.
SIRS is a constellation of symptoms of systemic inflammation that may or may not be the result of infection. For example, patients with acute pancreatitis and major trauma, including burns, may have findings of SIRS. Manifestations include
Sepsis is ≥ 2 SIRS criteria with known or suspected infection.
Severe sepsis is sepsis with organ dysfunction. Cardiovascular failure is typically manifested by hypotension, respiratory failure by hypoxemia, renal failure by oliguria and/or azotemia, and hematologic failure by coagulopathy.
Septic shock is sepsis with refractory hypotension and impaired end organ perfusion despite adequate fluid resuscitation.
Most cases of septic shock are caused by hospital-acquired gram-negative bacilli or gram-positive cocci and often occur in immunocompromised patients and patients with chronic and debilitating diseases. Rarely, it is caused by Candida or other fungi. A postoperative infection (deep or superficial) should be suspected as the cause of septic shock in patients who have recently had surgery. A unique, uncommon form of shock caused by staphylococcal and streptococcal toxins is called toxic shock (see Toxic Shock Syndrome (TSS)).
Septic shock occurs more often in neonates (see Neonatal Sepsis), the elderly, and pregnant women. Predisposing factors include diabetes mellitus; cirrhosis; leukopenia, especially that associated with cancer or treatment with cytotoxic drugs; invasive devices, including endotracheal tubes, vascular or urinary catheters, drainage tubes, and other foreign materials; and prior treatment with antibiotics or corticosteroids. Common causative sites of infection include the lungs and the urinary, biliary, and GI tracts.
The pathogenesis of septic shock is not completely understood. An inflammatory stimulus (eg, a bacterial toxin) triggers production of proinflammatory mediators, including TNF and IL-1. These cytokines cause neutrophil–endothelial cell adhesion, activate the clotting mechanism, and generate microthrombi. They also release numerous other mediators, including leukotrienes, lipoxygenase, histamine, bradykinin, serotonin, and IL-2. They are opposed by anti-inflammatory mediators, such as IL-4 and IL-10, resulting in a negative feedback mechanism.
Initially, arteries and arterioles dilate, decreasing peripheral arterial resistance; cardiac output typically increases. This stage has been referred to as warm shock. Later, cardiac output may decrease, BP falls (with or without an increase in peripheral resistance), and typical features of shock appear.
Even in the stage of increased cardiac output, vasoactive mediators cause blood flow to bypass capillary exchange vessels (a distributive defect). Poor capillary flow from this shunting along with capillary obstruction by microthrombi decreases delivery of O2 and impairs removal of CO2 and waste products. Decreased perfusion causes dysfunction and sometimes failure of one or more organs, including the kidneys, lungs, liver, brain, and heart.
Coagulopathy may develop because of intravascular coagulation with consumption of major clotting factors, excessive fibrinolysis in reaction thereto, and more often a combination of both.
Symptoms and Signs
Symptoms and signs of sepsis can be subtle and often easily mistaken for manifestations of other disorders (eg, delirium, primary cardiac dysfunction, pulmonary embolism), especially in postoperative patients. With sepsis, patients typically have fever, tachycardia, diaphoresis, and tachypnea; BP remains normal. Other signs of the causative infection may be present. As severe sepsis or septic shock develops, an early sign, particularly in the elderly or very young, may be confusion or decreased alertness. BP decreases, yet the skin is paradoxically warm. Later, extremities become cool and pale, with peripheral cyanosis and mottling. Organ dysfunction causes additional symptoms and signs specific to the organ involved (eg, oliguria, dyspnea).
Sepsis is suspected when a patient with a known infection develops systemic signs of inflammation or organ dysfunction. Similarly, a patient with otherwise unexplained signs of systemic inflammation should be evaluated for infection by history, physical examination, and tests, including urinalysis and urine culture (particularly in patients who have indwelling catheters), blood cultures, and cultures of other suspect body fluids. In patients with a suspected surgical or occult cause of sepsis, ultrasonography, CT, or MRI may be required, depending on the suspected source. Blood levels of C-reactive protein and procalcitonin are often elevated in severe sepsis and may facilitate diagnosis but they are not specific. Ultimately, the diagnosis is clinical.
Other causes of shock (eg, hypovolemia, MI) should be ruled out via history, physical examination, ECG, and serum cardiac markers. Even in the absence of MI, hypoperfusion caused by sepsis may result in ECG findings of ischemia including nonspecific ST-T wave abnormalities, T-wave inversions, and supraventricular and ventricular arrhythmias.
CBC, ABGs, chest x-ray, serum electrolytes, BUN and creatinine, Pco2, and liver function are monitored. Serum lactate levels, central venous O2 saturation (ScvO2), or both can be done to help guide treatment. WBC count may be decreased (< 4,000/μL) or increased (> 15,000/μL), and PMNs may be as low as 20%. During the course of sepsis, the WBC count may increase or decrease, depending on the severity of sepsis or shock, the patient's immunologic status, and the etiology of the infection. Concurrent corticosteroid use may elevate WBC count and thus mask WBC changes due to trends in the illness.
Hyperventilation with respiratory alkalosis (low Paco2 and increased arterial pH) occurs early, in part as compensation for lactic acidemia. Serum HCO3 is usually low, and serum and blood lactate levels increase. As shock progresses, metabolic acidosis worsens, and blood pH decreases. Early respiratory failure leads to hypoxemia with Pao2< 70 mm Hg. Diffuse infiltrates may appear on the chest x-ray (see Respiratory Arrest) due to acute respiratory distress syndrome (ARDS). BUN and creatinine usually increase progressively as a result of renal insufficiency. Bilirubin and transaminases may rise, although overt hepatic failure is uncommon in patients with normal baseline liver function.
Many patients with severe sepsis develop relative adrenal insufficiency (ie, normal or slightly elevated baseline cortisol levels that do not increase significantly in response to further stress or exogenous ACTH). Adrenal function may be tested by measuring serum cortisol at 8 AM; a level < 5 mg/dL is inadequate. Alternatively, cortisol can be measured before and after injection of 250 mcg of synthetic ACTH; a rise of < 9 mcg/dL is considered insufficient. However, in refractory septic shock, no cortisol testing is required before starting corticosteroid therapy.
Hemodynamic measurements with a central venous or pulmonary artery catheter (see Procedure) can be used when the specific type of shock is unclear or when large fluid volumes (eg, > 4 to 5 L 0.9% saline over 6 to 8 h) are needed. Bedside echocardiography in the ICU is a practical and noninvasive alternative method of hemodynamic monitoring. In septic shock, cardiac output is increased and peripheral vascular resistance is decreased, whereas in other forms of shock (see Etiology and Classification), cardiac output is typically decreased and peripheral resistance is increased. Neither CVP nor pulmonary artery occlusive pressure (PAOP) is likely to be abnormal in septic shock, unlike in hypovolemic, obstructive, or cardiogenic shock.
Overall mortality in patients with septic shock is decreasing and now averages 30 to 40% (range 10 to 90%, depending on patient characteristics). Poor outcomes often follow failure to institute early aggressive therapy (eg, within 6 h of suspected diagnosis). Once severe lactic acidosis with decompensated metabolic acidosis becomes established, especially in conjunction with multiorgan failure, septic shock is likely to be irreversible and fatal.
Patients with septic shock should be treated in an ICU. The following should be monitored hourly:
Urine output, a good indicator of renal perfusion, should be measured, usually with an indwelling catheter. The onset of oliguria (eg, < about 0.5 mL/kg/h) or anuria, or rising creatinine may signal impending renal failure.
Following evidence-based guidelines and formal protocols for timely diagnosis and treatment of sepsis has recently been shown to decrease mortality and length of stay in the hospital.
IV fluids are the first method used to restore perfusion. Isotonic crystalloid (eg, 0.9% saline) is preferred. Some clinicians add albumin to the initial fluid bolus in patients with severe sepsis or septic shock; albumin is more expensive than crystalloid but is generally a safe complement to crystalloid. Starch-based fluids (eg, hydroxyethyl starch) are associated with increased mortality and should not be used. Initially, 1 L of crystalloid is given rapidly. Most patients require a minimum of 30 mL/kg in the first 4 to 6 h. However, the goal of therapy is not to administer a specific volume of fluid but to achieve tissue reperfusion without causing pulmonary edema due to fluid overload. Estimates of successful reperfusion include ScvO2 and lactate clearance (ie, percent change in serum lactate levels). Target ScvO2 is ≥ 70%. Lactate clearance target is 10 to 20%. Risk of pulmonary edema can be controlled by optimizing preload; fluids should be given until CVP reaches 8 mm Hg (10 cm H2O) or PAOP reaches 12 to 15 mm Hg; however, patients on mechanical ventilation may require higher CVP levels. The quantity of fluid required often far exceeds the normal blood volume and may reach 10 L over 4 to 12 h. PAOP or echocardiography can identify limitations in left ventricular function and incipient pulmonary edema due to fluid overload.
If a patient with septic shock remains hypotensive after CVP or PAOP has been raised to target levels, norepinephrine or vasopressin (0.03 units/min) may be given to increase mean BP to at least 60 mm Hg. Epinephrine may be added if a second drug is needed. However, vasoconstriction caused by higher doses of these drugs may cause organ hypoperfusion and acidosis.
O2 is given by mask or nasal prongs. Tracheal intubation and mechanical ventilation may be needed subsequently for respiratory failure (see Respiratory Failure and Mechanical Ventilation).
Parenteral antibiotics should be given as soon as possible after specimens of blood, body fluids, and wound sites have been taken for Gram stain and culture. Very prompt empiric therapy, started immediately after suspecting sepsis, is essential and may be lifesaving. Antibiotic selection requires an educated guess based on the suspected source (eg, pneumonia, urinary tract infection), clinical setting, knowledge or suspicion of causative organisms and of sensitivity patterns common to that specific inpatient unit or institution, and previous culture results.
Typically, broad-spectrum gram-positive and gram-negative bacterial coverage is used initially; immunocompromised patients should also receive an empiric antifungal drug. There are many possible starting regimens; when available, institutional trends for infecting organisms and their antibiotic susceptibility patterns (antibiograms) should be used to select empiric treatment. In general, common antibiotics for empiric gram-positive coverage include vancomycin and linezolid. Empiric gram-negative coverage has more options and includes broad-spectrum penicillins (eg, piperacillin/tazobactam), 3rd- or 4th-generation cephalosporins, imipenems, and aminoglycosides. Initial broad coverage is narrowed based on culture and sensitivity data.
The source of infection should be controlled as early as possible. IV and urinary catheters and endotracheal tubes should be removed if possible or changed. Abscesses must be drained, and necrotic and devitalized tissues (eg, gangrenous gallbladder, necrotizing soft-tissue infection) must be surgically excised. If excision is not possible (eg, because of comorbidities or hemodynamic instability), surgical drainage may help. If the source is not controlled, the patient's condition will continue to deteriorate despite antibiotic therapy.
Other supportive measures:
Normalization of blood glucose improves outcome in critically ill patients, even those not known to be diabetic, because hyperglycemia impairs the immune response to infection. A continuous IV insulin infusion (starting dose 1 to 4 units/h) is titrated to maintain glucose between 110 and 180 mg/dL (7.7 to 9.9 mmol/L). This approach necessitates frequent (eg, every 1 to 4 h) glucose measurement.
Corticosteroid therapy may be beneficial in patients who remain hypotensive despite treatment with IV fluids, source control, antibiotics, and vasopressors. There is no need to measure cortisol levels before starting therapy. Treatment is with replacement rather than pharmacologic doses. One regimen consists of hydrocortisone 50 mg IV q 6 h (or 100 mg q 8 h). Continued treatment is based on patient response.
Trials of monoclonal antibodies and activated protein C (drotrecogin alfa—no longer available) have been unsuccessful.
Last full review/revision July 2013 by Paul M. Maggio, MD, MBA; Carla Carvalho, MD, MPH
Content last modified November 2013