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(See also Shock and Fluid Resuscitation.)
Sepsis, severe
sepsis, and septic shock are inflammatory states resulting from
the systemic response to bacterial infection. In severe sepsis and
septic shock, there is critical reduction in tissue perfusion. Common
causes include gram-negative organisms, staphylococci, and meningococci.
Symptoms often begin with shaking chills and include fever, hypotension,
oliguria, and confusion. Acute failure of multiple organs can occur,
including the lungs, kidneys, and liver. Treatment is aggressive fluid
resuscitation, antibiotics, surgical excision of infected or necrotic tissues
and drainage of pus, supportive care, and sometimes intensive control
of blood glucose and administration of corticosteroids and activated
protein C.
A spectrum of severity exists (see
Table 1: Sepsis and Septic Shock: Sepsis in the United States ).
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Table 1
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Sepsis in the United States
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Category
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Number of Cases
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Crude
Mortality (%)
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Number of Deaths
Annually
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Sepsis
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400,000
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15
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60,000
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Severe sepsis (sepsis plus organ failure)
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300,000
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20
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60,000
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Septic shock (severe sepsis plus refractory hypotension)
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200,000
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45
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90,000
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Sepsis is documented or suspected infection plus systemic inflammatory response syndrome including ≥ 2 of the following: temperature > 38° C or < 36° C; pulse > 90 beats/min; respirations > 20/min or Paco2 < 32 mm Hg; WBCs > 12,000 cells/μL or < 4,000 cells/μL, or > 10% immature forms.
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Data from Wenzel RP: Treating sepsis. N Engl J Med 2002; 347(13): 966–967.
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Sepsis is infection accompanied by an acute inflammatory reaction with systemic manifestations associated with release into the bloodstream of numerous endogenous mediators of inflammation. Acute pancreatitis and major trauma, including burns, may manifest with signs of sepsis. The inflammatory reaction typically manifests with 2 or more of the following:
However, these criteria are now viewed as suggestive but not sufficiently precise to be diagnostic.
Severe sepsis is sepsis accompanied by signs of failure of at least one organ. Cardiovascular failure is typically manifested by hypotension, respiratory failure by hypoxemia, renal failure by oliguria, and hematologic failure by coagulopathy.
Septic shock is severe sepsis with organ hypoperfusion and hypotension that are poorly responsive to initial fluid resuscitation.
Etiology
Most cases of septic shock are caused by hospital-acquired gram-negative bacilli or gram-positive cocci and often occur in immunocompromised patients and those with chronic and debilitating diseases. Rarely, it is caused by Candida or other fungi. A unique form of shock caused by staphylococcal and streptococcal toxins is called toxic shock (see Gram-Positive Cocci: Toxic Shock Syndrome (TSS)).
Septic shock occurs more often in neonates (see Infections in Neonates: Neonatal Sepsis), patients > 35 yr, 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.
Pathophysiology
The pathogenesis of septic shock is not completely understood. An inflammatory stimulus (eg, a bacterial toxin) triggers production of proinflammatory mediators, including tumor necrosis factor 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. These 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
With sepsis, the patient typically has fever, tachycardia, and tachypnea; BP remains normal. Other signs of the causative infection are generally present. As severe sepsis or septic shock develops, the first sign may be confusion or decreased alertness. BP generally falls, yet the skin is paradoxically warm. Oliguria (< 0.5 mL/kg/h) is likely to be present. Later, extremities become cool and pale, with peripheral cyanosis and mottling. Organ failure causes additional symptoms and signs specific to the organ involved.
Diagnosis
Sepsis is suspected in a patient with a known infection who 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), serial blood cultures, and cultures of other suspect body fluids. Blood levels of procalcitonin and C-reactive protein are elevated in severe sepsis and may facilitate diagnosis, but these are not specific. Ultimately, diagnosis is clinical.
Other causes of shock (eg, hypovolemia, MI) should be sought by history, physical examination, ECG, and serum cardiac markers. Even without MI, hypoperfusion may result in ECG findings of ischemia including nonspecific ST-T wave abnormalities, T-wave inversions, and supraventricular and ventricular arrhythmias.
CBC, ABG, chest x-ray, serum electrolytes, lactate levels or sublingual Pco2, and liver function are monitored. At the onset of septic shock, the WBC count may initially decrease to < 4,000/μL, and PMNs may be as low as 20%. However, this situation reverses within 1 to 4 h, and a significant increase in both the total WBC count to > 15,000/μL and PMNs to > 80% (with predominantly juvenile forms) usually occurs. A sharp decrease in platelet count to ≤ 50,000/μL is often present early.
Hyperventilation with respiratory alkalosis (low Paco
2
and increased arterial pH) occurs early, in part as compensation for lactic acidemia. Serum HCO
3
is usually low, and serum and blood lactate increase. As shock progresses, metabolic acidosis worsens, and blood pH decreases. Early respiratory failure leads to hypoxemia with Pao
2
< 70 mm Hg. Diffuse infiltrates may appear on the chest x-ray (see Acute Lung Injury and 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.
Up to 50% of 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 μg of synthetic ACTH; a rise of < 9 μg/dL is considered insufficient. However, most physicians simply give replacement doses of corticosteroids without testing.
Hemodynamic measurements with a central venous or pulmonary artery catheter 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. Unlike in hypovolemic shock, cardiac output during septic shock is more likely to be normal or increased, and peripheral resistance is decreased. Neither central venous pressure (CVP) nor pulmonary artery occlusive pressure (PAOP) is likely to be abnormal, unlike in hypovolemic, obstructive, or cardiogenic shock (see Shock and Fluid Resuscitation: Etiology and Classification). Echocardiography (including transesophageal echocardiography) is a useful alternative for evaluating cardiac performance.
Prognosis
Overall mortality in patients with septic shock is decreasing and now averages 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.
Treatment
Patients with septic shock should be treated in an ICU. The following should be monitored frequently (see also Approach to the Critically Ill Patient: Pulmonary Artery Catheter Monitoring): systemic pressure; CVP, PAOP, or both; pulse oximetry; ABGs; blood glucose, lactate, and electrolyte levels; renal function, and possibly sublingual Pco
2
. Urine output, a good indicator of renal perfusion, should be measured, usually with an indwelling catheter.
Fluid resuscitation with 0.9% saline should be given until CVP reaches 8 mm Hg (10 cm H
2
O) or PAOP reaches 12 to 15 mm Hg. Oliguria with hypotension is not a contraindication to vigorous fluid resuscitation. 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, dopamine may be given to increase mean BP to at least 60 mm Hg. If dopamine dose exceeds 20 μg/kg/min, another vasopressor, typically norepinephrine , may be added. However, vasoconstriction caused by higher doses of dopamine and norepinephrine poses risks of organ hypoperfusion and acidosis, and these drugs have not been shown to improve survival.
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 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, clinical setting, knowledge of or suspicion of causative organisms and sensitivity patterns common to that specific inpatient unit, and previous culture results.
One regimen for septic shock of unknown cause is gentamicin or tobramycin 5.1 mg/kg IV once/day plus a 3rd-generation cephalosporin ( cefotaxime 2 g q 6 to 8 h or ceftriaxone 2 g once/day, or, if Pseudomonas is suspected, ceftazidime 2 g IV q 8 h). Alternatively, ceftazidime plus a fluoroquinolone (eg, ciprofloxacin ) may be used. Monotherapy with maximal therapeutic doses of ceftazidime (2 g IV q 8 h) or imipenem (1 g IV q 6 h) may be effective but is not recommended.
Vancomycin must be added if resistant staphylococci or enterococci are suspected. If there is an abdominal source, a drug effective against anaerobes should be included (eg, metronidazole ). When culture and sensitivity results are available, the antibiotic regimen is changed accordingly. Antibiotics are continued for at least 5 days after shock resolves and evidence of infection subsides.
Abscesses must be drained and necrotic tissues (eg, infarcted bowel, gangrenous gallbladder, abscessed uterus) surgically excised. The patient's condition will continue to deteriorate despite antibiotic therapy unless septic foci are eliminated.
Normalization of blood glucose improves outcome in critically ill patients, even those not known to be diabetic. A continuous IV insulin infusion (crystalline zinc 1 to 4 U/h) is titrated to maintain glucose between 80 to 110 mg/dL (4.4 to 6.1 mmol/L). This approach necessitates frequent (eg, q 1 to 4 h) glucose measurement.
Corticosteroid therapy seems beneficial. Treatment is with replacement doses rather than pharmacologic doses. One regimen consists of hydrocortisone 50 mg IV q 6 h (or 100 mg q 8 h) plus fludrocortisone 50 μg po once/day during hemodynamic instability and for 3 days thereafter.
Activated protein C ( drotrecogin alfa ), a recombinant drug with fibrinolytic and anti-inflammatory activity, seems beneficial for severe sepsis and septic shock if begun early; benefit has been shown only in patients with significant risk of death as defined by APACHE II score > 25 (see Table 4: Approach to the Critically Ill Patient: Apache II Scoring System*). Dosage is 24 μg/kg/h by continuous IV infusion for 96 h. Bleeding is the most common complication; thus, contraindications include hemorrhagic stroke within 3 mo, spinal or intracranial surgery within 2 mo, acute trauma with a risk of bleeding, and intracranial neoplasm. Risk-benefit assessment is required in other patients with increased risk of serious bleeding (eg, with thrombocytopenia or recent GI bleeding, receiving concurrent heparin , or with recent aspirin or other anticoagulant use).
Other emerging therapies for severe sepsis include cooling for hyperthermia and early treatment of renal failure (eg, with continuous veno-venous hemofiltration).
Trials of monoclonal antibodies to the lipid A fraction of endotoxin, antileukotrienes, and antibodies to tumor necrosis factor have been unsuccessful.
Last full review/revision December 2007 by Max Harry Weil, MD, PhD
Content last modified December 2007
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