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1. Sepsis often develops in patients compromised by underlying disease, immunosuppressive therapy, or invasive procedures
2. Sepsis is most commonly caused by bacterial infection. Gram-negative aerobes are the most common pathogens; infection by these microbes has the worst prognosis.
3. Sepsis usually results in a hyperdynamic state with elevated cardiac output, decreased systemic vascular resistance, and normal to low cardiac filling pressure. Inadequate volume resuscitation or intrinsic myocardial dysfunction may less commonly result in low cardiac output and increased systemic vascular resistance.
4. Reversible myocardial dysfunction in sepsis results in a decreased ejection fraction, biventricular dilatation, and altered ventricular compliance.
5. The systemic response of sepsis may result in significant oral dysfunction including adult respiratory distress syndrome (ARDS), renal failure, encephalopathy, disseminated intravascular coagulation, and gastrointestinal dysfunction.
6. Clinical manifestations of sepsis include systemic findings and clinical signs of local infection. In many patients, no source can be localized by physical examination or routine laboratory tests
   
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1. Appropriate cultures of blood and focal sites should be obtained. Ideally, cultures should be obtained before initiation of antibiotic therapy, but delays should not occur
2. Laboratory tests such as complete blood cell count, coagulation profile, and serum chemistries should be obtained to assess organ function and acid base status.
3. Radiographic and other imaging procedures should be obtained as necessary, depending on the clinical suspicion of infected site.
4. A pulmonary artery catheter is helpful to guide therapy in patients with septic shock or evidence of hypoperfusion.

1. Infection should be eliminated through early use of appropriate antibiotics and surgical intervention when indicated.
2. Volume resuscitation should be accomplished in all patients with sepsis. The endpoints of resuscitation must be individualized.
3. If hypotension or hypoperfusion persists after volume is optimized, vasoactive drugs should be initiated. Drugs to be considered include vasopressors such as dopamine, norepinephrine, epinephrine, and phenylephrine as well as inotropic agents such as dobutamine.
4. Endpoints of resuscitation in septic shock are controversial. Goals may include an elevated cardiac output, oxygen delivery, or oxygen consumption, or reversal of hypotension and hypoperfusion using clinical and laboratory parameters.
5. In a septic normotensive patient, inotropic support with dobutamine to increase output may be warranted if there is evidence of hypoperfusion.
6. Mechanical ventilation, dialysis techniques, transfusion of blood products, and early nutritional support should be considered in the septic patient.

Acquired immunodeficiency syndrome
Burns, wounds, and multiple trauma
Diabetes mellitus
Extremes of age
Hepatic failure
Hyposplenism
Immunosuppressive medication
Indwelling urinary catheters
Invasive catheters or devices
Malignancy
Malnutrition
Organ transplantation
Radiation therapy
Renal failure

Shock develops in approximately 40% of patients with sepsis and substantially worsens the prognosis. Sixty percent to 80% of patients with septic shock die.

Infection: Microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.

Bacteremia: The presence of viable bacteria in the blood

Systemic Inflammatory Response Syndrome: The systemic inflammatory response to a variety of severe clinical results. The response is manifested by two or more of the following conditions:

Temperature > 380C or <360C

Heart rate > 90 bpm

Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg (<4.3 kPa)

WBC > 12,000 cells/mm3, < 4000 cells/mm3, or > 10% immature (band) forms

Sepsis: The systemic response to infection. This systemic response is manifested by two or more of the following conditions as a result of infection:

Temperature > 380C or < 360C

Heart rate > 90 mm bpm

Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg (<4.3 kPa)

WBC > 12,000 cells/mm3, < 4000 cells/mm3, or > 10% immature (band) forms

Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

Septic shock: Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.

Hypotension: A systolic BP of < 90 mm Hg or a reduction of >40 mm Hg from baseline in the absence of other causes for hypotension.

Multiple organ dysfunction syndrome: Presence of altered organ function in an acutely ill patient such that homeostatis cannot be maintained without intervention.

Sepsis is most often caused by infection with aerobic or anerobic bacteria. Both gram-positive and gram-negative organisms are associated with this condition; however, gram negative aerobes are the most common pathogens, and infection with these organisms has the worst prognosis. Escherichia coli, Klebsiella sp., and Pseudomonas aeruginosa are the most common gram-negative pathogens in this group. Other microorganisms including mycobacteria, fungi, viruses, rickettsia, and protozoa may produce a syndrome clinically indistinguishable from bacterial sepsis. The most common sites of infection in sepsis are the genitourinary tract, gastrointestinal tract, respiratory tract, wounds, and vascular access sites.

Depressed myocardial function in sepsis is common. Despite a normal or elevated cardiac output, a decreased ejection fraction and biventricular dilatation may be present. The myocardial depression is reversible, resolving if the sepsis clears. Abnormalities in ventricular compliance in response to volume loading also have been observed in sepsis. The reasons for myocardial dysfunction in sepsis are not entirely understood. A circulating substance that decreases myocardial contractility has been proposed.

Oxygen delivery is usually increased in sepsis because of the hyperdynamic state. However, peripheral oxygen extraction is decreased, as reflected in a narrow arteriovenous oxygen content difference. Tissue hypoxia associated with an elevated lactate level may result, even with an elevated oxygen delivery. Maldistribution of blood flow to tissues has been hypothesized to be responsible for ineffective oxygen utilization, but cellular defects also must be considered. Oxygen consumption in sepsis previously has been thought to be "flow dependent." In other words, as oxygen delivery increases or decreases, oxygen consumption increases or decreases respectively. This premise has been questioned because of mathematical coupling in calculated values. Direct measurements of oxygen consumption do not always support flow dependency in sepsis.

Clinical objectives in the hemodynamic management of sepsis include an adequate blood pressure (mean arterial pressure above 60mm Hg), a decrease in heart rate, adequate renal perfusion as manifested in mental status, or a decrease in lactate level. In most critically ill septic patients, a pulmonary artery catheter in useful to guide therapy. Parameters measured from invasive hemodynamic monitoring also may be used to optimize tissue perfusion. Numerous studies suggest that enhancing hemodynamic monitoring also may be used to optimize tissue perfusion. Numerous studies suggest that enhancing hemodynamic variables to "supranormal" levels (oxygen delivery [DO2] above 600mL/minute/M2, oxygen consumption [VO2] over 170mL/minute/m2, and cardiac index more than 4.5 L/minute/m2) may improve survival rather than the increase in DO2 itself. Other studies have not consistently found improved survival associated with increase in DO2 or VO2 or consumption. The heterogeneity of septic patients and the variety of methods used to increase DO2 indifferent studies make it difficult to arrive at firm conclusions.

Continuous mixed venous oximetry is generally not useful to guide therapy in sepsis. Despite controversy on the specific endpoints of hemodynamic management, the recommended interventions remain remarkably similar.

The greatest challenge lies in the care of the hypotensive septic patient. The first step in managing these patients is volume resuscitation.38 Most patients with sepsis have moderate to profound intravascular volume deficits because of vasodilatation and increases in microvascular permeability. Restoration of circulating blood volume enhances preload, cardiac performance, and DO2. The type and amount of fluid to be given are usually based on individual clinician choice. A clear-cut advantage of colloids (5% albumin, hydroxyethyl starch) or crystalloids (normal saline, lactated Ringer's solution) has not been established. Fluid boluses of 250 to mL can be administered over 10 to 15 minutes and repeated as needed with frequent clinical reassessment. The magnitude of the volume deficit may be extremely large in the first 24 to 48 hours of septic shock.

An optimum pulmonary artery occlusion pressure of 12 to 18mm Hg has been suggested for fluid resuscitation, but alterations of myocardial compliance must be taken into account. A more specific goal may be the optimization of cardiac performance of oxygen delivery. Volume resuscitation also must take into account pulmonary dysfunction. The presence of ARDS and significant hypoxemia amy require a lower pulmonary artery occlusion pressure to minimize pulmonary edema if oxygen concentrations are in a toxic range.

Volume resuscitations should improve oxygen delivery to tissues by increasing cardiac output. However, arterialoxygen content is the other parameter influencing oxygen delivery. Oxyhemoglobin saturation should be optimized (arterial oxyhemoglobin saturation greater than 90%) through use of supplemental oxygen and mechanical ventilation as needed. Transfusion of red blood cells to increase the hematocrit to approximately 30% or greater has been advocated as another means of increasing arterial oxygen content and oxygen delivery. However, clinical studies in septic patients have not supported a parallel increase in oxygen utilization with transfusion. Changes in stored blood that decrease red blood cell deformability and oxygen off-loading along with increased blood viscosity may alter microvascular blood flow and impede oxygen delivery.

When volume resuscitation fails to restore hemodynamic stability, vasoactive medications are usually inititated.41 No universal agreement exists as to how these agents should be used. Dopamine is commonly employed as the initial drug in the hypotensive septic patient. Its beta-adrengeric effects may support arterial blood pressure. Norepinephrine, epinephrine, and phenyleprine also have been used effectiley as vasopressor or inotropic agents in sepsis. Concerns regarding excessive vasoconstriction with norepinephrine seem unwarranted if intravascular volume is opotimized. Concurrent administration of low-dose dopamine has been advocated to preserve renal perfusion during use of norepinephrine. Dobutamine as an inotropic agent has been used alone or in combination with other catecholamines to improve cardiac performance. Traditional concepts of therapeutic ranges of vasoactive drugs may require adjustment in the septic patient. The correct does is best determined by the individual patient response in achieving target endpoints. The response to any one vasoactive drug is often unpredictable and the clinician should be willing to use other drugs to optimize management. Vasopresssor medication sused before restoration of blood volume may worsen tissue perfusion.

A less common, but no less challenging, management problem is the septic patients with adequate blood pressure who continues to have evidence of hyperperfusion. This may be manifested as elevated lactate level, inadequate urine output, or organ dysfunction. A reasonably option in this circumstance may be to increase oxygen delivery by increasing cardiac output with an inotropic agent such as doubtamine. Further objective clinical studies are needed to clarify the hemodynamic management of septic patients. Given the complex pathophysiologic mechanism of sepsis and heterogeneity of patients, it is unlikely that a single regime will be optimum for all ptatients.

Corticosteriods have been recommended in patients with septic shock in the past. Large, prospective, randomized trials document no benefit and suggest detrimental effects in selected patients. Nonsteroidal anti-inflammatory agents also have been used in patients with septic shock. The availably data are promising but preliminary, so these agents cannot be recommended.

Cytoprotectin of the gastric mucosa is suggested to prevent stress gastric ulceration. Our preference is use of an H2 receptor antagonist.

Sepsis results in an increased metabolic requirement. Nutritional support should be instituted early in the septic patient. The route of feeding should be individualized, but the enteral route offers several advantages. Preservation of the intestinal mucosal function may prevent translocation of bacteria or endotoxin, resulting in fewer infections.49 Parenteral nutrition is associated with more metablic and infectious complications.

Blood products should be used as necessary in the septic patient. Although disseminated intravascular coagulation is often noted by laboratory parameters, significant bleeding is less common. Platelets and fresh frozen plasma should be used only when significant bleeding occurs or an invasive procedure is necessary.

Intubation and mechanical ventilation often are necessary in septic patients. Indications for initiating mechanical ventilation do not differ significantly from other patients and include the need for airway protection, respiratory muscle fatigue, and hypoxemia. The ventilator mode selected should take into account the hemodynamic status, metabolic demands, acid-base status, and degree of pulmonary dysfunction to optimize oxygenation and ventilation.

Renal dysfunction may pose several problems in the patient with sepsis or septic shock. Choice of antibiotics and dosages must be carefully adjusted to prevent toxicity or renal injury. Volume overload may result from fluid administration in the oliguric patient. Loop diuretics are frequently used in the hemodynamically stable patent to induce a nonoliguric state. Low doses (1 to 3 g/kg/minute) of dopamine have also been advocated to improve renal perfusion and urine output, but beneficial effects have not been clearly demonstrated. Dialytic therapy may be warranted in the septic patient to mange fluid balance, electrolyte abnormalities, acid-base disturbances, or uremia. Hemodialysis is the most widely used method but may be unsuitable in the hemodynamically unstable patient because of fluctuations in blood pressure. Other techniques such as peritoneal dialysis, continuous arteriovenous hemodiafiltration, or continuous venovenous hemodiafiltration should be considered in the unstable patient.