Sepsis and Septic Shock

Definitions

Physiologically similar systemic inflammatory response syndrome  can be seen even in the absence of identifiable infection.

Pathophysiology

• The sites of infections that most frequently led to sepsis were the respiratory tract (40%), urinary tract (18%), and intra-abdominal space (14%). Sepsis may be caused by gram-negative or gram-positive bacteria, as well as by fungi or other microorganisms.
• Escherichia coli is the common pathogen isolated in sepsis; other common gram-negative pathogens include Klebsiella spp., Serratia spp., Enterobacter spp., and Proteus spp. Pseudomonas aeruginosa is the most frequent cause of sepsis fatality. Common gram-positive pathogens include Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, coagulase-negative staphylococci, and enterococci.
• Candida species (particularly Candida albicans) are a common cause of sepsis in hospitalized patients.
• The pathophysiologic focus of gram-negative sepsis has been on the lipopolysaccharide (endotoxin) component of the gram-negative cell wall.

Lipid A is a part of the endotoxin molecule that is highly immunoreactive and is responsible for most of the toxic effects. Endotoxin first associates with a protein called lipopolysaccharide-binding protein in plasma. This complex then engages a specific receptor (CD14) on the surface of the macrophage, which activates it and causes release of inflammatory mediators.

• Sepsis involves a complex interaction of proinflammatory (e.g., tumor necrosis factor О± [tumor necrosis factor-О±]; interleukin [IL]-1, IL-6) and anti-inflammatory mediators (e.g., IL-1 receptor antagonist, IL-4, and IL-10). IL-8, platelet activating factor, and a variety of prostaglandins, leukotrienes, and thromboxanes are also important.
• Tumor necrosis factor-О± is considered the primary mediator of sepsis, and concentrations are elevated early in the inflammatory response during sepsis. tumor necrosis factor-О± release leads to activation of other cytokines associated with cellular damage and it stimulates release of arachidonic acid metabolites that contribute to endothelial cell damage.
• The balance between pro- and anti-inflammatory mechanisms determines the degree of inflammation. After the initiation of sepsis there is often an imbalance of proinflammatory cytokines, which causes a systemic inflammatory response syndrome (SIRS), followed by a compensatory anti-inflammatory response syndrome (Compensatory anti-inflammatory response syndrome).
• A primary mechanism of injury with sepsis is through endothelial cells. With inflammation, endothelial cells allow circulating cells (e.g., granulocytes) and plasma constituents to enter inflamed tissues, which may result in organ damage.
• Endotoxin activates complement, which then augments the inflammatory response through stimulation of leukocyte chemotaxis, phagocytosis and lysozomal enzyme release, increased platelet adhesion and aggregation, and production of toxic superoxide radicals.
• Proinflammatory mechanisms in sepsis are also procoagulant and antifibrinolytic. Levels of activated protein C, a fibrinolytic and anti-inflammatory substance, are decreased in sepsis.
• Shock is the most ominous complication associated with gram-negative sepsis and causes death in about one-half of patients. Other important complications of sepsis are disseminated intravascular coagulatio, which occurs in 50% of patients with gram-negative sepsis. Disseminated intravascular coagulation causes activation of the coagulation cascade and inhibition of fibrinolysis, which can result in coagulopathy and microthrombosis. Acute respiratory distress syndrome is a common complication of sepsis, with mortality ranging from 19% to 90%.
• The hallmark of the hemodynamic effect of sepsis is the hyperdynamic state characterized by high cardiac output and an abnormally low systemic vascular resistance.
• Sepsis results in distributive shock characterized by inappropriately increased blood flow to selected tissue at the expense of other tissue, independent of oxygen needs.

Clinical presentation

• The signs and symptoms of early sepsis are quite variable and include fever, chills, and a change in mental status with lethargy and malaise. Hypothermia may occur instead of fever. Tachypnea and tachycardia are also evident. White blood cell count is usually elevated, as may be blood sugar. The patient may be hypoxic.
• Progression of uncontrolled sepsis leads to evidence of organ dysfunction, which may include oliguria, hemodynamic instability with hypotension or shock, lactic acidosis, hyperglycemia or hypoglycemia, possibly leukopenia, disseminated intravascular coagulation, thrombocytopenia, Acute respiratory distress syndrome, gastrointestinal hemorrhage, or coma.

Desired outcome

Treatment

The primary goals for treatment of sepsis are as follows:

• Timely diagnosis and identification of the pathogen
• Rapid elimination of the source of infection
• Early initiation of aggressive antimicrobial therapy
• Interruption of the pathogenic sequence leading to septic shock
• Avoidance of organ failure

An important overall approach for treatment of sepsis is «goal-directed» therapy. Mortality can be reduced by early placement and use of a central venous catheter, increased fluid volume administration, dobutamine therapy if needed, and red blood cell transfusion, to achieve specific physiologic goals in the first 6 hours.

Antimicrobial therapy

• Aggressive, early antimicrobial therapy is critical in the management of septic patients. The regimen selected should be based on the suspected site of infection, likely pathogens and the local antibiotic susceptibility patterns, whether the organism was acquired from the community or a hospital, and the patient’s immune status.
• If P. aeruginosa is suspected, a dual regimen of antipseudomonal penicillin or third- or fourth-generation cephalosporin and an aminoglycoside is recommended. When an aminoglycoside is undesirable, an antipseudomonal fluoroquinolone such as ciprofloxacin or levofloxacin can be used.
• When aminoglycosides are used, single daily doses (4 to 7 mg/kg for gentamicin and tobramycin and 10 to 15 mg/kg for amikacin) may be preferred to achieve high peak concentrations early in treatment. Single daily dose administration should not be used in pediatric patients, burn victims, pregnant patients, patients with preexisting or progressive renal dysfunction, or patients requiring aminoglycosides for synergy against gram-positive pathogens.
• Vancomycin should be added whenever the risk of methicillin-resistant staphylococci is significant.
• The average duration of antimicrobial therapy in the normal host with sepsis is 10 to 14 days.
• Suspected systemic mycotic leading to sepsis is treated frequently with parenteral amphotericin B empirically, especially if the patient is clinically unstable. Alternative agents include fluconazole and caspofungin.

Hemodynamic support

• Maintenance of adequate tissue oxygenation is important in the treatment of sepsis and is dependent on adequate perfusion and adequate oxygenation of the blood.
• Rapid fluid resuscitation is the best initial therapeutic intervention for treatment of hypotension in sepsis. The goal is to restore tissue perfusion by maximizing cardiac output with increased left ventricular preload.
• Fluid administration should be titrated to clinical endpoints such as heart rate, urine output, blood pressure, and mental status. Isotonic crystalloids, such as 0.9% sodium chloride or lactated Ringer’s solution, are commonly used for fluid resuscitation.
• Iso-oncotic colloid solutions (plasma and plasma protein fractions), such as 5% albumin and 6% hetastarch, offer the advantage of more rapid restoration of intravascular volume with less volume infused, but there is no significant clinical impact. Clinical outcome differences with the use of crystalloids or colloids have not been demonstrated, so crystalloids are generally recommended.

Inotrope and vasoactive drug support

When fluid resuscitation is insufficient to maintain tissue perfusion, the use of inotropes and vasoactive drugs is necessary. Selection and dosage are based on the pharmacologic properties of various catecholamines and how they influence hemodynamic parameters.

Suggested Protocol for the Use of Inotropes and Vasoactive Agents

• Dopamine is widely used in low doses (1 to 5 Вµg/kg/min) to increase renal and mesenteric perfusion. Dopamine in moderate doses (greater than 5 Вµg/kg/min) may be used to support blood pressure.
• Dobutamine (in doses of 2 to 20 Вµg/kg/min) is a β- adrenergic inotropic agent that is the preferred drug for improving cardiac output and oxygen delivery. Dobutamine should be considered in severely septic patients with adequate filling pressures and blood pressure but low cardiac index.
• Norepinephrine is a potent О±-adrenergic agent (0.01 to 3 Вµg/kg/min) useful in septic shock for vasoconstriction of peripheral beds. Phenylephrine may also be useful in patients with refractory hypotension.
• Epinephrine, in doses of 0.1 to 0.5 Вµg/kg/min, increases cardiac index and produces peripheral vasoconstriction. It is reserved for patients who fail to respond to traditional therapies.

• Prior to administering vasoactive agents, aggressive appropriate fluid resuscitation should occur. Vasoactive agents should not be considered an acceptable alternative to volume resuscitation.

Adjunctive therapies

• Glucocorticoids may be useful for patients with Acute respiratory distress syndrome and fibrotic disease when used 5 to 7 days after the onset of Acute respiratory distress syndrome. Routine use of glucocorticoids in patients with sepsis or shock is not supported. It is now recognized that many critically ill patients have adrenal insufficiency and may require low doses of corticosteroids.
• Early enteral nutrition is recommended in patients with severe sepsis or septic shock.
• Administration of activated protein C (drotrecogin) to promote fibrinolysis and associated anti-inflammatory mechanisms may be beneficial in patients with APACHE II score greater than 25. This agent reduced mortality in severe sepsis but poses an increased risk of serious bleeding.

Piperacillin

Ceftriaxone

Cefepime

Meropenem

Imipenem