Sepsis and septic shock

The systemic inflammatory response to infection, termed sepsis, is not unique to severe infections because similar manifestations may be encountered with noninfectious illnesses. Moreover, it does not necessarily indicate the presence of bacteremia. The use of the term SIRS has been suggested by the Society of Critical Care Medicine (SCCM), European Society of Intensive Care Medicine (ESICM), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and Surgical Infection Society (SIS). The SCCM/ESICM/ACCP/ATS/SIS conference introduced the concept of predisposition, insult infection, response, organ dysfunction (PIRO) to classify sepsis. Severe sepsis exists when the response is associated with organ dysfunction. The term MODS has been suggested to describe progressive dysfunction of two or more organs that is associated with sepsis. Septic shock is defined as acute circulatory failure—systolic blood pressure < 90 mm Hg, mean arterial pressure < 60 mm Hg, or a 40 mm Hg reduction in systolic blood pressure from baseline despite adequate volume resuscitation—in a patient with sepsis.

PATHOPHYSIOLOGY OF SIRS

A mild systemic inflammatory response to any bodily insult may normally have some salutatory effects. However, a marked or prolonged response, such as that associated with severe infections, is often deleterious and can result in widespread organ dysfunction. Although gram-negative organisms account for a majority of infection-related SIRS, many other infectious agents are capable of inducing the same syndrome. These organisms either elaborate toxins or stimulate release of substances that trigger this response. The most commonly recognized initiators are the lipopolysaccharides (LPSs), which are released by gram-negative bacteria. LPS is composed of an O polysaccharide, a core, and lipid A. The O polysaccharide distinguishes between different types of gram-negative bacteria, whereas lipid A, an endotoxin, is responsible for the compound's toxicity. The resulting response to endotoxin involves a complex interaction between macrophages/monocytes, neutrophils, lymphocytes, platelets, and endothelial cells that can affect nearly every organ.

The central mechanism in initiating SIRS appears to be the abnormal secretion of cytokines. These low-molecular-weight peptides and glycoproteins function as intercellular mediators and normally regulate many biological processes, including local and systemic immune responses, inflammation, wound healing, and hematopoiesis. The most important cytokines released during SIRS are IL-6, adrenomedullin, soluble (s)CD₁₄, sELAM-1, MIP-1, extracellular phospholipase A₂, and C-reactive protein. The resulting inflammatory response involves release of potentially harmful phospholipids, attraction of neutrophils, and activation of the complement, kinin, and coagulation cascades.

Increased phospholipase A₂ levels release arachidonic acid from cell membrane phospholipids. Cyclooxygenase converts arachidonic acid to thromboxane and [dx id=""]prostaglandins[/dx], whereas lipoxygenase converts arachidonic acid into leukotrienes (slow-reacting substances of anaphylaxis). Increased phospholipase A₂ and acetyltransferase activities result in the formation of another potent proinflammatory compound, platelet-activating factor (PAF). Attraction and activation of neutrophils release a variety of proteases and free radical compounds that damage vascular endothelium. Activation of monocytes causes them to express increased amounts of tissue factor, which in turn can activate both the intrinsic and extrinsic coagulation cascades.

INFECTIONS IN THE ICU

Infections are a leading cause of death in ICUs. Serious infections may be acquired outside the hospital (community acquired) or subsequent to admission for an unrelated illness (nosocomial). The term "nosocomial infection" describes hospital-acquired infections that develop at least 48 h following admission. The reported incidence of nosocomial infections in ICU patients ranges between 10% and 50%. Strains of bacteria resistant to commonly used antibiotics are often responsible. Host immunity plays an important role in determining not only the course of an infection but also the types of organisms that can cause infection. Thus, organisms that normally do not cause serious infections in immunocompetent patients can produce life-threatening infections in those who are immunocompromised

Critically ill patients frequently have demonstrable abnormal host defenses, including defective chemotaxis and phagocytosis, altered helper:suppressor T lymphocyte ratios, and impaired humoral immunity. Other host factors include age, drug therapy, integrity of mucosal and skin barriers, and underlying disease. Thus, advanced age (> 70 years), corticosteroid therapy, chemotherapy, prolonged use of invasive devices, respiratory failure, renal failure, head trauma, and burns are established risk factors for nosocomial infections. Patients with burns involving greater than 40% of body surface area have significantly increased mortality from infections. Use of topical antibiotics such as sodium mafenide, silver sulfadiazine, and nystatin delays but does not prevent wound infections. Early removal of the necrotic eschar followed by skin grafting and wound closure appears to reverse immunological defects and reduce infections.

Most nosocomial infections arise from the endogenous bacterial flora. Furthermore, many critically ill patients eventually become colonized with resistant bacterial strains. The urinary tract accounts for up to 35–40% of nosocomial infections. Urinary infections are usually due to gram-negative organisms and are associated with the use of indwelling catheters or urinary obstruction. Wound infections are the second most common cause, accounting for up to 25–30%, with pneumonia accounting for another 20–25%. Intravascular catheter-related infections are responsible for 5–10% of ICU infections.

Nosocomial pneumonias are usually caused by gram-negative organisms and are the leading cause of death in many ICUs. GI bacterial overgrowth with translocation into the portal circulation and retrograde colonization of the upper airway from the GI tract followed by aspiration are possible mechanisms for entry for these bacteria. Preservation of gastric acidity inhibits overgrowth of gram-negative organisms in the stomach and their migration into the oropharynx. Tracheal intubation does not appear to provide effective protection because patients commonly aspirate gastric fluid containing bacteria in spite of a properly functioning TT cuff; nebulizers and humidifiers can also be sources of infection. Selective decontamination of the gut with nonabsorbable antibiotics may reduce the incidence of infection but does not change outcome.

Wounds are common sources of sepsis in postoperative and trauma patients; limited antibiotic prophylaxis appears to decrease the incidence of postoperative infections in some groups of patients. Although more commonly seen in postoperative patients, intraabdominal infections due to perforated ulcer, diverticulitis, appendicitis, and acalculous cholecystitis can also develop in critically ill nonsurgical patients. Intravascular catheter-related infections are most commonly due to Staphylococcus epidermidis, Staphylococcus aureus, streptococci, Candida species, and gram-negative rods. Bacterial sinusitis may be an unrecognized source of sepsis in nasally intubated patients. The diagnosis is suspected from purulent drainage and confirmed by radiographs and cultures.

SEPTIC SHOCK

The SCCM/ESICM/ACCP/ATS/SIS Consensus Conference defines septic shock as sepsis associated with hypotension (systolic blood pressure < 90 mm Hg, mean arterial pressure < 60 mm Hg, or systemic blood pressure < 40 mm Hg from baseline) despite adequate fluid resuscitation. Septic shock is usually characterized by inadequate tissue perfusion and widespread cellular dysfunction. In contrast to other forms of shock (hypovolemic, cardiogenic, neurogenic, or anaphylactic), cellular dysfunction in septic shock is not necessarily related to the hypoperfusion. Instead, there may be a metabolic block at the cellular level that contributes to impaired cellular oxidation.

Pathophysiology

A severe or protracted SIRS can result in septic shock. Septic shock is most commonly due to gram-negative infections arising from the genitourinary tract or from the lungs in hospitalized patients, but identical presentations are also seen with other pathogens. Bacteremia is usually present but may be absent. Increased nitric oxide levels may be responsible for the vasodilation. The hypotension is also due to a decreased circulating intravascular volume resulting from a diffuse capillary leak. Many patients also manifest evidence of myocardial depression. Activation of platelets and the coagulation cascade can lead to the formation of fibrin-platelet aggregates, which further compromise tissue blood flow. Hypoxemia resulting from ARDS accentuates tissue hypoxia. The release of vasoactive substances, formation of microthrombi in the pulmonary circulation, or both together increase pulmonary vascular resistance.

HEMODYNAMIC SUBSETS

The circulation in patients with septic shock is often described as either hyperdynamic or hypodynamic. In reality, both represent the same process, but their expression depends on preexisting cardiac function and intravascular volume and where the patient is on the spectrum of response. Systemic venodilation and transudation of fluid into tissues result in relative hypovolemia in patients with sepsis.

Hyperdynamic septic shock is characterized by normal or elevated cardiac output and profound vasodilation (low systemic vascular resistance). Decreased myocardial contractility is often demonstrable even in hyperdynamic patients. Mixed venous oxygen saturation is characteristically high in the absence of hypoxemia and likely reflects the high cardiac output and the cellular metabolic defect in oxygen utilization.

Hypodynamic septic shock, usually seen later in the course of shock, is characterized by decreased cardiac output with low or normal systemic vascular resistance. It is more likely to be seen in severely hypovolemic patients and those with underlying cardiac disease. Myocardial depression is a prominent feature. Mixed venous oxygen saturation may be low in these patients. Pulmonary hypertension is also often prominent in septic shock. Elevation of pulmonary vascular resistance widens the normal pulmonary artery diastolic-to-wedge pressure gradient; large gradients have been associated with a higher mortality rate. The increase in pulmonary vascular resistance may contribute to right ventricular dysfunction.

Clinical Manifestations

Manifestations of septic shock appear to be primarily related to host response rather than the infective agent. Septic shock classically presents with an abrupt onset of chills, fever, nausea (and often vomiting), decreased mental status, tachypnea, hypotension, and tachycardia. The patient may appear flushed and feel warm (hyperdynamic) or pale with cool and often cyanotic extremities (hypodynamic); in the latter case, a high index of suspicion is required. In old, debilitated patients and in infants, the diagnosis often is less obvious and hypothermia may be seen.

Leukocytosis with a leftward shift to premature cell forms is typical, but leukopenia can be seen with overwhelming sepsis and is an ominous sign. Progressive metabolic acidosis (usually lactic acidosis) is typically partially compensated by a concomitant respiratory alkalosis. Elevated lactate levels reflect both increased production resulting from poor tissue perfusion and decreased uptake by the liver and kidneys. Hypoxemia may herald the onset of ARDS. Oliguria is most commonly due to the combination of hypovolemia, hypotension, and a systemic inflammatory insult and often progresses to ARF. Elevations in serum aminotransferases and bilirubin are due to hepatic dysfunction. Insulin resistance is uniformly present and produces hyperglycemia. Thrombocytopenia is common and is often an early sign of sepsis. Laboratory evidence of disseminated intravascular coagulation (DIC) is often present but is rarely associated with a bleeding diathesis. The latter responds only to control of the sepsis. Gastric mucosal stress ulceration is common. Respiratory and renal failure are the leading causes of death.

Neutropenic patients (absolute neutrophil count 500/L) may develop macular or papular lesions that can ulcerate and become gangrenous (ecthyma gangrenosum). These lesions are commonly associated with Pseudomonas septicemia but can be caused by other organisms. Perirectal abscesses can develop very quickly in neutropenic patients with few external signs; patients may complain only of perirectal pain.

Treatment

Septic shock is a medical emergency that requires immediate and aggressive intervention. Treatment is threefold: (1) control and eradication of the infection by appropriate and timely intravenous antibiotics, drainage of abscesses, debridement of necrotic tissues, and removal of infected foreign bodies; (2) maintenance of adequate perfusion with intravenous fluids and inotropic and vasopressor agents; and (3) supportive treatment of complications such as ARDS, ARF, GI bleeding, and DIC.

Antibiotic treatment must be initiated before pathogens are identified but after adequate cultures are obtained (usually of blood, urine, wounds, and sputum). Combination therapy with two or more antibiotics is generally indicated until pathogens are known. In most instances, the combination of a penicillin/-lactamase inhibitor or third-generation cephalosporin with an aminoglycoside is adequate. Additional diagnostic studies may be indicated (eg, thoracentesis, paracentesis, lumbar puncture, or computed tomographic scans). Debridement and drainage of infections and abscesses should be undertaken expeditiously.

Empiric antibiotic therapy in immunocompromised patients should be based on pathogens that are generally associated with the immune defect. Vancomycin is added if intravascular catheter-related infection is suspected. Clindamycin or metronidazole should be given to neutropenic patients if a rectal abscess is suspected. Many clinicians initiate amphotericin B, fluconazole, or caspofungin therapy for a presumed fungal infection or when an immunocompromised patient continues to experience fever after 96 h of antibiotic therapy. Granulocyte colony-stimulating factor or granulocyte–macrophage colony-stimulating factor may be used to shorten the period of neutropenia; granulocyte transfusion may occasionally be used in refractory gram-negative bacteremia. Diffuse interstitial infiltrates on a chest radiograph may suggest unusual bacterial, parasitic, or viral pathogens; many clinicians initiate empiric therapy with trimethoprim-sulfamethoxazole and erythromycin in such instances. Nodular infiltrates on a radiograph suggest a fungal pneumonia and may warrant antifungal therapy. Antiviral therapy should be considered in septic patients who are more than 1 month post–bone marrow or solid organ transplantation.

Tissue oxygenation and perfusion are maintained with oxygen therapy, intravenous fluids, inotropes, vasopressors and packed red blood cell transfusions to keep hemoglobin levels > 8–10 g/dL. Marked "third spacing" is characteristic of septic shock. An inotrope should be used if intravenous fluids fail to quickly restore adequate perfusion. Colloid solutions more rapidly restore intravascular volume compared with crystalloid solutions but otherwise offer no proven additional benefit. Inotropic therapy is generally initiated if 1–3 L of intravenous fluids do not correct the hypotension. Hematocrit should probably be maintained at or above 24–30% to enhance oxygen delivery. Pulmonary artery catheterization greatly facilitates management in such instances because it allows measurement of PAOP and cardiac output. Most clinicians generally select dopamine as the initial inotrope; others may use dobutamine because it more effectively increases cardiac output and oxygen delivery (Table 49–14). Some studies suggest that patient mortality may be lower if oxygen delivery can be increased. When either dopamine or dobutamine is ineffective in increasing blood pressure and cardiac output, epinephrine (2–18 g/min) is the agent of choice. In patients with refractory hypotension, norepinephrine, vasopressin, or both are administered with a good improvement in blood pressure but without evidence that it affects outcome. Severe acidosis may decrease the efficacy of inotropes and should therefore generally be corrected (pH > 7.20) with bicarbonate therapy in patients with refractory hypotension. Even in the absence of arterial hypotension, "renal" doses of dopamine may help maintain urinary output but have not been shown to improve outcome. The use of corticosteroids, naloxone, opsonins (fibronectin), and monoclonal antibodies directed against lipopolysaccharide in septic shock has been disappointing, but inhibitors of the coagulation cascade show promise. One such agent, activated protein C, drotrecogin alfa, has been approved by the U.S. Food and Drug Administration for use during sepsis. Because of the expense of this agent and questions about long-term outcome, many ICUs have criteria for when it can be administered to patients that are derived from the original study results