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A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance ≤ 12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs.

better understanding of the inflammatory, procoagulant, and immunosuppressive aspects of sepsis has contributed to rational therapeutic plans from which several important themes emerge. 1 First, rapid diagnosis (within the first 6 hours) and expeditious treatment are critical, since early, goaldirected therapy can be very effective. 2 Second, multiple approaches are necessary in the treatment of sepsis. 1 Third, it is important to select patients for each given therapy with great care, because the efficacy of treatment-as well as the likelihood and type of adverse results-will vary, depending on the patient. THE SPEC TRUM OF SEPSIS Nomenclature is important when it helps us understand the pathophysiology of a disease. This is true for sepsis, since nomenclature has informed the design of randomized, controlled trials and, ultimately, the prognosis of sepsis. Sepsis is defined as suspected or proven infection plus a systemic inflammatory response syndrome (e.g., fever, tachycardia, tachypnea, and leukocytosis). 3 Severe sepsis is defined as sepsis with organ dysfunction (hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia, or obtundation). Septic shock is defined as severe sepsis with hypotension, despite adequate fluid resuscitation. Septic shock and multiorgan dysfunction are the most common causes of death in patients with sepsis. 4 The mortality rates associated with severe sepsis and septic shock are 25 to 30% 5 and 40 to 70%, 6 respectively. There are approximately 750,000 cases of sepsis a year in the United States, 7 and the frequency is increasing, given an aging population with increasing numbers of patients infected with treatment-resistant organisms, patients with compromised immune systems, and patients who undergo prolonged, high-risk surgery. 7 PATHOPH YSIOL OGY Sepsis is the culmination of complex interactions between the infecting microorganism and the host immune, inflammatory, and coagulation responses. 8 The rationale for the use of therapeutic targets in sepsis has arisen from concepts of pathogenesis (Table 1). Both the host responses and the characteristics of the infecting organism influence the outcome of sepsis. Sepsis with organ dysfunction occurs primarily when host responses to infection are inadequate. In addition, sepsis often progresses when the host cannot contain the primary infection, a problem most often related to characteristics of the microorganism, such as a high burden of infection and the presence of superantigens and other virulence factors, resistance to opsonization and phagocytosis, and antibiotic resistance.