Management of Sepsis

Sepsis is the leading cause of death of critically ill patients in the United States and develops in 750,000 people annually.^[48] Mortality from severe sepsis has remained at 30% to 50% despite improvements in critical care, including those discussed in this chapter.^{[49] [50]} The economic costs of sepsis are large, with annual expenditures of nearly $17 billion.^[48] The high mortality rate and economic costs have led to considerable interest in the development of effective therapies for sepsis. As with other areas of medicine, adoption and integration of new treatment strategies into routine clinical practice has been slow. After many years of unsuccessful clinical trials, randomized, controlled trials have begun to show efficacy. Three trials—the use of early goal-directed therapy, the use of low dose corticosteroids, and administration of activated protein C—have all shown significant efficacy in patients with severe sepsis.^{[51] [52] [53]}

2795

Resuscitation in Shock

Circulatory abnormalities found in sepsis, such as intravascular volume depletion, peripheral vasodilatation, myocardial depression, and increased metabolism, can lead to an imbalance between systemic oxygen delivery and demand, producing tissue hypoxia and shock.^[54] Earlier resuscitation strategies employing supraphysiologic oxygen delivery with manipulation of cardiac contractility, preload, and afterload failed to reduce mortality and, in two studies, proved to be detrimental.^{[55] [56]} Conversely, Boyd and associates^[57] found that increasing perioperative oxygen delivery decreased mortality rates for high-risk surgical patients.

The controversy over hemodynamic management was fueled further by the study by Rivers and colleagues,^[51] who hypothesized that patients with global tissue hypoxia as reflected by elevated lactate concentrations may benefit from early goal-oriented therapy before admission to the ICU. In this study, patients were treated in the emergency department shortly after the diagnosis of septic shock. Two hundred sixty-three patients were enrolled, and the intervention group received central venous catheterization with central venous oxygen saturation monitoring. Patients were first given fluid boluses to achieve a central venous pressure of 8 to 12 mm Hg, and then vasopressors were given if mean arterial pressure was below 65 mm Hg. Red blood cells were transfused for a central venous oxygen saturation of less than 70% if the hematocrit was less than 30%. If central venous oxygen saturation remained at less than 70% after transfusion, dobutamine was started. Patients in whom hemodynamic optimization could not be achieved were mechanically ventilated and sedated. Therapy was continued for 6 hours in the emergency department, and then patients were transferred to the ICU. The in-hospital mortality rate was 30.5% in the early goal-directed therapy group and 46.5% in the standard therapy group (P = .009).

The most important difference between the Rivers study^[51] and those that preceded it may be the early, rapid intervention in the emergency department.^{[55] [56]} Other factors may include the short duration of therapy (only 6 hours) or the strict protocol used, which included transfusion to a hematocrit of 30% and increased use of dobutamine in the treatment group. Although controversy remains, it is likely that early, protocol-driven resuscitation is beneficial.

The use of pulmonary artery catheters (PACs) in critically ill patients remains controversial. Most studies have failed to show efficacy or have demonstrated harm. The best known of these investigations was the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), which was a retrospective, observational study involving 5735 critically ill patients.^[58] In these patients, use of a PAC was associated with increased mortality and cost. Richard and coworkers^[59] completed a prospective, observational trial of PACs versus central venous pressure catheters in patients with ARDS or shock. Clinical management was left at the discretion of the treating physician. In 676 patients in 36 French ICUs, there was no difference in any of the outcome variables measured.^[59]

The data are no better for use of PACs in surgical patients. Sandham and associates^[60] randomized 1994 high-risk surgical patients (age >60 years, ASA class III) to management with or without a PAC. Goal-directed therapy was used in the treatment group, with a target oxygen delivery of 550 to 600 mL/min/m³ of body surface area. There was no difference in any of the outcomes measured, except for an increased incidence of pulmonary thromboembolism in the intervention group. Yu and colleagues^[61] performed a case-control study that examined the efficacy of PACs in patients with severe sepsis. As in the Richard study,^[59] there were no differences in mortality rates and resource use.

The PAC is a monitoring device that can be difficult to interpret, especially in the setting of critical illness. Perhaps more important than the device itself is the therapy that is driven by the device. Most data suggest that use of a PAC to guide routine care is futile or harmful. The Rivers study^[51] suggests that early goal-directed therapy may be helpful in patients with septic shock. Additional prospective, randomized studies are required to settle this issue. Ongoing trials in the United States (Fluids and Catheters Treatment Trial^[62] ) and the United Kingdom (Pulmonary Artery Catheters in Patient Management in Intensive Care^[63] ) may definitively determine the proper use of PACs.

Small Doses of Corticosteroids for Septic Shock

With the recognition that severe sepsis represented a state of overwhelming inflammation, corticosteroids were among the first therapies tested in randomized trials of patients with sepsis. At high doses and during short courses, the studies showed a negative effect.^{[64] [65]} A better understanding of the complexity of the systemic inflammatory response syndrome (SIRS) revealed that many patients were in a state of relative immunosuppression despite systemic inflammation and that late mortality might be caused by immune dysfunction. ^{[66] [67]} However, other investigators observed that severe sepsis was also associated with relative adrenal insufficiency^[68] or glucocorticoid receptor resistance.^[69] Two additional studies showed that a single intravenous administration of only 50 mg of hydrocortisone could improve responsiveness to norepinephrine and phenylephrine in patients with septic shock. ^{[70] [71]} In 2000, Annane and coworkers^[72] demonstrated that mortality in patients with septic shock could be predicted by serum cortisol levels and adrenal responsiveness testing. Patients who presented with serum cortisol levels less than 34 µg/dL and were able to respond appropriately to a short corticotropin test had the best prognosis, whereas patients with serum cortisol levels greater than 34 µg/dL and unable to respond to a short corticotropin test had the worst prognosis.^[72]

Prompted by this information along with two small, placebo-controlled, randomized trials that showed that low doses of hydrocortisone over a longer period (≥5 days) significantly improved the time to vasopressor therapy withdrawal in patients with sepsis,^{[73] [74]} Annane and associates^[52] studied whether low doses of hydrocortisone and fludrocortisone could improve survival of patients with sepsis. All patients with septic shock received a short corticotropin test and then were randomized to hydrocortisone (50 mg given intravenously every 6 hours) plus fludrocortisone (50 µg given orally every day) or placebo

2796

In summary, intensivists should not use large doses of corticosteroids in patients with severe sepsis, but low-dose hydrocortisone with fludrocortisone may have an important role in patients with septic shock and adrenal insufficiency. One approach to consider is to perform a short corticotropin test for patients with septic shock and treat empirically with hydrocortisone until the results of the testing are available. If adrenal insufficiency is demonstrated, treatment can continue. If adrenal responsiveness is normal, the corticosteroids could be discontinued.

Use of Activated Protein C in Severe Sepsis

A number of studies have demonstrated that patients with severe sepsis have coagulation abnormalities that range from subtle elevations in plasma D-dimer levels to frank disseminated intravascular coagulation.^{[76] [77]} Recognition that sepsis can cause microthrombosis and that patients with sepsis have low circulating levels of activated protein C (APC) led to the investigation of APC as a specific therapy for sepsis.^[78] Activated protein C is a naturally occurring anticoagulant that inactivates factors Va and VIIIa and prevents the generation of thrombin,^[79] which is capable of stimulating multiple inflammatory pathways. Additional effect of APC include a permissive effect on thrombolysis (through inhibition of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1), which allows clearance of systemic microthrombosis.^[77] APC also decreases expression of tissue factor and can bind selectins, which activate neutrophils on the endothelial surface.^[53]

Recombinant human APC (Xigris) is the first pharmacologic agent that has demonstrated efficacy in the treatment of severe sepsis.^[53] In a study of 1690 patients with severe sepsis randomized to receive APC or placebo, the mortality rate was 30.8% in the placebo group and 24.7% in the APC group (P = .005). The intravenous infusion of APC at 24 µg/kg/hour for 96 hours was associated with a 6.1% absolute reduction in the risk of death. The most important adverse effect was serious bleeding (3.5% versus 2%, P = .06), as would be expected because of its anticoagulant effect.^[53]

APC is recommended for use in patients with severe sepsis, greater severity of illness (i.e., Acute Physiology and Chronic Health Evaluation [APACHE] II score of 25 or more), and a reasonable life expectancy if they survive the episode of sepsis.^[80] The cost per quality-adjusted life-year gained by treating with APC was estimated to be about $33,000 for patients with an APACHE II score of 25 or higher and more than $958,000 for patients with an APACHE II score of less than 25. Caution is advised for the use of APC in patients with thrombocytopenia (platelet count <30,000) or a coagulopathy (international normalized ratio >3) because of the increased risk of bleeding.