Meeting Unmet Needs in Patients With Sepsis: the Role of Drotrecogin Alfa (Activated)

Sepsis has been with us through the ages. Almost 5000 years ago, the Chinese were investigating therapies for patients with fever. Significant advances in the therapy of sepsis occurred at the beginning of the 20th century when Paul Ehrlich ushered in the era of antimicrobial therapy with the use of organic arsenical for syphilis. Since then, interventions for patients with severe sepsis have produced gradual improvements in outcomes. Improvements in care include development of new pharmaceutical agents for hemodynamic support and antibiosis, certification in the specialties of critical care medicine and nursing, and implementation of critical care units staffed by physicians and nurses who are board certified or eligible for certification in critical care who can respond rapidly to changes in patients’ medical conditions. Other improvements are the results of advances in diagnostic procedures, monitoring methods, supportive care, and implementation of critical care guidelines and pathways. For example, the Acute Respiratory Distress Syndrome Clinical Network investigators found that compared with ventilation with traditional tidal volumes, ventilation with lower tidal volumes significantly reduced mortality in patients with acute lung injury and acute respiratory distress syndrome, a major cause of organ failure and death in patients with sepsis and acute organ dysfunction (severe sepsis). As we enter the 21st century, however, sepsis remains a major clinical problem affecting thousands of patients in the United States each year. With a death rate that hovers in the range of 28% to 50%, severe sepsis accounts for at least 215 000 deaths annually and is the leading cause of death in noncoronary intensive care units. Severe sepsis affects patients of all ages, with increased prevalence in the very young and the elderly. Patients in all medical settings and populations experience this disease. It occurs not only in patients who are neutropenic after chemotherapy but also in otherwise healthy persons after elective surgery, automobile accidents, and other traumatic situations. It can also complicate pregnancy and infections that appear to be resolving. Furthermore, the incidence of severe sepsis has been projected to increase at a rate of 1.5% per year well into the middle of this century, a rate that outstrips the growth in the general population. The increase in the number of patients with severe sepsis most likely is due to a number of factors, including the aging of the population, an increase in the number of immunosuppressed patients, and the increased use of invasive procedures. One problem in fully understanding the implications of severe sepsis for modern society is our failure to fully identify and characterize patients with this condition. Because a large proportion of patients with severe sepsis will have progressed from earlier stages of sepsis to multiple organ dysfunction syndrome, septic shock, and death, early recognition and treatment can decrease mortality associated with severe sepsis. Great steps were made in this direction when the American College of Chest Physicians and the Society of Critical Care Medicine developed consensus guidelines for identification and characterization of patients with sepsis. However, these guidelines were based on expert opinion and have limitations. For example, the guidelines did not address the basic pathophysiology of the condition, and the criteria for systemic inflammatory response syndrome (SIRS) were considered too sensitive and not reflective of the severity of the underlying disease process. Consequently, a committee composed of representatives from the American College of Chest Physicians, the Society of Critical Care Medicine, the American Thoracic GUEST EDITORIAL