For the diagnosis and management of sepsis, the past 10 years have brought significant changes. Initial treatment involving fluid resuscitation, antibiotics, and source control is similar to what it was a decade ago, but we now realize that the speed of diagnosis coupled with expedited management is critical.1 New ways to support failing organ systems2 and the introduction of a pharmacological agent to reduce mortality3 have shed light on this disease and have given clinicians new optimism. Slowly but surely, we are making the transition toward delivering a multitude of treatments simultaneously in an effort to improve clinical care.
In this 2-part article, we will review the latest strategies for managing sepsis.
THE SEPSIS CONTINUUM
Sepsis is a significant public health problem that occurs at the rate of approximately 3 cases per 1000 persons, affecting nearly 900,000 persons every year in the United States and nearly 20,000,000 worldwide.4 As the leading cause of death in noncoronary ICUs and the 10th leading cause of death overall in the United States,4-6 sepsis has a tremendous economic and social burden. Not only does sepsis mortality range from 20% to 80% depending on illness severity4,5,7-9 but survivors experience a significant increase in morbidity and reduced quality of life.10,11
Recent data from the United States show that the incidence of sepsis is increasing, with a growing number of deaths despite an overall decrease in proportionate mortality.4 With the aging population, increased use of immunosuppressive drugs, emergence of HIV, increasing microbial resistance, and expanding availability of health care and health care interventions, the incidence of sepsis will continue to increase globally.
DEFINITION AND CASE FINDING
The diagnosis of sepsis can still be perplexing despite a well-accepted consensus definition. In 1992, the American College of Chest Physicians/Society of Critical Care Medicine consensus conference arrived at the current definition of sepsis as a systemic inflammatory syndrome (defined by a change in 2 or more abnormal clinical findings: temperature, heart rate, respiration rate, and white blood cell count) with a concomitant pathological infection (Table 1).12
Sepsis severity was defined by the addition of acute organ dysfunction, hypoperfusion, or hypotension, based on criteria proposed by Marshall and associates13 or by criteria used for Sequential Organ Failure Assessment score.14 Septic shock refers to sepsis-induced hypotension that persists despite adequate fluid resuscitation.
Sepsis is difficult to diagnose, particularly in the earlier stages when the symptoms may be subtle. Although it would be clearly beneficial to have an accurate test that identifies sepsis, no diagnostic test exists and the recognition of early sepsis often requires an astute clinician who is knowledgeable about the sepsis syndrome.
Various biomarkers have been evaluated for diagnosis, risk stratification, and prognosis in sepsis, including procalcitonin, C-reactive protein (CRP), B-type natriuretic peptide,15,16 and protein C. Although the procalcitonin level has limited diagnostic value in patients with systemic inflammatory response syndrome from other causes,17 it appears to be a better marker for illness severity and prognosis than the CRP level.18-21 The directional change in protein C levels has been shown to correlate with outcomes in patients with severe sepsis22 and may prove to be a useful tool in the future.
A soluble triggering receptor expressed on myeloid cells-1, a recently discovered receptor expressed on the surface of neutrophils, has been reported to trigger the synthesis of proinflammatory cytokines in the presence of microbial products23 and has been found to predict outcome in patients with sepsis.24 However, none of the above-mentioned biomarkers has thus far proved clinically useful for the diagnosis of sepsis.
Over the years, a considerable amount has changed in our thinking about sepsis pathophysiology. Initially considered a syndrome of exaggerated inflammation,12 sepsis is now recognized as a complex set of interactions between the inciting microbe, the host immune response, and the inflammatory and coagulation pathways (Figure).
Figure – The pathophysiology of sepsis involves a complex set of interactions between the inciting microbe, the host immune response, and the inflammatory and coagulation pathways. Infecting pathogens have unique cell wall molecules that bind to toll-like receptors (TLRs) on the surface of immune cells. The release of cytokines, such as tumor necrosis factor (TNF)-α, interleukin-1β, and interleukin-10, causes endothelial injury and activates the coagulation cascade. Sepsis can lead to the development of multiorgan failure, such as cardiovascular dysfunction, circulatory shock, and respiratory failure. (LPS, lipopolysaccharide; TRAF6, TNF receptor–associated factor 6; NIK, nuclear factor-κB–inducing kinase; NF-κB, nuclear factor-κB.)
Inflammation and immune response
An infectious insult, classically described as bacterial endotoxin, initiates a pathophysiological cascade involving pattern-recognition receptors that are called toll-like receptors.25 Binding of these receptors to microorganisms results in the release of a number of proinflammatory cytokines, especially tumor necrosis factor-α, which are important for host immune defense and resolution of the inflammatory response as they interact with invading pathogens.26,27 These pathways frequently yield further activation of other myeloid-derived and/or endothelial cells.28
Simultaneously, activation of anti-inflammatory pathways may lessen the inflammatory response.29
In recent years, it has been recognized that the coagulation system acts in concert with the inflammatory cascade in the pathophysiology of sepsis.30-33 These abnormalities range from subclinical prolongation of clotting times to fulminant disseminated intravascular coagulation, characterized by global microvascular thrombosis and bleeding.30 Amelioration of this coagulopathy appears to attenuate organ failure and, subsequently, survival.3,32
The protein C pathway serves as an anticoagulant system, promoting fibrinolysis by inhibiting thrombosis and inflammation.34 Thrombin binds to thrombomodulin at the endothelial protein C receptor (EPCR) on the endothelium, resulting in a complex that rapidly activates protein C, which binds to protein S, inactivating factors Va and VIIIa.35,36 EPCR deletion exaggerates the host responses to lipopolysaccharide,33 suggesting that EPCR is important in controlling endotoxin-induced coagulation and inflammatory responses.