25 The term sepsis is derived from the Greek word sepsin, which means “to make putrid.” The relationship between infection and sepsis has been recognized for many years. However, the precise mechanisms by which infection results in sepsis, severe sepsis, septic shock, or multiple organ dysfunction remain to be fully elucidated. Improvements in our understanding of this syndrome have led to the development of novel therapeutic strategies and have increased our appreciation for the complex interactions that exist in sepsis between pathogens and the host response to infection. Despite these advances, severe sepsis remains one of the most significant causes of morbidity and mortality in patients admitted to the intensive care unit (ICU).1 In this chapter we will discuss the current definitions, epidemiology, and pathogenesis of severe sepsis and multiple organ dysfunction. In addition, we will review current management options and discuss an approach to treatment based on pathophysiology. For many years the term sepsis was loosely applied in clinical practice and was used to describe a very heterogeneous patient population. In recognition of this problem, a consensus conference was convened to create standardized definitions and formulate a blueprint to guide future research in sepsis.2 The term systemic inflammatory response syndrome (SIRS) was introduced. SIRS can occur in response to a variety of severe clinical insults and is defined by the presence of two or more of the following conditions: (1) temperature > 38° C or < 36° C, (2) heart rate > 90 beats per minute, (3) respiratory rate > breaths per minute or a PaCO2 < 32 mm Hg, and (4) white blood cell count > 12,000 cells/mm3. Sepsis occurs when SIRS is caused by infection. Severe sepsis is sepsis with associated organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Septic shock is defined by the presence of sepsis-induced hypotension (systolic blood pressure < 90 mm Hg or a reduction ≥ 40 mm Hg from baseline in the absence of other causes for hypotension), despite adequate fluid resuscitation along with the presence of perfusion abnormalities.2 The introduction of these definitions created a common language that was especially helpful in designing and defining populations for clinical trials.3 On the other hand, criticism of these definitions pointed out that they were too sensitive and were not useful when applied clinically to individual patients.4 In 2001 a second consensus conference with a broader representation was convened to revisit these definitions.5 The conference recommended keeping the 1992 definitions unchanged secondary to lack of new evidence to support new definitions. However, the consensus conference recommended expanding the diagnostic criteria for sepsis in an effort to enhance recognition at the bedside (Box 25.1). In addition, the Predisposition Insult infection Response Organ dysfunction (PIRO) system for staging sepsis was proposed. This staging system is still relatively new and further development and research will be needed prior to its implementation in clinical practice. Examples and possible measures for the future in each domain are shown in Table 25.1. Table 25.1 The PIRO System for Staging Sepsis SIRS, systemic inflammatory response syndrome; TNF, tumor necrosis factor. Adapted from Levy M, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-1256. Severe sepsis constitutes a major health care problem.6–8 Estimates of the incidence of severe sepsis in the United States report that approximately 750,000 cases occur per year (3 cases per 1000 population).6 Almost 70% of these cases receive care in a high dependency unit (ICU, intermediate care unit, or coronary care unit).6 The incidence of severe sepsis and septic shock has increased over time both in North America and in Europe.6–8 The incidence of severe sepsis is projected to increase by 1.5% every year.6 These increases in incidence are attributed to an aging population with a growing number of patients with a compromised immune system, infected with resistant pathogens, and undergoing prolonged, high-risk surgical interventions.8 Severe sepsis is more frequent with increased age, in males, and in nonwhite patients.6,8 Before the mid-1980s, gram-negative bacteria were the most common pathogens responsible for severe sepsis. Over the years an increase in cases from gram-positive bacteria has been reported, and today gram-positive bacteria are the predominant pathogens in severe sepsis.8 The incidence of sepsis resulting from fungal organisms has increased substantially since the 1990s.8 The most common sites of infection include the respiratory system, the bloodstream, and the genitourinary tract.6,7,9 Although mortality for severe sepsis and septic shock has decreased over time, severe sepsis still kills one in four patients affected worldwide.6,7,10,11 Mortality increases with age in black men and with increased number of failing organs.8 Over time the hospital length of stay for patients with sepsis has decreased, and the number of discharges to nonacute medical care facilities has increased.8 In addition to causing high morbidity and mortality, severe sepsis has a significant economic impact. Estimates report an average cost per patient of $22,000, representing on annual impact to the health care system in excess of $16.5 billion in the United States alone.6 Severe sepsis is the result of complex interactions between infecting organisms and the host response. Important components of this host response in the early phases of sepsis include the immune system, activation of the inflammatory cascade, and alterations in hemostasis. In later stages of sepsis, organ failure, immunosuppression, and apoptosis play an important pathophysiologic role. Both characteristics of the infecting organism and of the host response influence the outcome of sepsis. Virulence factors, high burden of infection, and resistance to antibiotics are all organism characteristics associated with increased risk of severe sepsis. There is a growing body of literature suggesting that host responses might be influenced by genetic polymorphisms.12–17 This might explain why some patients develop severe sepsis to a particular pathogen and others do not. We will further discuss some of the relevant components of the host response in severe sepsis. The immune response to infection takes place through the actions of two pathways: the innate immune system and the adaptive immune system. The goal of the innate immune system is to provide protection in the first minutes to hours after an infectious challenge. Although initially thought to be a nonspecific response, research has demonstrated that the innate immune system recognizes pathogens by means of pattern-recognition receptors (Toll-like receptors [TLRs], Table 25.2). Toll-like receptors bind to highly conserved structures on microorganisms, which are not easily altered by microbes to evade detection and are present on broad groups of organisms.18 Our current understanding of TLRs suggests that the immune cells use different TLRs to detect several features of an organism and based on the composite information gained generate a tailored response to the invading pathogen.18 Activation of Toll-like receptors by microorganisms stimulates signaling pathways that increase production of pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nuclear factor-κB (NF-κB), as well as anti-inflammatory cytokines such as interleukin-10 (IL-10).18,19 Toll-like receptor activation also results in up-regulation of microbial killing mechanisms, such as the production of reactive nitrogen species.20 Toll-like receptors play a pivotal role in initiating the innate immune response and are important regulators of the adaptive immune response to infection. Recognition of these proteins and their functions expanded our understanding of the pathophysiology of sepsis and has provided a new target for therapeutic interventions.21 The adaptive immune system amplifies the response initiated by the innate immune system with a higher degree of specificity. In addition to their interactions with the innate immune system, microorganisms stimulate specific cell-mediated and humoral adaptive immune responses. Two types of lymphocytes, B cells and T cells, play an important role in the adaptive immune response. Adaptive immune responses (humoral and cellular) require days to develop. However, they are amnestic through the generation of memory T and B lymphocytes and, in the case of reexposure to the same pathogen, can elicit a faster response. CD4 T cells are divided into two types: type 1 helper T-cell (Th1) and type 2 helper T-cell (Th2). Factors such as type of organism, site of infection, and burden of infection influence the response elicited by T cells. In general, Th1 cells secrete pro-inflammatory cytokines (TNF-α and interleukin-1β) and Th2 cells secrete anti-inflammatory cytokines (interleukin-4 and interleukin-10).22 B lymphocyte cells are responsible for releasing immunoglobulins in response to microorganisms. These immunoglobulins bind to organism-specific antigens and enhance recognition and destruction by other immune cells (natural killer cells and neutrophils). Several other cell types are involved in the adaptive immune response to infection (Fig. 25.1). For many years the prevailing theory has been that sepsis is the result of an uncontrolled inflammatory response.1,2 This paradigm was based on extensive animal experimentation with models of inflammation that may not necessarily reflect human disease. Animal models of sepsis that utilized large doses of endotoxin or bacteria created a “cytokine storm” that when blocked resulted in improvements in mortality. However, in human sepsis most patients have a complex host response that includes activation of both pro-inflammatory and anti-inflammatory cascades. Early death from overwhelming inflammation is not the norm, and most patients who die develop complications related to immunosuppression, apoptosis, and multiorgan failure later in the course of the disease. These differences may partially explain why so many anti-inflammatory compounds worked in animal models yet failed to improve mortality in human clinical trials. The interplay between pro-inflammatory cytokines, anti-inflammatory cytokines, and cytokine inhibitors is a dynamic process that influences the host response to sepsis. Pro-inflammatory cytokines such as TNF-α and IL-1β increase early in sepsis and have overlapping and synergistic effects in further stimulating the inflammatory cascade.23 Pro-inflammatory cytokines activate monocytes, macrophages, and neutrophils; stimulate neutrophil margination; and increase gluconeogenesis. In addition, pro-inflammatory cytokines have an important role in the development of clinical abnormalities such as fever, hypotension, capillary leakage with decreased intravascular volume, and myocardial depression.23 More recently, pro-inflammatory cytokines such as macrophage migration inhibitory factor (MIF) and high mobility group 1 protein (HMG-1) have received attention as downstream mediators of inflammation and potential therapeutic targets.24–27 The role of anti-inflammatory cytokines in sepsis is still not fully understood. Current understanding suggests that sepsis-induced multiorgan failure and death may be caused in part by a shift to an anti-inflammatory phenotype and by apoptosis of key immune cells.28,29 This shift is driven in part by increased levels of anti-inflammatory cytokines and results from a shift in helper T-cell populations (from Th1 to Th2).30 Inflammation plays an important role in the host response to sepsis. It is now apparent that simple therapeutic strategies that block specific pro-inflammatory cytokines are insufficient to modulate this response.31,32 As our understanding of the intricate relationship between pro-inflammatory and anti-inflammatory responses increases, we might become more successful in modulating these to improve patients’ outcomes. Another important factor in the pathophysiology of sepsis is the alteration of the hemostatic balance. In sepsis this balance is altered by an increase in procoagulant factors paired with a decrease in anticoagulant factors (Fig. 25.2). Under normal conditions the intraluminal vascular surface has anticoagulant properties. During sepsis, stimulation from cytokines promotes expression of tissue factor on endothelial cells, monocytes, and neutrophils.33,34 Tissue factor triggers the extrinsic coagulation pathway by activating factor VII. Activation of the extrinsic pathway leads to the formation of thrombin. The intrinsic pathway is triggered by activation of factor XI and leads to amplification of the coagulation cascade with further formation of thrombin. Excessive coagulation is normally counterbalanced by several anticoagulant factors. Anticoagulant factors such as antithrombin III, activated protein C, protein S, and tissue factor pathway inhibitor are decreased in sepsis.35 These circumstances push the hemostatic balance toward the procoagulant state. Activation of the coagulation cascade leads to a consumption of coagulation factors. The clinical expression of this phenomenon is disseminated intravascular coagulation (DIC). Disseminated intravascular coagulation is characterized by a consumptive coagulopathy, which can result in an increased risk of bleeding but more commonly in sepsis causes damage by increasing the risk of thrombosis. In sepsis the excessive formation of fibrin from thrombin compounded by the suppression of fibrinolysis and the impairment of anticoagulant pathways leads to widespread formation of microthrombi. It has been proposed that these microthrombi lead to microcirculatory alterations and play an integral role in the pathogenesis of organ failure.36,37 Severe sepsis is a medical emergency. When one considers its morbidity and the relationship between number of organ failures and mortality (Fig. 25.3), it makes sense to treat patients emergently and institute therapies that can prevent the progression of organ failure and improve outcomes in a time-sensitive fashion. Several therapies for severe sepsis have a potential time-sensitive effect on outcome (e.g., when instituted early have a higher likelihood of improving outcomes than when instituted with time delays) (Box 25.2). Although severe sepsis is associated with a higher mortality than other diseases considered medical emergencies, such as trauma, acute ischemic stroke, and acute myocardial infarction, it is still not treated with the same degree of urgency. This may be secondary to difficulties in recognizing severe sepsis early and a lack of understanding its consequences and their therapeutic implications by physicians outside the intensive care unit. Recognizing these problems, the Society of Critical Care Medicine (SCCM), the European Society of Intensive Care Medicine (ESICM), and the International Sepsis Forum (ISF) created the Surviving Sepsis Campaign (SSC). The SSC conglomerates experts in the field of sepsis from around the world and currently counts with the endorsement of 29 international medical societies and the Institute for Healthcare Improvement (www.ihi.gov). The campaign has aimed to improve standards of patient care, secure funding for research, and ultimately reduce the mortality of severe sepsis worldwide. To achieve these goals, the SCC has published evidence-based practice guidelines and consensus recommendations for the management of patients with severe sepsis.38,39,39a These guidelines were first published in 2004 and revised in 2008, and a second revision for 2012 is currently in press. To increase the impact of these clinical guidelines at the bedside, the SCC created the sepsis bundles.40 The sepsis resuscitation bundle should be implemented over the first 6 hours after recognition of a patient with severe sepsis, and the sepsis management bundle should be implemented over the first 24 hours of admission to the hospital. A number of nonrandomized studies have shown that compliance with the bundles and application of their clinical recommendations in the form of protocols can improve patient outcomes.41–43 More important, the publication of phase 2 of the SSC international performance improvement program demonstrated the significant impact compliance with the sepsis bundles has on reducing mortality in severe sepsis.44 This large prospective study evaluated the implementation of a multifaceted intervention to facilitate compliance with selected guideline recommendations in the intensive care unit, emergency department, and wards of hospitals from around the world. Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased from 10.9% to 31.3% by the end of 2 years (p < 0.0001). Compliance with the entire management bundle started at 18.4% and increased to 36.1% by the end of 2 years (p = 0.008). This increase in compliance was associated with a decrease in unadjusted hospital mortality from 37% to 30.8% (p = .001). The adjusted odds ratio for mortality improved the longer the site participated in the SSC.44 Based on emerging data and recently published studies, the last revision of the guidelines recommends dropping the management bundle and dividing the resuscitation bundle into two parts:39a The complete new bundles are shown in Box 25.3 and Box 25.4. The optimal treatment of severe sepsis is a dynamic and constantly evolving process. We will discuss current treatment recommendations based on up-to-date clinical data. However, as new research emerges it is likely that new therapies will be described, and treatment recommendations presented in this chapter may need to be modified. Like in other medical emergencies the first priority in treating patients with severe sepsis should be assessing and optimizing the “ABCs”: airway, breathing, and circulation. In conjunction with initial stabilization of physiologic abnormalities, one should initiate appropriate diagnostic interventions to assess potential sources of infection and severity of organ dysfunction. Therapeutic interventions for severe sepsis should be implemented quickly and in conjunction. For the sake of discussion we will approach the treatment of severe sepsis based on pathophysiologic abnormalities produced by the syndrome (Fig. 25.4). We will discuss in further detail management of the infectious insult, hemodynamic optimization, modulation of the host response, and finally supportive therapies. Severe sepsis is initiated by an infectious insult. Therefore, infection management constitutes one of the cornerstones of treatment in these patients. Infection management consists of source control and the administration of appropriate empiric antimicrobials that are effective against presumed causative pathogens. Administration of appropriate antibiotics is a time-sensitive intervention. Administration of antibiotics is often delayed, and this can result in worse outcomes.45 Delays in appropriate antibiotic administration are much more likely to result from system failures (e.g., order not written by physician, delay from pharmacy, etc.) than from bacteriologic resistance.46 Current guidelines recommend that appropriate antibiotics be administered to patients with severe sepsis within 1 hour of diagnosis.39 Results from a retrospective study in a large group of septic shock patients suggests that every hour appropriate antibiotics are delayed after the onset of hypotension, the odds ratio for mortality increases in a stepwise manner.47 Additional studies have shown increased mortality with delays in appropriate antibiotic administration.43,44,48,49 One study done in patients in the emergency department showed that if antibiotics were given prior to the onset of shock, mortality was significantly decreased.50 However, among patients who received antibiotics after shock recognition, mortality did not change with hourly delays in antibiotic administration.50 The goal should be to administer appropriate antibiotics as soon as possible in patients with severe sepsis. To accomplish this objective, hospitals must examine their particular dynamics and devise systems to optimize antibiotic administration. Studies in patients with sepsis have reported an incidence of positive blood cultures in the range of 20% to 50%.8,51–53 Considering the growing need for broad-spectrum empirical regimens and the need to narrow down antimicrobial regimens in order to decrease resistance, obtaining blood cultures prior to the administration of antibiotics is essential. In most cases, one must start antibiotics without bacteriologic confirmation of the causative pathogen. Studies have demonstrated that the appropriateness of initial antibiotic therapy has a significant impact on patient outcomes.54,55 In one prospective cohort study of critically ill patients, inadequate initial antibiotic therapy was associated with a statistically significant increase in all-cause and infection-related hospital mortality.56 Factors associated with administration of inadequate antibiotics included prior administration of antibiotics, bloodstream infections, increasing acute physiology and chronic health evaluation (APACHE II) scores, and decreasing age.56 If one considers the detrimental effect on mortality, it is apparent that in patients with severe sepsis, one cannot afford to miss potential causative organisms when empirically selecting an antimicrobial regimen. The choice of antibiotics should be based on the following factors:
Severe Sepsis and Multiple Organ Dysfunction
Introduction
Definitions
Domain
Present
Future
Predisposition
Premorbid conditions, age, and sex
Genetic polymorphism in components of the inflammatory response (e.g., TNF)
Insult infection
Culture and sensitivity of pathogens; identification of possible target for source control
Assays of specific microbial products and gene transcript profiles
Response
SIRS, other signs of sepsis, septic shock, C-reactive protein
Markers of activated inflammation or impaired host responsiveness
Organ dysfunction
Organ dysfunction as number of failing organs or composite scores
Measure of cellular response to insult-apoptosis, cytopathic hypoxia, cell stress
Epidemiology
Pathophysiology
Role of the Immune System in the Early Phases of Sepsis
Role of Inflammation
Alterations of Hemostasis
Management
Infection Management
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Severe Sepsis and Multiple Organ Dysfunction
